Note: Descriptions are shown in the official language in which they were submitted.
CA 02336225 2001-O1-24
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1
DESCRIPTION
THCHNT . T. T .T.~
The present invention relates to human proteins having
hydrophobic domains, DNAs coding for these proteins, and
expression vectors for these DNAs as well as eucaryotic
IO cells expressing these DNAs. The proteins of the present
invention can be employed as pharmaceuticals or as antigens
for preparing antibodies against these proteins. The human
cDNAs of the present invention can be utilized as probes for
the genetic diagnosis and gene sources for the gene therapy.
Furthermore, the cDNAs can be utilized as gene sources for
large-scale production of the proteins encoded by these
cDNAs. Cells into which these genes are introduced to
express secretory proteins and membrane proteins in large
amounts can be utilized for detection of the corresponding
receptors and ligands, screening of novel low-molecular
pharmaceuticals, and so on.
BOiIND ART
Cells secrete many proteins outside the cells. These
secretory proteins play important roles for the
proliferation control, the differentiation induction, the
material transportation, the biological protection, etc. in
the cells. Different from intracellular proteins, the
secretory proteins exert their actions outside the cells,
whereby they can be administered in the intracorporeal
manner such as the injection or the drip, so that there are
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hidden potentialities as medicines. In fact, a number of
human secretory proteins such as interferons, interleukins,
erythropoietin, thrombolytic agents, etc. have been
currently employed as medicines. In addition, secretory
proteins other than those described above have been
undergoing clinical trials to develop as pharmaceuticals.
Because it has been conceived that the human cells still
produce many unknown secretory proteins, availability of
these secretory proteins as well as genes coding for them is
expected to lead to development of novel pharmaceuticals
utilizing these proteins.
on the other hand, membrane proteins play important
roles, as signal receptors, ion channels, transporters, etc.
in the material transportation and the information
transmission through the cell membrane. Examples thereof
include receptors for a variety of cytokines, ion channels
for the sodium ion, the potassium ion, the chloride ion,
etc., transporters for saccharides and amino acids, and so
on, where the genes for many of them have been cloned
already. It has been clarified that abnormalities of these
membrane proteins are associated with a number of hitherto-
cryptogenic diseases. Therefore, discovery of a new membrane
protein is anticipated to lead to elucidation of the causes
of many diseases, so that isolation of a new gene coding for
the membrane protein has been desired.
Heretofore, owing to difficulty in the purification
from human cells, these secretory proteins and membrane
proteins have been isolated by an approach from the gene
side. A general method is the so-called expression cloning
which comprises introduction of a cDNA library into
eucaryotic cells to express cDNAs and then screening of the
cells secreting, or expressing on the surface of membrane,
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the objective active protein. However, this method is
applicable only to cloning of a gene for a protein with a
known function.
In general, secretory proteins and membrane proteins
possess at least one hydrophobic domain inside the proteins,
wherein, after synthesis thereof in the ribosome, this
domain works as a secretory signal or remains in the
phospholipid membrane to be trapped in the membrane.
Accordingly, the evidence of this cDNA for encoding a
secretory protein and a membrane protein is provided by
determination of the whole base sequence of a full-length
cDNA followed by detection of highly hydrophobic domains)
in the amino acid sequence of the protein encoded by this
cDNA.
OB~ T O TH . TNVF'NTTnN
The main object of the present invention is to provide
novel human proteins having hydrophobic domains, DNAs coding
for these proteins, and expression vectors for these DNAs as
well as transformed eucaryotic cells that are capable of
expressing these DNAs. This object as well as other objects
and advantages of the present invention will become apparent
to those skilled in the art from the following description
with reference to the accompanying drawings.
D .~, RT1~TTON O D AWTNCS
Fig. 1 illustrates the hydrophobicity/hydrophilicity
profile of the protein encoded by clone HP01550.
Fig. 2 illustrates the hydrophobicity/hydrophilicity
profile of the protein encoded by clone HP02593.
Fig. 3 illustrates the hydrophobicity/hydrophilicity
profile of the protein encoded by clone HP10195.
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4
Fig. 4 illustrates the hydrophobicity/hydrophilicity
profile of the by clone HP10423.
protein
encoded
Fig. 5 illustrates the hydrophobicity/hydrophilicity
profile of the by clone HP10506.
protein
encoded
Fig. 6 illustrates the hydrophobicity/hydrophilicity
profile of the by clone HP10507.
protein
encoded
Fig. 7 illustrates the hydrophobicity/hydrophilicity
profile of the by clone HP10548.
protein
encoded
Fig. 8 illustrates the hydrophobicity/hydrophilicity
profile of the by clone HP10566.
protein
encoded
Fig. 9 illustrates the hydrophobicity/hydrophilicity
profile of the by clone HP10567.
protein
encoded
Fig. 10 illustrates the hydrophobicity/hydrophilicity
profile of the protein encoded by clone HP10568.
Fig. I1 illustrates the hydrophobicity/hydrophilicity
profile of the protein encoded by clone HP01426.
Fig. 12 illustrates the hydrophobicity/hydrophilicity
profile of the protein encoded by clone HP02515.
Fig. I3 illustrates the hydrophobicity/hydrophilicity
profile of the protein encoded by clone HP02575.
Fig. 14 illustrates the hydrophobicity/hydrophilicity
profile of the protein encoded by clone HP10357.
Fig. 15 illustrates the hydrophobicity/hydrophilicity
profile of the protein encoded by clone HP10447.
Fig. 16 illustrates the hydrophobicity/hydrophilicity
profile of the protein encoded by clone HP10477.
Fig. 17 illustrates the hydrophobicity/hydrophilicity
profile of the protein encoded by clone HP10513.
Fig. 18 illustrates the hydrophobicity/hydrophilicity
profile of the protein encoded by clone HP10540.
Fig. 19 illustrates the hydrophobicity/hydrophilicity
profile of the protein encoded by clone HP10557.
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Fig. 20 illustrates the hydrophobicity/hydrophilicity
profile of
the protein
encoded
by clone
HP10563.
Fig. 21 illustrates the hydrophobicity/hydrophilicity
profile of the by clone HP01467.
protein
encoded
5 Fig. 22 illustrates the hydrophobicity/hydrophilicity
profile of the by clone HPOI956.
protein
encoded
Fig. 23 illustrates the hydrophobicity/hydrophilicity
profile of the by clone HP02545.
protein
encoded
Fig. 24 illustrates the hydrophobicity/hydrophilicity
profile of the by clone HP02551.
protein
encoded
Fig. 25 illustrates the hydrophobicity/hydrophilicity
profile of the by clone HP02631.
protein
encoded
Fig. 26 illustrates the hydrophobicity/hydrophilicity
profile of the by clone HP02632.
protein
encoded
Fig. 27 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP10488.
Fig. 28 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP10538.
Fig. 29 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP10542.
Fig. 30 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP10571.
Fig. 31 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP01470.
Fig. 32 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP02419.
Fig. 33 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP02631.
Fig. 34 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP02695.
Fig. 35 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP10031.
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Fig. 36 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP10530.
Fig. 37 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP10541.
Fig. 38 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP10550.
Fig. 39 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP10590.
Fig. 40 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP10591.
Fig. 41 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP01462.
Fig. 42 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP02485.
Fig. 43 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP02798.
Fig. 44 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP10041.
Fig. 45 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP10246.
Fig. 46 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP10392.
Fig. 47 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP10489.
Fig. 48 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP10519.
Fig. 49 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP10531.
Fig. 50 illustrates the hydrophobicity/hydrophilicity
profile of theprotein encoded by clone HP10574.
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As the result of intensive studies, the present
inventors have been successful in cloning of cDNAs coding
for proteins having hydrophobic domains from the human full-
length cDNA bank, thereby completing the present invention.
In other words, the present invention provides human
proteins having hydrophobic domains, namely proteins
comprising any of the amino acid sequences represented by
SEQ ID Nos. 1 to 10, 31 to 40, 61 to 70, 91 to 100, and 121
to 130. Moreover, the present invention provides DNAs coding
for the above-mentioned proteins, exemplified by cDNAs
comprising any of the base sequences represented by SEQ ID
Nos. 11 to 20, 41 to 50, 71 to 80, 101 to 110, and 131 to
140, as well as expression vectors that are capable of
expressing any of these DNAs by in vitro translation or in
eucaryotic cells and transformed eucaryotic cells that are
capable of expressing these DNAs and of producing the above-
mentioned proteins.
nFmAILED DE~CRTPTTON OF H. I .NT ON
The proteins of the present invention can be obtained,
for example, by a method for isolation from human organs,
cell lines, etc., a method for preparation of peptides by
the chemical synthesis, or a method for production with the
recombinant DNA technology using the DNAs coding for the
hydrophobic domains of the present invention, among which
the method for production with the recombinant DNA
technology is employed preferably. For instance, in vitro
expression of the proteins can be achieved by preparation of
an RNA by in vitro transcription from a vector having one of
the cDNAs of the present invention, followed by in vitro
translation using this RNA as a template. Also, introduction
of the translated region into a suitable expression vector
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by the method known in the art leads to expression of a
large amount of the encoded protein in prokaryotic cells
such as Escherichia coli, Bacillus subtilis, etc., and
eucaryotic cells such as yeasts, insect cells, mammalian
cells, etc.
In the case where one of the proteins of the present
invention is produced by expressing the DNA by in vitro
translation, the protein of the present invention can be
produced in vitro, when the translated region of this cDNA
is introduced into a vector having an RNA polymerase
promoter, followed by addition of the vector to an in vitro
translation system such as a rabbit reticulocyte lysate or a
wheat germ extract, containing an RNA polymerase
corresponding to the promoter. RNA polymerase promoters are
exemplified by T7, T3, SP6, and the like. The vectors
containing these RNA polymerase promoters are exemplified by
pKAl, pCDMB, pT3/T7 18, pT7/3 19, pHluescript II, and so on.
Furthermore, the protein of the present invention can be
expressed as the secreted form or the form incorporated into
the microsome membrane, when a canine pancreas microsome or
the like is added to the reaction system.
In the case where one of the protein of the present
invention is produced by expressing the DNA in a
microorganism such as Escherichia coli etc., a recombinant
expression vector bearing the translated region of the cDNA
of the present invention is constructed in an expression
vector having an origin which can be replicated in the
microorganism, a promoter, a ribosome-binding site, a cDNA-
cloning site, a terminator etc. and, after transformation of
the host cells with this expression vector, the resulting
transformant is incubated, whereby the protein encoded by
said cDNA can be produced on a large scale in the
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microorganism. In this case, a protein fragment containing
any region can be obtained by carrying out the expression
with inserting an initiation codon and a termination codon
in front of and behind the selected translated region.
Alternatively, a fusion protein with another protein can be
expressed. Only the portion of the protein encoded by this
cDNA can be obtained by cleavage of this fusion protein with
a suitable protease. The expression vector for Escherichia
coli is exemplified by the pUC series, pBluescript II, the
pET expression system, the pGEX expression system, and so on.
In the case where one of the proteins of the present
invention is produced by expressing the DNA in eucaryotic
cells, the protein of the present invention can be produced
as a secretory protein or as a membrane protein on the cell
membrane surface, when the translated region of this cDNA is
introduced into an expression vector for eucaryotic cells
that has a promoter, a splicing region, a poly(A) addition
site, etc., followed by introduction into the eucaryotic
cells. The expression vector is exemplified by pKAl,
pED6dpc2, pCDM8, pSVK3, pMSG, pSVL, pBK-CMV, pBK-RSV, EHV
vector, pRS, pYES2, and so on. Examples of eucaryotic cells
to be used in general include mammalian cultured cells such
as simian kidney cells COS7, Chinese hamster ovary cells CHO,
etc., budding yeasts, fission yeasts, silkworm cells,
Xenopus oocytes, and so on, but any eucaryotic cells may be
used, provided that they are capable of expressing the
proteins of the present invention. The expression vector can
be introduced into the eucaryotic cells by methods known in
the art such as the electroporation method, the calcium
phosphate method, the liposome method, the DEAE-dextran
method, and so on.
After one of the proteins of the present invention is
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expressed in prokaryotic cells or eucaryotic cells, the
objective protein can be isolated from the culture and
purif ied by a combination of separation procedures known in
the art. Such examples include treatment with a denaturing
5 agent such as urea or a detergent, sonication, enzymatic
digestion, salting-out or solvent precipitation, dialysis,
centrifugation, ultrafiltration, gel filtration, SDS-PAGE,
isoelectric focusing, ion-exchange chromatography,
hydrophobic chromatography, affinity chromatography, reverse
10 phase chromatography, and so on.
The proteins of the present invention include peptide
fragments (5 amino acid residues or more) containing any
partial amino acid sequence in the amino acid sequences
represented by SEQ ID Nos. 1. to 10, 31 to 40, 61 to 70, 91
to 100, and 121 to 130. These peptide fragments can be
utilized as antigens for preparation of antibodies. Hereupon,
among the proteins of the present invention, those having
the signal sequences are secreted in the form of mature
proteins, after the signal sequences are removed. Therefore,
these mature proteins shall come within the scope of the
present invention. The N-terminal amino acid sequences of
the mature proteins can be easily determined by using the
method for the determination of cleavage site of a signal
sequence [JP 8-187100 A]. Furthermore, some membrane
proteins undergo the processing on the cell surface to be
converted to the secretory forms. Such proteins or peptides
in the secretory forms shall come within the scope of the
present invention. In the case where sugar chain-binding
sites are present in the amino acid sequences, expression in
appropriate eucaryotic cells affords proteins to which sugar
chains are attached. Accordingly, such proteins or peptides
to which sugar chains are attached shall come within the
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scope of the present invention.
The DNAs of the present invention include all the DNAs
coding for the above-mentioned proteins. These DNAs can be
obtained by using a method by chemical synthesis, a method
by cDNA cloning, and so on.
The cDNAs of the present invention can be cloned, for
example, from cDNA libraries derived from the human cells.
These cDNAs are synthesized by using as templates poly(A)+
RNAs extracted from human cells. The human cells may be
cells delivered from the human body, for example, by the
operation or may be the cultured cells. The cDNAs can be
synthesized by using any method selected from the Okayama-
Berg method [Okayama, H. and Herg, P., Mol. Cell. Biol. 2:
161-170 (1982)j, the Gubler-Hoffman method [Gubler, U. and
Hoffman, J. Gene 25: 263-269 ( 1983 ) ] , and so on, but it is
preferred to use the capping method [Kato, S. et al., Gene
150: 243-250 (1994)], as exemplified in Examples, in order
to obtain a full-length clone in an effective manner. In
addition, commercially available, human cDNA libraries can
be utilized. Cloning of the cDNAs of the present invention
from the cDNA libraries can be carried out by synthesis of
an oligonucleotide on the basis of base sequences of any
portion in the cDNA of the present invention, followed by
screening using this oligonucleotide as the probe according
to the colony or plaque hybridization by a method known in
the art. In addition, the cDNA fragments of the present
invention can be prepared by synthesis of oligonucleotides
which hybridize with both termini of the objective cDNA
fragment, followed by the usage of these oligonucleotides as
the primers for the RT-PCR method using an mRNA isolated
from human cells.
The cDNAs of the present invention are characterized by
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comprising either of the base sequences represented by SEQ
ID Nos. 11 to 20, 41 to 50, 71 to 80, 101 to 110, and 131 to
140 or the base sequences represented by SEQ ID Nos. 21 to
30, 51 to 60, 81 to 90, 111 to 120, and 141 to 150. Table 1
summarizes the clone number (HP number), the cells from
which the cDNA was obtained, the total base number of the
cDNA, and the number of the amino acid residues of the
encoded protein, for each of the cDNAs.
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Table 1
Number
SEQ ID No. HP Cells Base of amino
number number acid
residues
l, 11,21 HP01550 Stomachcancer 510 125
2, 12,22 HP02593 Saos-2 697 131
3, 13,23 HP10195 HT-1080 1619 24.2
4, 14,24 HP10423 U-2 1066 264
OS
5, 15,25 HP10506 Stomachcancer 618 I12
6, 16,26 HP10507 Stomachcancer 1021 146
7, 17,27 HP10548 Stomachcancer 1432 344
8, 18,28 HP10566 Stomachcancer 601 97
9, 19,29 HP10567 Stomachcancer 585 124
10, 20,30 HP10568 Stomachcancer 1100 327
31, 41,51 HP01426 Stomachcancer 1065 313
32, 42,52 HP02515 Saos-2 937 229
33, 43,53 HP02575 Saos-2 1678 467
34, 44,54 HP10357 Stomachcancer 467 99
35, 45,55 HP10447 Liver 875 189
36, 46,56 HP10477 Liver 1256 363
37, 47,57 HP105I3 Stomachcancer 884 249
38, 48,58 HP10540 Saos-2 589 98
39, 49,59 HP10557 Stomachcancer 673 172
40, 50,60 HP10563 Saos-2 1425 120
61, 71,81 HP01467 HT-1080 1436 307
62, 72,82 HP01956 Liver 997 183
63, 73,83 HP02545 Saos-2 1753 327
64, 74,84 HP02551 Saos-2 1117 223
65, 75,85 HP02631 Saos-2 1380 48
66, 76,86 HP02632 HT-1080 1503 371
67, 77,87 HP10488 Liver 733 90
68, 78,88 HP10538 Saos-2 3768 499
69, 79,89 HP10542 Stomachcancer 770 106
70, 80,90 HP10571 Stomachcancer 1229 152
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91, 101,111 HP01470 Stomachcancer 1619 358
92, 102,112 HP024I9 Stomachcancer 2054 226
93, 103,113 HP02631 Saos-2 1380 195
94, 104,114 HP02695 Stomachcancer 1292 339
95, 105,115 HP10031 Saos-2 2168 487
96, 106,116 HP10530 Saos-2 1357 393
97, 107,117 HP1054I Stomachcancer 711 196
98, 108,118 HP10550 Stomachcancer 651 107
99, 109,119 HP10590 HT-1080 1310 350
100, 110,120 HP10591 HT-1080 1400 107
121, 131,14I HP01462 HT-1080 2050 483
122, 132,142 HP02485 Stomachcancer 2746 334
123, 133,143 HP02798 HT-1080 1136 267
124, 134,144 HP10041 Saos-2 619 106
125, 135,145 HP10246 KB 864 224
126, 136,146 HP10392 U-2 1527 258
OS
127, 137,147 HP10489 Stomachcancer 659 110
128, 138,148 HP10519 Stomachcancer 710 91
129, 139,149 HP10531 Saos-2 2182 344
130, 140,150 HP10574 Stomachcancer 2773 428
Hereupon, the same clones as the cDNAs of the present
invention can be easily obtained by screening of the cDNA
libraries constructed from the human cell lines or human
tissues utilized in the present invention by the use of an
oligonucleotide probe synthesized on the basis of the cDNA
base sequence described in any of SEQ ID Nos. 11 to 30, 41
to 60, 71 to 90, 101 to 120, and 131 to 150.
In general, the polymorphism due to the individual
difference is frequently observed in human genes.
Accordingly, any cDNA in which one or plural nucleotides are
inserted, deleted and/or substituted with other nucleotides
in SEQ ID Nos. 11 to 30, 41 to 60, 71 to 90, 101 to 120, and
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131 to 150 shall come within the scope of the present
invention.
In a similar manner, any protein in which one or plural
amino acids are inserted, deleted and/or substituted with
5 other amino acids shall come within the scope of the present
invention, as far as the protein possesses the activity of
any protein having the amino acid sequences represented by
SEQ ID Nos. 1 to 10, 31 to 40, 61 to 70, 91 to 100, and 121
to 130.
10 The cDNAs of the present invention include cDNA
fragments (10 by or more) containing any partial base
sequence in the base sequences represented by SEQ ID Nos. 11
to 20, 41 to 50, 71 to 80, 101 to 110, and 131 to 140 or in
the base sequences represented by SEQ ID Nos. 21 to 30, 51
15 to 60, 81 to 90, 111 to 120, and 141 to 150. Also, DNA
fragments consisting of a sense strand and an anti-sense
strand shall come within this scope. These DNA fragments can
be utilized as the probes for the genetic diagnosis.
In addition to the activities and uses described above,
the polynucleotides and proteins of the present invention
may exhibit one or more of the uses or biological activities
(including those associated with assays cited herein)
identified below. Uses or activities described for proteins
of the present invention may be provided by administration
or use of such proteins or by administration or use of
polynucleotides encoding such proteins (such as, for example,
in gene therapies or vectors suitable for introduction of
DNA).
Research Us and Llti 1 i i _s
The polynucleotides provided by the present invention
can be used by the research community for various purposes.
The polynucleotides can be used to express recombinant
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16
protein for analysis, characterization or therapeutic use;
as markers for tissues in which the corresponding protein is
preferentially expressed (either constitutively or at a
particular stage of tissue differentiation or development or
in disease states); as molecular weight markers on Southern
gels; as chromosome markers or tags (when labeled) to
identify chromosomes or to map related gene positions; to
compare with endogenous DNA sequences in patients to
identify potential genetic disorders; as probes to hybridize
and thus discover novel, related DNA sequences; as a source
of information to derive PCR primers for genetic
fingerprinting; as a probe to "subtract-out" known sequences
in. the process of discovering other novel polynucleotides;
for selecting and making oligomers for attachment to a "gene
chip" or other support, including for examination of
expression patterns; to raise anti-protein antibodiesusing
DNA immunization techniques; and as an antigen to raise
anti-DNA antibodies or elicit another immune response.
Where the polynucleotide encodes a protein which binds or
potentially binds to another protein (such as, for example,
in a receptor-ligand interaction), the polynucleotide can
also be used in interaction trap assays (such as, for
example, that described in Gyuris et al., Cell 75:791-803
(1993)) to identify polynucleotides encoding the other
protein with which binding occurs or to identify inhibitors
of the binding interaction.
The proteins provided by the present invention can
similarly be used in assay to determine biological activity,
including in a panel of multiple proteins for high-
throughput screening; to raise antibodies or to elicit
another immune response; as a reagent (including the labeled
reagent) in assays designed to quantitatively determine
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levels of the protein (or its receptor) in biological
fluids; as markers for tissues in which the corresponding
protein is preferentially expressed (either constitutively
or at a particular stage of tissue differentiation or
development or in a disease state); and, of course, to
isolate correlative receptors or ligands. Where the protein
binds or potentially binds to another protein (such as, for
example, in a receptor-ligand interaction), the protein can
be used to identify the other protein with which binding
occurs or to identify inhibitors of the binding interaction.
Proteins involved in these binding interactions can also be
used to screen for peptide or small molecule inhibitors or
agonists of the binding interaction.
Any or all of these research utilities are capable of
being developed into reagent grade or kit format for
commercialization as research products.
Methods for performing the uses listed above are well
known to those skilled in the art. References disclosing
such methods include without limitation "Molecular Cloning:
A Laboratory Manual", 2d ed., Cold Spring Harbor Laboratory
Press, Sambrook, J., E.F. Fritsch and T. Maniatis eds., 1989,
and "Methods in Enzymology: Guide to Molecular Cloning
Techniques", Academic Press, Berger, S.L. and A.R. Kimmel
eds., 1987.
Nut_r,'_t,'_onal_ UseR
Polynucleotides and proteins of the present invention
can also be used as nutritional sources or supplements.
Such uses include without limitation use as a protein or
amino acid supplement, use as a carbon source, use as a
nitrogen source and use as a source of carbohydrate. In
such cases the protein or polynucleotide of the invention
can be added to the feed of a particular organism or can be
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18
administered as a separate solid or liquid preparation, such
as in the form of powder, pills, solutions, suspensions or
capsules. In the case of microorganisms, the protein or
polynucleotide of the invention can be added to the medium
in or on which the microorganism is cultured.
C~~toki_ne and C;11 Prol_iferatlQri/Di_ffrPntiatinn
Activity
A protein of the present invention may exhibit cytokine,
cell proliferation (either inducing or inhibiting) or cell
differentiation (either inducing or inhibiting) activity or
may induce production of other cytokines in certain cell
populations. Many protein factors discovered to date,
including all known cytokines, have exhibited activity in
one or more factor dependent cell proliferation assays, and
hence the assays serve as a convenient confirmation of
cytokine activity. The activity of a protein of the present
invention is evidenced by any one of a number of routine
factor dependent cell proliferation assays for cell lines
including, without limitation, 32D, DA2, DA1G, T10, H9,
B9/11, BaF3, MC9/G, M+ (preH M+), 2E8, RB5, DA1, 123, T1165,
HT2, CTLL2, TF-1, Mo7e and CMK.
The activity of a protein of the invention may, among
other means, be measured by the following methods:
Assays for T-cell or thymocyte proliferation include
without limitation those described in: Current Protocols in
Immunology, Ed by ,T. E. Coligan, A.M. Kruisbeek, D.H.
Margulies, E.M. Shevach, W Strober, Pub. Greene Publishing
Associates and Wiley-Interscience (Chapter 3, In Vitro
assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7,
Immunologic studies in Humans); Takai et al., J. Immunol.
137:3494-3500, 1986; Hertagnolli et al., J. Immunol.
145:1706-1712, 1990; Bertagnolli et al., Cellular
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19
Immunology 133:327-341, 1991; Bertagnolli, et al., J.
Immunol. 149:3778-3783, 1992; Bowman et al., J. Immunol.
152: 1756-1761, 1994.
Assays for cytokine production and/or proliferation of
spleen cells, lymph node cells or thymocytes include,
without limitation, those described in: Polyclonal T cell
stimulation, Kruisbeek, A.M. and Shevach, E.M. In Current
Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp.
3.12.1-3.12.14, John Wiley and Sons, Toronto. 1994; and
Measurement of mouse and human Interferon y, Schreiber, R.D.
In Current Protocols in Immunology. J.E.e.a. Coligan eds.
Vol 1 pp. 6.8.1-6.8.8, John Wiley and Sons, Toronto. 1994.
Assays for proliferation and differentiation of
hematopoietic and lymphopoietic cells include, without
limitation, those described in: Measurement of Human and
Murine Interleukin 2 and Interleukin 4, Bottomly, K., Davis,
L.S. and Lipsky, P.E. In Current Protocols in Immunology.
J.E.e.a. Coligan eds. Vol 1 pp. 6.3.1-6.3.12, John Wiley and
Sons, Toronto. 1991; deVries et al., J. Exp. Med. 173:1205-
1211, 1991; Moreau et al., Nature 336:690-692, 1988;
Greenberger et al., Proc. Natl. Acad. Sci. U.S.A. 80:2931-
2938, 1983; Measurement of mouse and human interleukin 6-
Nordan, R. In Current Protocols in Immunology. J.E.e.a.
Coligan eds. Vol 1 pp. 6.6.1-6.6.5, John Wiley and Sons,
Toronto. 1991; Smith et al., Proc. Natl. Acad. Sci. U.S.A.
83:1857-1861, 1986; Measurement of human Interleukin 11 -
Hennett, F., Giannotti, J., Clark, S.C. and Turner, K. J.
In Current Protocols in Immunology. J.E.e.a. Coligan eds.
Vol 1 pp. 6.15.1 John Wiley and Sons, Toronto. 1991;
Measurement of mouse and human Interleukin 9 - Ciarletta, A.,
Giannotti, J., Clark,S.C. and Turner, K.J. In Current
Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp.
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6.13.1, John Wiley and Sons, Toronto. 1991.
Assays for T-cell clone responses to antigens (which
will identify, among others,. proteins that affect APC-T cell
interactions as well as direct T-cell effects by measuring
5 proliferation and cytokine production) include, without
limitation, those described in: Current Protocols in
Immunology, Ed by J. E. Coligan, A.M. Kruisbeek, D.H.
Margulies, E.M. Shevach, W Strober, Pub. Greene Publishing
Associates and Wiley-Interscience (Chapter 3, In Vitro
10 assays for Mouse Lymphocyte Function; Chapter 6, Cytokines
and their cellular receptors; Chapter 7, Immunologic studies
in Humans); Weinberger et al., Proc. Natl. Acad. Sci. USA
77:6091-6095, 1980; Weinberger et al., Eur. J. Immun.
11:405-411, 1981; Takai et al., J. Immunol. 137:3494-3500,
15. 1986; Takai et al., J. Immunol. 140:508-512, 1988.
I~ne St i mu1_at,'_nr~r o_r Supyres s my Act i vi tv
A protein of the present invention may also exhibit
immune stimulating or immune suppressing activity, including
without limitation the activities for which assays are
20 described herein. A protein may be useful in the treatment
of various immune deficiencies and disorders (including
severe combined immunodeficiency (SLID)), e.g., in
regulating (up or down) growth and proliferation of T and/or
H lymphocytes, as well as effecting the cytolytic activity
of NR cells and other cell populations. These immune
deficiencies may be genetic or be caused by viral (e. g.,
HIV) as well as bacterial orfungal infections, or may result
from autoimmune disorders. More specifically, infectious
diseases causes by viral, bacterial, fungal or other
infection may be treatable using a protein of the present
invention, including infections by HIV, hepatitis viruses,
herpesviruses, mycobacteria, Leishmania spp., malaria spp.
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21
and various fungal infections such as candidiasis. Of
course, in this regard, a protein of the present invention
may also be useful where a boost to the immune system
generally may be desirable, i.e., in the treatment of cancer.
Autoimmune disorders which may be treated using a
protein of the present invention include, for example,
connective tissue disease, multiple sclerosis, systemic
lupus erythematosus, rheumatoid arthritis, autoimmune
pulmonary inflammation, Guillain-Barre syndrome, autoimmune
thyroiditis, insulin dependent diabetes mellitis, myasthenia
gravis, graft-versus-host disease and autoimmune
inflammatory eye disease. Such a protein of the present
invention may also to be useful in the treatment of allergic
reactions and conditions, such as asthma (particularly
allergic asthma) or other respiratory problems. Other
conditions, in which immune suppression is desired
(including, for example, organ transplantation), may also be
treatable using a protein of the present invention.
Using the proteins of the invention it may also be
possible to immune responses, in a number of ways. Down
regulation may be in the form of inhibiting or blocking an
immune response already in progress or may involve
preventing the induction of an immune response. The
functions of activated T cells may be inhibited by
suppressing T cell responses or by inducing specific
tolerance in T cells, or both. Immunosuppression of T cell
responses is generally an active, non-antigen-specific,
process which requires continuous exposure of the T cells to
the suppressive agent. Tolerance, which involves inducing
non-responsiveness or anergy in T cells, is distinguishable
from immunosuppression in that it is generally antigen-
specific and persists after exposure to the tolerizing agent
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22
has ceased. Operationally, tolerance can be demonstrated by
the lack of a T cell response upon reexposure to specific
antigen in the absence of the tolerizing agent.
Down regulating or preventing one or more antigen
functions (including without limitation B lymphocyte antigen
functions (such as , for example, B7}), e.g., preventing
high level lymphokine synthesis by activated T cells, will
be useful in situations of tissue, skin and organ
transplantation and in graft-versus-host disease (GVHD}.
For example, blockage of T cell function should result in
reduced tissue destruction in tissue transplantation.
Typically, in tissue transplants, rejection of the
transplant is initiated through its recognition as foreign
by T cells, followed by an immune reaction that destroys the
transplant. The administration of a molecule which inhibits
or blocks interaction of a B7 lymphocyte antigen with its
natural ligand(s) on immune cells (such as a soluble,
monomeric form of a peptide having B7-2 activity alone or in
conjunction with a monomeric form of a peptide having an
activity of another B lymphocyte antigen (e.g., B7-1, B7-3)
or blocking antibody } , prior to transplantation can lead to
the binding of the molecule to the natural ligand(s) on the
immune cells without transmitting the corresponding
costimulatory signal. Blocking B lymphocyte antigen
function in this matter prevents cytokine synthesis by
immune cells, such as T cells, and thus acts as an
immunosuppressant. Moreover, the lack of costimulation may
also be sufficient to anergize the T cells, thereby inducing
tolerance in a subject. Induction of long-term tolerance by
B lymphocyte antigen-blocking reagents may avoid the
necessity of repeated administration of these blocking
reagents. To achieve sufficient immunosuppression or
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23
tolerance in a subject, it may also be necessary to block
the function of a combination of B lymphocyte antigens.
The efficacy of particular blocking reagents in
preventing organ transplant rejection or GVHD can be
assessed using animal models that are predictive of efficacy
in humans. Examples of appropriate systems which can be
used include allogeneic cardiac grafts in rats and
xenogeneic pancreatic islet cell grafts in mice, both of
which have been used to examine the immunosuppressive
effects of CTLA4Ig fusion proteins in vivo as described in
Lenschow et al., Science 257:789-792 (1992) and Turka et al.,
Proc. Natl. Acad. Sci USA, 89:11102-11105 (1992). In
addition, murine models of GVHD (see Paul ed., Fundamental
Immunology, Raven Press, New York, 1989, pp. 846-847) can be
used to determine the effect of blocking B lymphocyte
antigen function in vivo on the development of that disease.
Blocking antigen function may also be therapeutically
useful for treating autoimmune diseases. Many autoimmune
disorders are the result of inappropriate activation of T
cells that are reactive against self tissue and which
promote the production of cytokines and autoantibodies
involved in the pathology of the diseases. Preventing the
activation of autoreactive T cells may reduce or eliminate
disease symptoms. Administration of reagents which block
costimulation of T cells by disrupting receptor:ligand
interactions of B lymphocyte antigens can be used to inhibit
T cell activation and prevent production of autoantibodies
or T cell-derived cytokines which may be involved in the
disease process. Additionally, blocking reagents may induce
antigen-specific tolerance of autoreactive T cells which
could lead to long-term relief from the disease. The
efficacy of blocking reagents in preventing or alleviating
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24
autoimmune disorders can be determined using a number of
well-characterized animal models of human autoimmune
diseases. Examples include murine experimental autoimmune
encephalitis, systemic lupus erythmatosis in l~tL/lpr/lpr
mice or NZB hybrid mice, murine autoimmune collagen
arthritis, diabetes mellitus in NOD mice and BH rats, and
murine experimental myasthenia gravis (see Paul ed.,
Fundamental Immunology, Raven Press, New York, /989, pp.
840-856).
Upregulation of an antigen function (preferably a B
lymphocyte antigen function), as a means of up regulating
immune responses, may also be useful in therapy.
Upregulation of immune responses may be in the form of
enhancing an existing immune response or eliciting an
initial immune response. For example, enhancing an immune
response through stimulating B lymphocyte antigen function
may be useful in cases of viral infection. In addition,
systemic viral diseases such as influenza, the commoncold,
and encephalitis might be alleviated by the administration
of stimulatory forms of B lymphocyte antigens systemically.
Alternatively, anti-viral immune responses may be
enhanced in an infected patient by removing T cells from the
patient, costimulating the T cells in vitro with viral
antigen-pulsed APCs either expressing a peptide of the
present invention or together with a stimulatory form of a
soluble peptide of the present invention and reintroducing
the in vitro activated T cells into the patient. Another
method of enhancing anti-viral immune responses would be to
isolate infected cells from a patient, transfect them with a
nucleic acid encoding a protein of the present invention as
described herein such that the cells express all or a
portion of the protein on their surface, and reintroduce the
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
transfected cells into the patient. The infected cells
would now be capable of delivering a costimulatory signal to,
and thereby activate, T cells in vivo.
In another application, up regulation or enhancement of
5 antigen function (preferably B lymphocyte antigen function}
may be useful in the induction of tumor immunity. Tumor
cells (e. g., sarcoma, melanoma, lymphoma, leukemia,
neuroblastoma, carcinoma) transfected with a nucleic acid
encoding at least one peptide of the present invention can
10 be administered to a subject to overcome tumor-specific
tolerance in the subject. If desired, the tumor cell can be
transfected to express a combination of peptides. For
example, tumor cells obtained from a patient can be
transfected ex vivo with an expression vector directing the
15 expression of a peptide ~ having B7-2-like activity alone, or
in conjunction with a peptide having B7-1-like activity
and/or B7-3-like activity. The transfected tumor cells are
returned to the patient to result in expression of the
peptides on the surface of the transfected cell.
20 Alternatively, gene therapy techniques can be used to target
a tumor cell for transfection in vivo.
The presence of the peptide of the present invention
having the activity of a B lymphocyte antigens) on the
surface of the tumor cell provides the necessary
25 costimulation signal to T cells to induce a T cell mediated
immune response against the transfected tumor cells. In
addition, tumor cells which lack MHC class I or I~iC class II
molecules, or which fail to reexpress sufficient amounts of
MHC class I or 1~IC class II molecules, can be transfected
with nucleic acid encoding all or a portion of (e.g., a
cytopiasmic-domain truncated portion) of an MHC class I a
chain protein and Z microglobulin protein or an I~iC class
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26
II chain protein and an MHC class II chain protein to
thereby express MHC class I or MHC class II proteins on the
cell surface. Expression of the appropriate class I or
class II MHC in conjunction with a peptide having the
activity of a H lymphocyte antigen (e.g., B7-1, B7-2, B7-3)
induces a T cell mediated immune response against the
transfected tumor cell. optionally, a gene encoding an
antisense construct which blocks expression of an MHC class
II associated protein, such as the invariant chain, can also
be cotransfected with a DNA encoding a peptide having the
activity of a B lymphocyte antigen to promote presentation
of tumor associated antigens and induce tumor specific
immunity. Thus, the induction of a T cell mediated immune
response in a human subject may be sufficient to overcome
tumor-specific tolerance in the subject.
The activity of a protein of the invention may, among
other means, be measured by the following methods:
Suitable assays for thymocyte or splenocyte
cytotoxicity include, without limitation, those described
in: Current Protocols in Immunology, Ed by J. E. Coligan,
A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W Strober, Pub.
Greene Publishing Associates and Wiley-Interscience (Chapter
3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19;
Chapter 7, Immunologic studies in Humans); Herrmann et al.,
Proc. Natl. Acad. Sci. USA 78:2488-2492, 1981; Herrmann et
al., J. Immunol. 128:1968-1974, 1982; Handa et al., J.
Immunol. 135:1564-1572, 1985; Takai et al., J. Immunol.
137:3494-3500, 1986; Takai et al., J. Immunol. 140:508-512,
1988; Herrmann et al., Proc. Natl. Acad. Sci. USA 78:2488-
2492, 1981; Herrmann et al., J. Immunol. 128:1968-1974,
1982; Handa et al., J. Immunol. 135:1564-1572, 1985; Takai
et al., J. Immunol. 137:3494-3500, 1986; Bowmanet al., J.
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27
Virology 61:1992-1998; Takai et al., J. Immunol. 140:508-512,
1988; Bertagnolli et al., Cellular Immunology 133:327-341,
1991; Brown et al., J. Immunol. 153:3079-3092, 1994.
Assays for T-cell-dependent immunoglobulin responses
and isotype switching (which will identify, among others,
proteins that modulate T-cell dependent antibody responses
and that affect Thl/Th2 profiles) include, without
limitation, those described in: Maliszewski, J. Immunol.
144:3028-3033, 1990; and Assays for B cell function: In
vitro antibody production, Mond, J.J. and Brunswick, M. In
Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1
pp. 3.8.1-3.8.16, John Wiley and Sons, Toronto. 1994.
Mixed lymphocyte reaction (MLR) assays (which will
identify, among others, proteins that generate predominantly
Thl and CTL responses) include, without limitation, those
described in: Current Protocols in Immunology, Ed by J. E.
Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W
Strober, Pub. Greene Publishing Associates and Wiley-
Interscience (Chapter 3, In Vitro assays for Mouse
Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies
in Humans); Takai et al., J. Immunol. 137:3494-3500, 1986;
Takai et al., J. Immunol. 140:508-512, 1988; Bertagnolli et
al., J. Immunol. 149:3778-3783, 1992.
Dendritic cell-dependent assays (which will identify,
among others, proteins expressed by dendritic cells that
activate naive T-cells) include, without limitation, those
described in: Guery et al., J. Immunol. 134:536-544, 1995;
Inaba et al., Journal of Experimental Medicine 173:549-559,
1991; Macatonia et al., Journal of Immunology 154:5071-5079,
1995; Porgador et al., Journal of Experimental Medicine
182:255-260, 1995; Nair et al., Journal of Virology
67:4062-4069, 1993; Huang et al., Science 264:961-965,
CA 02336225 2001-O1-24
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28
1994; Macatonia et al., Journal of Experimental Medicine
169:1255-1264, 1989; Bhardwaj et al., Journal of Clinical
Investigation 94:797-807, 1994; and Inaba et al., Journal
of Experimental Medicine 172:631-640, 1990.
Assays for lymphocyte survival/apoptosis (which will
identify, among others, proteins that prevent apoptosis
after superantigen induction and proteins that regulate
lymphocyte homeostasis) include, without limitation, those
described in: Darzynkiewicz et al., Cytometry 13:795-808,
1992; Gorczyca et al., Leukemia 7:659-670, 1993; Gorczyca et
al., Cancer Research 53:1945-1951, 1993; Itoh et al., Cell
66:233-243, 1991; Zacharchuk, Journal of Immunology
145:4037-4045, 1990; Zamai et al., Cytometry 14:891-897,
1993; Gorczyca et al., International Journal of Oncology
1:639-648, 1992.
Assays for proteins that influence early steps of T-
cell commitment and development include, without limitation,
those described in: Antica et al., Blood 84:111-117, 1994;
Fine et al. , Cellular Immunology 155:111-122, 1994; Galy et
al., Blood 85:2770-27?8, 1995; Toki et al., Proc. Nat. Acad
Sci. USA 88:7548-7551, 1991.
Hematogo,'_esss Re~u a ~ n~ Act ~ vi tv
A protein of the present invention may be useful in
regulation of hematopoiesis and, consequently, in the
treatment of myeloid or lymphoid cell deficiencies. Even
marginal biological activity in support of colony forming
cells or of factor-dependent cell lines indicates
involvement in regulating hematopoiesis, e.g. in supporting
the growth and proliferation of erythroid progenitor cells
alone or in combination with other cytokines, thereby
indicating utility, for example, in treating various anemias
or for use in conjunction with irradiation/chemotherapy to
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29
stimulate the production of erythroid precursors and/or
erythroid cells; in supporting the growth and proliferation
of myeloid cells such as granulocytes and
monocytes/macrophages (i.e., traditional CSF activity)
useful, for example, in conjunction with chemotherapy to
prevent or treat consequent myelo-suppression; in supporting
the growth and proliferation of megakaryocytes and
consequently of platelets thereby allowing prevention or
treatment of various platelet disorders such as
thrombocytopenia, and generally for use in place of or
complimentary to platelet transfusions; and/or in supporting
the growth and proliferation of hematopoietic stem cells
which are capable of maturing to any and all of the above-
mentioned hematopoietic cells and therefore find therapeutic
utility in various stem cell disorders (such as those
usually treated with transplantation, including, without
limitation, aplastic anemia and paroxysmal nocturnal
hemoglobinuria), as well as in repopulating the stem cell
compartment post irradiation/chemotherapy, either in-vivo or
ex-vivo (i.e., in conjunction with bone marrow
transplantation or with peripheral progenitor cell
transplantation (homologous or heterologous)) as normal
cells or genetically manipulated for gene therapy.
The activity of a protein of the invention may, among
other means, be measured by the following methods:
Suitable assays for proliferation and differentiation
of various hematopoietic lines are cited above.
Assays for embryonic stem cell differentiation (which
will identify, among others, proteins that influence
embryonic differentiation hematopoiesis) include, without
limitation, those described in: Johansson et al. Cellular
Biology 15:141-151, 1995; Keller et al., Molecular and
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Cellular Biology 13:473-486, 1993; McClanahan et al., Blood
81:2903-2915, 1993.
Assays for stem cell survival and differentiation
(which will identify, among others, proteins that regulate
5 lympho-hematopoiesis) include, without limitation, those
described in: Methylcellulose colony fonaing assays,
Freshney, M.G. In Culture of Hematopoietic Cells. R.I.
Freshney, et al. eds. Vol pp. 265-268, Wiley-Liss, Inc.,
New York, NY. 1994; Hirayama et al., Proc. Natl. Acad. Sci.
10 USA 89:5907-5911, 1992; Primitive hematopoietic colony
forming cells with high proliferative potential, McNiece,
I.K. and Briddell, R.A. In Culture of Hematopoietic Cells.
R.I. Freshney, et al. eds. Vol pp. 23-39, Wiley-Liss, Inc.,
New York, NY. 1994; Neben et al., Experimental Hematology
15 22:353-359, 1994; Cobblestone area forming cell assay,
Ploemacher, R.E. In Culture of Hematopoietic Cells. R.I.
Freshney, et al. eds. Vol pp. 1-21, Wiley-Liss, Inc., New
York, NY. 1994; Long term bone marrow cultures in the
presence of stromal cells, Spooncer, E., Dexter, M. and
20 Allen, T. In Culture of Hematopoietic Cells. R.I. Freshney,
et al. eds. Vol pp. I63-179, Wiley-Liss, Inc., New York, NY.
1994; Long term culture initiating cell assay, Sutherland,
H.J. In Culture of Hematopoietic Cells. R.I. Freshney, et al.
eds. Vol pp. 139-162, Wiley-Liss, Inc., New York, NY. 1994.
25 Tissm Growth Activity
A protein of the present invention also may have
utility in compositions used for bone, cartilage, tendon,
ligament and/or nerve tissue growth or regeneration, as well
as for wound healing and tissue repair and replacement, and
30 in the treatment of burns, incisions and ulcers.
A protein of the present invention, which induces
cartilage and/or bone growth in circumstances where bone is
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31
not normally formed, has application in the healing of bone
fractures and cartilage damage or defects in humans and
other animals. Such a preparation employing a protein of
the invention may have prophylactic use in closed as well as
open fracture reduction and also in the improved fixation of
artificial joints. De novo bone formation induced by an
osteogenic agent contributes to the repair of congenital,
trauma induced, or oncologic resection induced craniofacial
defects, and also is useful in cosmetic plastic surgery.
A protein of this invention may also be used in the
treatment of periodontal disease, and in other tooth repair
processes. Such agents may provide an environment to
attract bone-forming cells, stimulate growth of bone-forming
cells or induce differentiation of progenitors of bone-
forming cells. A protein of the invention may also be
useful in the treatment of osteoporosis or osteoarthritis,
such as through stimulation of bone and/or cartilage repair
or by blocking inflammation or processes of tissue
destruction (collagenase activity, osteoclast activity,
etc.) mediated by inflammatory processes.
Another category of tissue regeneration activity that
may be attributable to the protein of the present invention
is tendon/ligament formation. A protein of the present
invention, which induces tendon/ligament-like tissue or
other tissue formation in circumstances where such tissue is
not normally formed, has application in the healing of
tendon or ligament tears, deformities and other tendon or
ligament defects in humans and other animals. Such a
preparation employing a tendon/ligament-like tissue inducing
protein may have prophylactic use in preventing damage to
tendon or ligament tissue, as well as use in the improved
fixation of tendon or ligament to bone or other tissues, and
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32
in repairing defects to tendon or ligament tissue. De novo
tendon/ligament-like tissue formation induced by a
composition of the present invention contributes to the
repair of congenital, trauma induced, or other tendon or
ligament defects of other origin, and is also useful in
cosmetic plastic surgery for attachment or repair of tendons
or ligaments. The compositions of the present invention may
provide an environment to attract tendon or ligament-forming
cells, stimulate growth of tendon- or ligament-forming cells,
induce differentiation of progenitors of tendon- or
ligament-forming cells, or induce growth of tendon/ligament
cells or progenitors ex vivo for return in vivo to effect
tissue repair. The compositions of the invention may also
be useful in the treatment of tendinitis, carpal tunnel
syndrome and other tendon or ligament defects. The
compositions may also include an appropriate matrix and/or
sequestering agent as a carrier as is well known in the art.
The protein of the present invention may also be useful
for proliferation of neural cells and for regeneration of
nerve and brain tissue, i.e. for the treatment of central
and peripheral nervous system diseases and neuropathies, as
well as mechanical and traumatic disorders, which -involve
degeneration, death or trauma to neural cells or nerve
tissue. More specifically, a protein may be used in the
treatment of diseases of the peripheral nervous system, such
as peripheral nerve injuries, peripheral neuropathy and
localized neuropathies, and central nervous system diseases,
such as Alzheimer~s, Parkinson's disease, Huntington~s
disease, amyotrophic lateral sclerosis, and Shy-Drager
syndrome. Further conditions which may be treated in
accordance with the present invention include mechanical and
traumatic disorders, such as spinal cord disorders, head
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33
trauma and cerebrovascular diseases such as stroke.
Peripheral neuropathies resulting from chemotherapy or other
medical therapies may also be treatable using a protein of
the invention.
Proteins of the invention may also be useful to promote
better or faster closure of non-healing wounds, including
without limitation pressure ulcers, ulcers associated with
vascular insufficiency, surgical and traumatic wounds, and
the like.
It is expected that a protein of the present invention
may also exhibit activity for generation or regeneration of
other tissues, such as organs (including, for example,
pancreas, liver, intestine, kidney, skin, endothelium),
muscle (smooth, skeletal or cardiac) and vascular (including
vascular endothelium) tissue, or for promoting the growth of
cells comprising such tissues. Part of the desired effects
may be by inhibition or modulation of fibrotic scarring to
allow normal tissue to regenerate. A protein of the
invention may also exhibit angiogenic activity.
A protein of the present invention may also be useful
for gut protection or regeneration and treatment of lung or
liver fibrosis, reperfusion injury in various tissues, and
conditions resulting from systemic cytokine damage.
A protein of the present invention may also be useful
for promoting or inhibiting differentiation of tissues
described above from precursor tissues or cells; or for
inhibiting the growth of tissues described above.
The activity of a protein of the invention may, among
other means, be measured by the following methods:
Assays for tissue generation activity include, without
limitation, those described in: International Patent
Publication No. W095/16035 (bone, cartilage, tendon);
CA 02336225 2001-O1-24
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34
International Patent Publication No. W095/05846 (nerve,
neuronal); International Patent Publication No. W091/07491
(skin, endothelium ).
Assays for wound healing activity include, without
limitation, those described in: Winter, Epidern~al Wound
Healing, pps. 71-112 (Maibach, HI and Rovee, DT, eds.), Year
Hook Medical Publishers, Inc., Chicago, as modified by
Eaglstein and Mertz, J. Invest. Dermatol 71:382-84 (1978).
Acti_v,'_n/Tnh,'_b1n Act,'_v,'_tv
A protein of the present invention may also exhibit
activin- or inhibin-related activities. Inhibins are
characterized by their ability to inhibit the release of
follicle stimulating hormone (FSH), while activins and are
characterized by their ability to stimulate the release of
follicle stimulating hormone (FSH). Thus, a protein of the
present invention, alone or in heterodimers with a member of
the inhibin family, may be useful as a contraceptive based
on the ability of inhibins to decrease fertility in female
mammals and decrease sperznatagenesis in male mammals.
Administration of sufficient amounts of other inhibins can
induce infertility in these mammals. Alternatively, the
protein of the invention, as a homodimer or as a heterodimer
with other protein subunits of the inhibin- group, may be
useful as a fertility inducing therapeutic, based upon the
ability of activin molecules in stimulating FSH release from
cells of the anterior pituitary. See, for example, United
States Patent 4,798,885. A protein of the invention may
also be useful for advancement of the onset of fertility in
sexually immature mammals, so as to increase the lifetime
reproductive performance of domestic animals such as cows,
sheep and pigs.
The activity of a protein of the invention may, among
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other means, be measured by the following methods:
Assays for activin/inhibin activity include, without
limitation, those described in: Vale et al., Endocrinology
91:562-572, 1972; Ling et al., Nature 321:779-782, 1986;
5 Vale et al. , Nature 321: 776-779, 1986; Mason et al. , Nature
318:659-663, 1985; Forage et al., Proc. Natl. Acad: Sci. USA
83:3091-3095, 1986.
Chemotactic/Chemokinetic stivit~
A protein of the present invention may have chemotactic
10 or chemokinetic activity (e.g., act as a chemokine) for
mammalian cells, including, for example, monocytes,
fibroblasts, neutrophils, T-cells, mast cells, eosinophils,
epithelial and/or endothelial cells. Chemotactic and
chemokinetic proteins can be used to mobilize or attract a
15 desired cell population to a desired site of action.
Chemotactic or chemokinetic proteins provide particular
advantages in treatment of wounds and other trauma to
tissues, as well as in treatment of localized infections.
For example, attraction of lymphocytes, monocytes or
20 neutrophils to tumors or sites of infection may result in
improved immune responses against the tumor or infecting
agent.
A protein or peptide has chemotactic activity for a
particular cell population if it can stimulate, directly or
25 indirectly, the directed orientation or movement of such
cell population. Preferably, the protein or peptide has the
ability to directly stimulate directed movement of cells.
Whether a particular protein has chemotactic activity for a
population of cells can be readily determined by employing
30 such protein or peptide in any known assay for cell
chemotaxis.
The activity of a protein of the invention may, among
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36
other means, be measured by the following methods:
Assays for chemotactic activity (which will identify
proteins that induce or prevent chemotaxis)consist of assays
that measure the ability of a protein to induce the
migration of cells across a membrane as well as the ability
of a protein to induce the adhesion of one cell population
to another cell population. Suitable assays for movement and
adhesion include, without limitation, those described in:
Current Protocols in Immunology, Ed by J.E. Coligan, A.M.
Kruisbeek, D.H. Margulies, E.M. Shevach, W.Strober, Pub.
Greene Publishing Associates and Wiley-Interscience (Chapter
6.12, Measurement of alpha and beta Chemokines 6.12.1-
6.12.28; Taub et al. J. Clin. Invest. 95:1370-1376, 1995;
Lind et al. APMIS 103:140-146, 1995; Muller et al Eur. J.
Immunol. 25: 1744-1748; Gruber et al. J. of Immunol.
152:5860-5867, 1994; Johnston et al. J. of Immunol. 153:
1762-1768, 1994.
Hemostatic and Thrombolytic Actjvitw
A protein of the invention may also exhibit hemostatic
or thrombolytic activity. As a result,such a protein is
expected to be useful in treatment of various coagulation
disorders (includinghereditary disorders, such as
hemophilias) or to enhance coagulation and other hemostatic
events in treating wounds resulting from trauma, surgery or
other causes. A protein of the invention may also be useful
for dissolving or inhibiting formation of thromboses and for
treatment and prevention of conditions resulting therefrom
(such as, for example, infarction of cardiac and central
nervous system vessels (e. g., stroke).
The activity of a protein of the invention may, among
other means, be measured by the following methods:
Assay for hemostatic and thrombolytic activity include,
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37
without limitation, those described in: Linet et al., J.
Clin. Pharmacol. 26:131-140, 1986; Burdick et al.,
Thrombosis Res. 45:413-419, 1987; Humphrey et al.,
Fibrinolysis 5:71-79 (1991); Schaub, Prostaglandins 35:467
474, 1988.
y or/r. i sand Act i_v,'_tv
A protein of the present invention may also demonstrate
activity as receptors, receptor ligands or inhibitors or
agonists of receptor/ligand interactions. Examples of such
receptors and ligands include, without limitation, cytokine
receptors and their ligands, receptor kinases and their
ligands, receptor phosphatases and their ligands, receptors
involved in cell-cell interactions and their ligands
(including without limitation, cellular adhesion molecules
(such as selectins, integrins and their ligands) and
receptor/ligand pairs involved in antigen presentation,
antigen recognition and development of cellular and humoral
immune responses). Receptors and ligands are also useful
for screening of potential peptide or small molecule
inhibitors of the relevant receptor/ligand interaction. A
protein of the present invention (including, without
limitation, fragments of receptors and ligands) may
themselves be useful as inhibitors of receptor/ligand
interactions.
The activity of a protein of the invention may, among
other means, be measured by the following methods:
Suitable assays for receptor-ligand activity include
without limitation those described in:Current Protocols in
Immunology, Ed by J.E. Coligan, A.M. Kruisbeek, D.H.
Margulies, E.M. Shevach, W.Strober, Pub. Greene Publishing
Associates and Wiley-Interscience (Chapter 7.28, Measurement
of Cellular Adhesion under static conditions 7.28.1-7.28.22),
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38
Takai et al., Proc. Natl. Acad. Sci. USA 84:6864-6868, 1987;
Bierer et al., J. Exp. Med. 168:1145-1156, 1988; Rosenstein
et al., J. Exp. Med. 169:149-160 1989; Stoltenborg et
al., J. Immunol. Methods 175:59-68, 1994; Stitt et al.,
Cell 80:661-670, 1995.
Anti-Tnfl,mma or'~~ Activity
Proteins of the present invention may also exhibit
anti-inflammatory activity. The anti-inflammatory activity
may be achieved by providing a stimulus to cells involved in
the inflammatory response, by inhibiting or promoting cell-
cell. interactions (such as, for example, cell adhesion}, by
inhibiting or promoting chemotaxis of cells involved in the
inflammatory process, inhibiting or promoting cell
extravasation, or by stimulating or suppressing production
of other factors which more directly inhibit or promote an
inflammatory response. Proteins exhibiting such activities
can be used to treat inflammatory conditions including
chronic or acute conditions), including without limitation
inflammation associated with infection (such as septic shock,
sepsis or systemic inflammatory response syndrome (SIRS)),
ischemia-reperfusion injury, endotoxin lethality, arthritis,
complement-mediated hyperacute rejection, nephritis,
cytokine or chemokine-induced lung injury, inflammatory
bowel disease, Crohn's disease or resulting from over
production of ytokines such as TNF or IL-1. Proteins of the
invention may also be useful to treat anaphylaxis and
hypersensitivity to an antigenic substance or material.
In addition to the activities described above for
immunological treatment or prevention of tumors, a protein
of the invention may exhibit other anti-tumor activities. A
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39
protein may inhibit tumor growth directly or indirectly
(such as, for example, via ADCC). A protein may exhibit its
tumor inhibitory activity by acting on tumor tissue or tumor
precursor tissue, by inhibiting formation of tissues
necessary to support tumor growth ( such as, for example, by
inhibiting angiogenesis), by causing production of other
factors, agents or cell types which inhibit tumor growth, or
by suppressing, eliminating or inhibiting factors, agents or
cell types which promote tumor growth
Ot-h-e_r Act sv~ t ~ es
A protein of the invention may also exhibit one or more
of the following additional activities or effects:
inhibiting the growth, infection or function of, or killing,
infectious agents, including, without limitation, bacteria,
viruses, fungi and other parasites; effecting (suppressing
or enhancing) bodily characteristics, including, without
limitation, height, weight, hair color, eye color, skin, fat
to lean ratio or other tissue pigmentation, or organ or body
part size or shape (such as, for example, breast
augmentation or diminution, change in bone form or shape);
effecting biorhythms or caricadic cycles or rhythms;
effecting the fertility of male or female subjects;
effecting the metabolism, catabolism, anabolism, processing,
utilization, storage or elimination of dietary fat, lipid,
protein, carbohydrate, vitamins, minerals, cofactors. or
other nutritional factors or component(s); effecting
behavioral characteristics, including, without limitation,
appetite, libido, stress, cognition (including cognitive
disorders), depression (including depressive disorders) and
violent behaviors; providing analgesic effects or other pain
reducing effects; promoting differentiation and growth of
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embryonic stem cells in lineages other than hematopoietic
lineages; hormonal or endocrine activity; in the case of
enzymes, correcting deficiencies of the enzyme and treating
deficiency-related diseases; treatment of hyperproliferative
5 disorders (such as, for example, psoriasis); immunoglobulin-
like activity (such as, for example, the ability to bind
antigens or complement); and the ability to act as an
antigen in a vaccine composition to raise an immune response
against such protein or another material or entity which is
10 cross-reactive with such protein.
Examples
The present invention is specifically illustrated in
more detail by the following Examples, but Examples are not
15 intended to restrict the present invention. The basic
operations with regard to the recombinant DNA and the
enzymatic reactions were carried out according to the
literature ("Molecular Cloning. A Laboratory Manual~~, Cold
Spring Harbor Laboratory, 1989]. Unless otherwise stated,
20 restrictive enzymes and a variety of modification enzymes to
be used were those available from Takara Shuzo. The buffer
compositions and the reaction conditions for each of the
enzyme reactions were as described in the manufacturer's
instructions. The cDNA synthesis was carried out according
25 to the literature [Kato, S. et al., Gene 150: 243-250
(1994)].
(1) Selection of cDNAs Encoding Proteins Having Hydrophobic
Domains
The cDNA library of fibrosarcoma cell line HT-1080
30 (W098/11217), the cDNA library of osteosarcoma cell line
Saos-2 (W097/33993), the cDNA library of osteosarcoma cell
line U-2 OS (W098/21328), the cDNA library of epiderznoid
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41
carcinoma cell line KH (W098/1I217), the cDNA library of
tissues of stomach cancer delivered by the operation
(WO98/21328), the cDNA library of liver tissue delivered by
the operation (WO98/2I328), and were used for the DNA
libraries. Full-length cDNA clones were selected from
respective libraries and the whole base sequences thereof
were determined to construct a homo-protein cDNA bank
consisting of the full-length cDNA clones. The
hydrophobicity/hydrophilicity profiles were determined for
the proteins encoded by the full-length cDNA clones
registered in the homo-protein cDNA bank by the Kyte-
Doolittle method [Kyte, J. & Doolittle, R. F., J. Mol. Biol.
157: 105-132 (1982)] to examine the presence or absence of a
hydrophobic region. Any clone that has a hydrophobic region
being putative as a secretory signal or a transmembrane
domain in the amino acid sequence of the encoded protein was
selected as a clone candidate.
(2) Protein Synthesis by In Vitro Translation
The plasmid vector bearing the cDNA of the present
invention was used for in vitro transcription/translation
with a TNT rabbit reticulocyte lysate kit (Promega). In this
case, ['ss]methionine was added to label the expression
product with a radioisotope. Each of the reactions was
carried out according to the protocols attached to the kit.
Two micrograms of the plasmid was subjected to the reaction
at 30°C for 90 minutes in the reaction solution of a total
volume of 25 ul containing I2.5 ~1 N of TNT rabbit
reticulocyte lysate, 0.5 N1 of a buffer solution (attached
to the kit), 2 N1 of an amino acid mixture (without
methionine), 2 N1 of ['SS]methionine (Amersham) (0.37 MHq/N1),
0.5 girl of T7 RNA polymerase, and 20 U of RNasin. Also, an
experiment in the presence of a membrane system was carried
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42
out by adding to this reaction system 2.5 N1 of a canine
pancreas microsome fraction (Promega). To 3 ul of the
resulting reaction solution was added 2 N1 of the SDS
sampling buffer (125 mM Tris-hydrochloric acid buffer, pB
6.8, 120 mM 2-mercaptoethanol, 2% SDS solution, 0.025%
bromophenol blue, and 20% glycerol) and the resulting
mixture was heated at 95°C for 3 minutes and then subjected
to SDS-polyacrylamide gel electrophoresis. The molecular
weight of the translation product was determined by carrying
out the autoradiography.
(3) Expression by COS7
Escherichia coli cells bearing the expression vector
for the protein of the present invention was incubated at
37°C for 2 hours in 2 ml of the 2xYT culture medium
I5 containing 100 pg/ml of ampicillin, the helper phage M13R07
( 50 a 1 ) was added, and the incubation was continued at 37 °C
overnight. A supernatant separated by centrifugation
underwent precipitation with polyethylene glycol to obtain
single-stranded phage particles. These particles were
suspended in 100 N1 of 1 mM Tris-0.1 mM EDTA, pH 8 (TE}.
The cultured cells derived from simian kidney, COS7,
were incubated at 37°C in the presence of 5% COz in the
Dulbecco's modified Eagle's culture medium (DMEM) containing
10% fetal calf serum. Into a 6-well plate (Nunc, well
diameter: 3 cm) were inoculated with 1 x lOs COS7 cells and
incubation was carried out at 37°C for 22 hours in the
presence of 5% COz. After the culture medium was removed,
the cell surface was washed with a phosphate buffer solution
and then washed again with DMEM containing 50 mM Tris-
hydrochloric acid (pH 7.5) (TDMEM). To the resulting cells
was added a suspension of 1 Nl of the single-stranded phage
suspension, 0.6 ml of the DMEM culture medium, and 3 pl of
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43
TRANSFECTAM~'' (IBF) and the resulting mixture was incubated
at 37°C for 3 hours in the presence of 5% COz. After the
sample solution was removed, the cell surface was washed
with TDMEM, 2 ml per well of DMEM containing 10% fetal calf
serum was added, and the incubation was carried out at 37 °C
for 2 days in the presence of 5% COz. After the culture
medium was replaced by a culture medium containing
['SS]cystine or ['SS]methionine, the incubation was carried
out for one hour. After the culture medium and the cells
were separated by centrifugation, proteins in the culture
medium fraction and the cell-membrane fraction were
subjected to SDS-PAGE.
(4) Clone Examples
<HP01550> (SEQ ID Nos. 1, 11, and 21)
Determination of the whole base sequence of the cDNA
insert of clone HP01550 obtained from cDNA library of human
stomach cancer revealed the structure consisting of a 65-by
5'-untranslated region, a 378-by ORF, and a 67-by 3'-
untranslated region. The ORF codes for a protein consisting
of 125 amino acid residues and there existed one putative
transmembrane domain. Figure 1 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte-
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 15 kDa that was almost identical with the molecular
weight of 13,825 predicted from the ORF.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the Caenorhabditis elegans
hypothetical protein F45G2.c (GenBank Accession No. Z93382).
Table 2 shows the comparison between amino acid sequences of
the human protein of the present invention (HP) and the C.
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44
elegans hypothetical protein F45G2.c (CE). Therein, the
marks of -, *, and . represent a gap, an amino acid residue
identical with that of the protein of the present invention,
and an amino acid residue similar to that of the protein of
the present invention, respectively. The both proteins
shared a homology of 44.5% in the entire region.
Table 2
HP MAKYLAQIIVMGVQWGRAFARALRQEF------AASRAAADARGRAGHRSAAASNLS-
.. . . ..*..*..**.*.*. **..**..... .. *..*.** .
CE MPWRTALKVALAAGEAVAKALTRAVRDEIKQTQQAAARHAASTGQSASETRENANSNAKL
HP GLSLQEAQQILNV-SKLSPEEVQKNYEHLFKVNDKSVGGSFYLQSKWRAKERLDEEL-K
*,**,*, ***** , * " ***,*,***** " **** ** " ****** *****,***, .
CE GISLEESLQILNVKTPLNREEVEKHYEHLFNINDKSKGGTLYLQSKVFRAKERIDEEFGR
HP IQAQEDREKGQMPHT
*. .*...*.. ..*
CE IELKEEKKKEENAKTE
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA338859) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP02593> (SEQ ID Nos. 2, 12, and 22)
Determination of the whole base sequence of the cDNA
insert of clone HP02593 obtained from cDNA library of human
osteosarcoma cell line Saos-2 revealed the structure
consisting of a 103-by 5'-untranslated region, a 396-by ORF,
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and a 198-by 3'-untranslated region. The ORF codes for a
protein consisting of 131 amino acid residues and there
existed four putative transmembrane domains at the C-
terminus. Figure 2 depicts the hydrophobicity/hydrophilicity
5 profile, obtained by the Kyte-Doolittle method, of the
present protein. In vitro translation resulted in formation
of a translation product of a high molecular weight.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
10 protein was similar to a human OB-R gene-related protein
(E1~L Accession No. Y12670). Table 3 shows the comparison
between amino acid sequences of the human protein of the
present invention (HP) and the human OB-R gene-related
protein (OB) . Therein, the marks of -, *, and . represent a
15 gap, an amino acid residue identical with that of the
protein of the present invention, and an amino acid residue
similar to that of the protein of the present invention,
respectively. The both proteins shared a homology of 67.9%
in the entire region.
Table 3
HP MAGIKALISLSFGGAIGLMFLMLGCALPIYNKYWPLFVLFFYILSPIPYCIARRLVDDTD
***_***__*** ***** ******** *_ *******_*_ _****_ **.*
OB MAGVKALVALSFSGAIGLTFLMLGCALEDYGVYWPLFVLIFHAISPIPHFIAKRVTYDSD
HP AMSNACKELAIFLTTGIWSAFGLPIVFARAHLIEWGACALVLTGNTVIFATILGFFLVF
* *,**,*** *,**********,*,..**. .*.****,***,**,*** ** ****,*
OB ATSSACRELAYFFTTGIWSAFGFPVILARVAVIKWGACGLVLAGNAVIFLTIQGFFLIF
HP GSNDDFSWQQW
*..*****.**
OB GRGDDFSWEQW
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46
Furthermore, the search of the GenHank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA306490) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP10195> (SEQ ID Nos. 3, 13, and 23)
Determination of the whole base sequence of the cDNA
insert of clone HP10195 obtained from cDNA library of human
fibrosarcoma HT-1080 revealed the structure consisting of a
286-by 5'-untranslated region, a 729-by ORF, and a 604-by
3'-untranslated region. The ORF codes for a protein
consisting of 242 amino acid residues and there existed one
putative transmembrane domain at the C-terminus. Figure 3
depicts the hydrophobicity/hydrophilicity profile, obtained
by the Kyte-Doolittle method, of the present protein. In
vitro translation resulted in formation of a translation
product of 32 kDa that was somewhat larger than the
molecular weight of 27,300 predicted from the ORF. When
expressed in COS7 cells, an expression product of about 21
kDa was observed in the supernatant fraction and the
membrane fraction.
The search of the protein data base using the amino
acid sequence of the present protein has revealed the
registration of sequences that were similar to the Aplysia
VAP-33 (SWISS-PROT Accession No. P53173). Table 4 shows the
comparison between amino acid sequences of the human protein
of the present invention (HP) and the Aplysia VAP-33 (AP).
Therein, the marks of -, *, and . represent a gap, an amino
acid residue identical with that of the protein of the
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47
present invention, and an amino acid residue similar to that
of the protein of the present invention, respectively. The
both proteins shared a homology of 46.5% in the entire
region.
Table 4
HP MAKHEQILVLDPPTDLKFKGPFTDWTTNLKLRNPSDRKVCFKVKTTAPRRYCVRPNSGI
**,*** *,*,*,..*.********** " ***,**,**" *********,**********
AP MASHEQALILEPAGELRFKGPFTDVVTADLKLSNPTDRRICFKVRTTAPKRYCVRPNSGI
HP IDPGSTVTVSVMLQPFDYDPNEKSKHKFMVQTIFAPPNTSD-MEAVWKEAKPDELMDSKL
..* ....*.******,******,*******,..** .. . * .**.* *~~***~**
AP LEPKTSIAVAVMLQPFNYDPNEKNKHKFMVQSMYAPDHWESQELLWKDAPPESLMDTKL
HP RCVFEMPNENDKLNDMEPSK--------------AVPLNASKQDGPMPKP-HSVSLNDTE
*******..... . ..*. . .....* ... **. .*. ....
AP RCVFEMPDGSHQAPASDASRATDAGAHFSESALEDPTVASRKTETQSPKRVGAVGSAGED
HP TRKLMEECKRLQGEMMKLSEENRHLRDEGLRLRKVAHSD--KPGSTSTASFRDNVTSPLP
..** .* *. *.*. .*..**..*.***.****** .* .*.. .... ........*
AP VKKLQHELKKAQSEITSLKGENSQLKDEGIRLRKVAMTDTVSPTPLNPSPAPAAAVRAFP
HP SLLWIAAIFIGFFLGRFIL
... *,*** " *...***,*
AP PWYWAAIILGLIIGKFLL
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA447905) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP10423> (SEQ ID Nos. 4, 14, and 24)
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48
Determination of the whole base sequence of the cDNA
insert of clone HP10423 obtained from cDNA library of human
osteosarcoma cell line U-2 OS revealed the structure
consisting of a 64-by 5~-untranslated region, a 795-by ORF,
and a 207-by 3'-untranslated region. The ORF codes for a
protein consisting of 264 amino acid residues and there
existed a secretory signal at the N-terminus and one
putative transmembrane domain at the N-terminus. Figure 4
depicts the hydrophobicity/hydrophilicity profile, obtained
by the Kyte-Doolittle method, of the present protein. In
vitro translation resulted in formation of a translation
product of 30 kDa that was almost identical with the
molecular weight of 29,377 predicted from the ORF. When
expressed in COS7 cells, an expression product of about 3I
kDa was observed in the membrane fraction.
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. D80116) in ESTs, but, since they are
partial sequences, it can not be judged whether or not any
of these sequences codes for the same protein as the protein
of the present invention.
<HP10506> (SEQ ID Nos. 5, 15, and 25)
Determination of the whole base sequence of the cDNA
insert of clone HP10506 obtained from cDNA library of human
stomach cancer revealed the structure consisting of a 53-by
5'-untranslated region, a 339-by ORF, and a 226-by 3~-
untranslated region. The ORF codes for a protein consisting
of 112 amino acid residues and there existed one putative
transmembrane domain. Figure 5 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte-
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49
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 12 kDa that was almost identical with the molecular
weight of 11,821 predicted from the ORF. When expressed in
COS7 cells, an expression product of about 13 kDa was
observed in the membrane fraction.
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA282544) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP10507> (SEQ ID Nos. 6, 16, and 26)
Determination of the whole base sequence of the cDNA
insert of clone HP10507 obtained from cDNA library of human
stomach cancer revealed the structure consisting of a 412-by
5'-untranslated region, a 441-by ORF, and a 168-by 3~-
untranslated region. The ORF codes for a protein consisting
of 146 amino acid residues and there existed a secretory
signal at the N-terminus and one putative transmembrane
domain at the C-terminus. Figure 6 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte-
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 19 kDa that was somewhat larger than the molecular weight
of 16,347 predicted from the oRF.
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA424759) in ESTs, but, since they
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are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
5 <HP10548> (SEQ ID Nos. 7, 17, and 27)
Determination of the whole base sequence of the cDNA
insert of clone HP10548 obtained from cDNA~library of human
stomach cancer revealed the structure consisting of a 330-by
5'-untranslated region, a 1035-by ORF,
and a 67-by 3'-
10 untranslated region. The ORF codes for
a protein consisting
of 344 amino acid residues and there existed four putative
transmembrane domains. Figure 7 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte-
Doolittle method, of the present protein. In vitro
15 translation resulted in formation of a translation product
of a high molecular weight.
Furthermore, the search of the GenBank
using the base
sequences of the present cDNA has revealed
the registration
of sequences that shared a homology of 90% or more (for
20 example, Accession No. AA143152) in
ESTs, but, since they
are partial sequences, it can not be judged whether or
not
any of these sequences codes for the same protein as the
protein of the present invention.
25 <HP10566> (SEQ ID Nos. 8, 18, and 28)
Determination of the whole base sequence of the cDNA
insert of clone HP10566 obtained from cDNA library of the
human stomach cancer revealed the structure consisting of a
61-by 5'-untranslated region, a 294-by ORF, and a 246-by 3'-
30 untranslated region. The ORF codes for a protein consisting
of 97 amino acid residues and there existed one putative
transmembrane domain at the C-terminus. Figure 8 depicts the
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51
hydrophobicity/hydrophilicity profile, obtained by the Kyte-
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 12 kDa that was almost identical with the molecular
weight of 11,452 predicted from the ORF. When expressed in
COS7 cells, an expression product of about 12 kDa was
observed in the membrane fraction.
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for '
example, Accession No. W79821) in ESTs, but, since they are
partial sequences, it can not be judged whether or not any
of these sequences codes for the same protein as the protein
of the present invention.
<HP10567> (SEQ ID Nos. 9, 19, and 29)
Determination of the whole base sequence of the cDNA
insert of clone HP10567 obtained from cDNA library of the
human stomach cancer revealed the structure consisting of a
77-by 5'-untranslated region, a 375-by ORF, and a 133-by 3~-
untranslated region. The ORF codes for a protein consisting
of 124 amino acid residues and there existed one putative
transmembrane domain at the C-terminus. Figure 9 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte-
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 14 kDa that was almost identical with the molecular
weight of 14,484 predicted from the ORF.
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA428475) in ESTs, but, since they
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52
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP10568> (SEQ ID Nos. 10, 20, and 30)
Determination of the whole base sequence of the cDNA
insert of clone HP10568 obtained from cDNA library of the
human stomach cancer revealed the structure consisting of a
56-by 5 ~-untranslated region, a 984-by ORF, and a 60-by 3 ~-
untranslated region. The ORF codes for a protein consisting
of 327 amino acid residues and there existed a secretory
signal at the N-terminus and one putative transmembrane
domain at the C-terminus. Figure 10 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte-
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 36.5 kDa that was almost identical with the molecular
weight of 34,326 predicted from the ORF. In this case, the
addition of a microsome led to the formation of a product of
40 kDa which is considered to have a sugar chain being
attached. In addition, there exist in the amino acid
sequence of this protein two sites at which N-glycosylation
may occur (Asn-Leu-Thr at position 138 and Asn-Leu-Ser at
position 206). Application of the (-3,-1) rule, a method for
predicting the cleavage site of the secretory signal
sequence, allows to expect that the mature protein starts
from valine at position 24. When expressed in COS7 cells, an
expression product of about 31 kDa was observed in the
supernatant fraction and the membrane fraction.
The search of the protein data base using the amino
acid sequence of the present protein has revealed that the
protein was similar to the human cell-surface A33 antigen
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53
(SWISS-PROT Accession No. Q99795). Table 5 shows the
comparison between amino acid sequences of the human protein
of the present invention (HP) and the human cell-surface A33
antigen (A3). Therein, the marks of -, *, and . represent a
gap, an amino acid residue identical with that of the
protein of the present invention, and an amino acid residue
similar to that of the protein of the present invention,
respectively. The both proteins shared a homology of 30.0%
in the N-terminal region of 243 residues.
Table 5
HP MAELPGPFLCGALLGFLCLSGLAVEVKVPTEPLSTPLGKTAELTCTYSTSVGDSFAL-EW
*..*..* . *... **...*.*** **,... .* .*
A3 MVGKMWPVLWTLCAVRVTVDAISVETPQDVLRASQGKSVTLPCTYHTSTSSREGLIQW
HP SFVQPGKPISESHPILYFTNGHLYPTGSKSKRVSLLQNPPTVGVATLKLTDVHPSDTGTY
. . . .*. * *,* . * *. *. , * .. . *....... ,*,***
A3 DKLL--LTHTERWIWPFSNKN-YIHGELYKNRVSISNNAEQSDASITIDQLTMADNGTY
HP LCQVNNPPDFYTNGLGLINLTVLVPPSNPLCSQSGQTSVGGSTALRCSSSEGAPKPVYNW
* *. .*. .*. . ..* ******,* *, .*.* ,*....* * *.**,*,* *,*
A3 ECSVSLMSDLEGNTKSRVRLLVLVPPSKPECGIEGETIIGNNIQLTCQSKEGSPTPQYSW
HP VRLGTFPTPSPGSMVQDEVSGQLILTNLSLTSSGTYRCVATNQMGSASCELTLSVTEPS
* ... * ..* . . .. *.*.* ..** * *,..*. *.. *..*..* ,**
A3 KRYNILNQEQP--LAQPASGQPVSLKNISTDTSGYYICTSSNEEGTQFCNITVAVRSPSM
HP -QGRVAGALIGVLLGVLLLSVAAFCLVRFQKERGKKPKETYGGSDLREDAIAPGISEHTC
.* .**. ....... .*
A3 NVALYVGIAVGWAALIIIGIIIYCCCCRGKDDNTEDKEDARPNREAYEEPPEQLRELSR
HP MRADSSKGFLERPSSASTVTTTKSKLPMW
A3 EREEEDDYRQEEQRSTGRESPDHLDQ
Furthermore, the search of the GenHank using the base
sequences of the present cDNA has revealed the registration
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54
of sequences that shared a homology of 90% or more (for
example, Accession No. T24595) in ESTs, but, since they are
partial sequences, it can not be judged whether or not any
of these sequences codes for the same protein as the protein
of the present invention.
<HP01426> (SEQ ID Nos. 31, 41, and 51)
Determination of the whole base sequence of the cDNA
insert of clone HP01426 obtained from cDNA library of human
stomach cancer revealed the structure consisting of a 1-by
5'-untranslated region, a 942-by ORF, and a 122-by 3~-
untranslated region. The ORF codes for a protein consisting
of 313 amino acid residues and there existed a putative
secretory signal. Figure 11 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte-
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 36 kDa that was almost identical with the molecular
weight of 34, 955 predicted from the ORF. In this case, the
addition of a microsome led to the formation of a product of
38 kDa which is considered to have a sugar chain being
attached after secretion. In addition, there exists in the
amino acid sequence of this protein one site at which N-
glycosylation may occur (Asn-Ser-Ser at position 163).
Application of the (-3,-1) rule, a method for predicting the
cleavage site of the secretory signal sequence, allows to
expect that the mature protein starts from tryptophan at
position 17. When expressed in COS7 cells, an expression
product of about 39 kDa was observed in the supernatant
fraction and the membrane traction.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
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protein was similar to the Xenopus laevis cortical granule
lectin (EMBL Accession No. X82626}. Table 6 shows the
comparison between amino acid sequences of the human protein
of the present invention (HP) and the X. laevis cortical
5 granule lectin (XL). Therein, the marks of -, *, and
represent a gap, an amino acid residue identical with that
of the protein of the present invention, and an amino acid
residue similar to that of the protein of the present
invention, respectively. The both proteins shared a homology
10 of 67.9% in the region other than the N-terminal region.
Table 6
HP MNQLSFLLFLIATTRGWSTDEANTYFKEWTCSSSPSLPRSCKEIKDECPSAFDGLYFLRT
15 * ** * ********, ,* **,* * ,
XL MLVHILLLLVTGGLSQSCEPWIVASKNMVKQLDCDKFRSCKEIKDSNEEAQDGIYTLTS
HP ENGVIYQTFCDMTSGGGGWTLVASVHENDMRGKCTVGDRWSSQQGSKADYPEGDGNWANY
..*. ******** " *************,* ****,********* " *************
XL SDGISYQTFCDMTTNGGGWTLVASVHENNMAGKCTIGDRWSSQQGNRADYPEGDGNWANY
20 HP NTFGSAEAATSDDYKNPGYYDIQAKDLGIWHVPNKSPMQHWRNSSLLRYRTDTGFLQTLG
****** " **************,* ,**,******,*, ****** **** " *,* ,
XL NTFGSAGGATSDDYKNPGYYDIEAYNLGVWHVPNKTPLSVWRNSSLQRYRTTDGILFRHG
HP HNLFGIYQKYPVKYGEGKCWTDNGPVIPWYDFGDAQKTASYYSPYGQREFTAGFVQFRV
*** " *, ****** *,* ,*,** " *****,*,*, ***,*** ...**.*..***
25 XL GNLFSLYRIYPVKYGIGSCSKDSGPTVPWYDLGSAKLTASFYSPDFRSQFTPGYIQFRP
HP FNNERAANALCAGMRVTGCNTEHHCIGGGGYFPEASPQQCGDFSGFDWSGYGTHVGYSSS
*,*,** ***,**,...**.** ***********,*,*****,..*..****, *..
XL INTEKA.ALALCPGMKMESCNVEHVCIGGGGYFPEADPRQCGDFAAYDFNGYGTKRFNSAG
HP REITEAAVLLFYR
30 ***********
XL IEITEAAVLLFYL
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Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. 806009 ) in ESTs, but, since they are
partial sequences, it can not be judged whether or not any
of these sequences codes for the same protein as the protein
of the present invention.
<HP02515> (SEQ ID Nos. 32, 42, and 52)
Determination of the whole base sequence of the cDNA
insert of clone HP02515 obtained from cDNA library of human
osteosarcoma cell line Saos-2 revealed the structure
consisting of a 176-by 5'-untranslated region, a 690-by ORF,
and a 71-by 3'-untranslated region. The ORF codes for a
protein consisting of 229 amino acid residues and there
existed a putative secretory signal at N-terminus and one
putative transmembrane domain at the C-tern~inus. Figure 12
depicts the hydrophobicity/hydrophilicity profile, obtained
by the Kyte-Doolittle method, of the present protein. In
vitro translation resulted in formation of a translation
product of 27 kDa that was almost identical with the
molecular weight of 26,000 predicted from the ORF. In this
case, the addition of a microsome led to the formation of a
product of 25.5 kDa from which the secretory signal is
considered to have been cleaved. Application of the (-3,-1)
rule, a method for predicting the cleavage site of the
secretory signal sequence, allows to expect that the mature
protein starts from phenylalanine at position 28.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the human T1/ST2 receptor binding
protein (GenBank Accession No. U41804). Table 7 shows the
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57
comparison between amino acid sequences of the human protein
of the present invention (HP) and the human T1/ST2 receptor
binding protein (T1). Therein, the marks of -, *, and
represent a gap, an amino acid residue identical with that
of the protein of the present invention, and an amino acid
residue similar to that of the protein of the present
invention, respectively. The both proteins shared a homology
of 55.8% in the entire region.
Tabie 7
HP MGDKIWLPFPVLLLAALPPVLLPGAAGFTPSLDSDFTFTLPAGQKECFYQPMPLKASLE
*.... ** ,*** , *,** ,* *" *** ****,*,****, * ,****
T1 MMAAGAALALALWLL--MPPVEV-GGAGPPPIQDGEFTFLLPAGRKQCFYQSAPANASLE
HP IEYQVLDGAGLDIDFHLASPEGKTLVFEQRKSDGVHTVE-TEVGDYMFCFDNTFSTISEK
,****" *****,** *,**,* ** * **,******* **,***" ****,*******
T1 TEYQVIGGAGLDVDFTLESPQGVLLVSESRKADGVHTVEPTEAGDYKLCFDNSFSTISEK
HP VIFFELILDNMGEQAQEQEDWKKYITGTDILDMKLEDILESINSIKSRLSKSGHIQILLR
..*****.*.. ....* *.* . .. ...**.*.*** ***.....**..* .. .***
T1 LVFFELIFDSL-QDDEEVEGWAEAVEPEEMLDVKMEDIKESIETMRTRLERSIQMLTLLR
HP AFEARDRNIQESNFDRVNFWSMVNLVVMVWSAIQVYMLKSLFEDKRKSRT
********,**,*"****** **"*...*...**. **"*,*** ,*
T1 AFEARDRNLQEGNLERVNFWSAVNVAVLLLVAVLQVCTLKRFFQDKRPVPT
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA381943) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
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58
<HP02575> (SEQ ID Nos. 33, 43, and 53)
Determination of the whole base sequence of the cDNA
insert of clone HP02575 obtained from cDNA library of human
osteosarcome cell line Saos-2 revealed the structure
consisting of a 55-by 5'-untranslated region, a 1404-by ORF,
and a 219-by 3'-untranslated region. The ORF codes for a
protein consisting of 467 amino acid residues and there
existed a putative secretory signal at the N-terminus.
Figure 13 depicts the hydrophobicity/hydrophilicity profile,
obtained by the Kyte-Doolittle method, of the present
protein. In vitro translation resulted in formation of a
translation product of 52 kDa that was almost identical with
the molecular weight of 54,065 predicted from the ORF. In
this case, the addition of a microsome led to the formation
of a product of 57 kDa which is considered to have a sugar
chain being attached afetr secretion. In addition, there
exist in the amino acid sequence of this protein three sites
at which N-glycosylation may occur (Asn-Arg-Thr at position
171, Asn-Ser-Thr at position 239 and Asn-Asp-Thr at position
377). Application of the (-3,-1) rule, a method for
predicting the cleavage site of the secretory signal
sequence, allows to expect that the mature protein starts
from histidine at position 29. When expressed in COS7 cells,
an expression product of about 55 kDa was observed in the
supernatant fraction.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the human a -L-fucosidase (SWISS-PROT
Accession No. P04066). Table 8 shows the comparison between
amino acid sequences of the human protein of the present
invention ( HP ) and the human a -L-fucosidase ( FC ) . Therein,
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59
the marks of -, *, and . represent a gap, an amino acid
residue identical with that of the protein of the present
invention, and an amino acid residue similar to that of the
protein of the present invention, respectively. The both
proteins shared a homology of 54.8% in the entire region.
Table 8
HP MRPQELPRLAFPLLLLLLLLLPPPPC-PAHSATRFDPTWESLDARQLPAWFDQAKFGIFI
,******,* .. . .*... *..*.* ***,*,******,****,**
FC MRSRPAGPALLLLLLFLGAAESVRRAQPPRRYTPDWPSLDSRPLPAWFDEAKFGVFI
HP HWGVFSVPSFGSEWFWWYWQKEKIPKYVEFMKDNYPPSFKYEDFGPLFTAKFFNANQWAD
******** " *******,** * *,* **,*****,*,*,**** ***,**,...***
FC HWGVFSVPAWGSEWFWWHWQGEGRPQYQRFMRDNYPPGFSYADFGPQFTARFFHPEEWAD
HP IFQASGAKYIVLTSKHHEGFTLWGSEYSWNWNAIDEGPKRDIVKELEVAIRNRTDLRFGL
***,****,***,******* * * *****, * **,**,* ** " *,*,* ..*.**
FC LFQAAGAKYWLTTKHHEGFTNWPSPVSWNWNSKDVGPHRDLVGELGTALRRR-NIRYGL
HP YYSLFEWFHPLFLEDESSSFHKRQFPVSRTLPELYELVNNYQPEVLWSDGDGGAPDQYWN
*,**,******,* *,...*....* .**.****,***,*,*,..****, , ** ***
FC YHSLLEWFHPLYLLDKKNGFKTQHFVSAKTMPELYDLVNSYKPDLIWSDGEWECPDTYWN
HP STGFLAWLYNESPVRGTWTNDRWGAGSICKHGGFYTCSDRYNPGHLLPHKWENCMTIDK
**,**,****,***,..**,*****,.. *.***,*,*,*,..* * **** * ,***
FC STNFLSWLYNDSPVKDEVVVNDRWGQNCSCHHGGYYNCEDKFKPQSLPDHKWEMCTSIDK
HP LSWGYRREAGISDYLTIEELVKQLVETVSCGGNLLMNIGPTLDGTISWFEERLRQMGSW
,******, ..** . .*....**.*** *** *,***** ** * ,*,*** " *,*
FC FSWGYRRDMALSDVTEESEIISELVQTVSLGGNYLLNIGPTKDGLIVPIFQERLLAVGKW
HP LKVNGEAIYETHTWRSQNDTVTPDVWYTSKPKEKLVYAIFLKWPTSGQLFLGHPKAILGA
* " ****** ** * * ****** , ****** **
.... .. .. . . .. . .. ..
FC LSINGEAIYASKPWRVQWEKNTTSVWYTSKGSA--VYAIFLHWPENGVLNLESPITT-ST
HP TEVKLLGHGQPLNWISLEQNGIMVELPQLTIHQMPCKWGWALALTNVI
*....** *.* . ..*....****. ..* ...*.. **.*
FC TKITMLGIQGDLKWSTDPDKGLFISLPQLPPSAVPAEFAWTIKLTGVK
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sa
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. N28668) in ESTs, but, since they are
partial sequences, it can not be judged whether or not any
of these sequences codes for the same protein as the protein
of the present invention.
<HP10357> (SEQ ID Nos. 34, 44, and 54)
Determination of the whole base sequence of the cDNA
insert of clone HP10357 obtained from cDNA library of human
stomach cancer revealed the structure consisting of a 113 -by
5'-untranslated region, a 300-by ORF, and a 54-by 3'-
untranslated region. The ORF codes for a protein consisting
of 99 amino acid residues and there existed two putative
transmembrare domains. Figure 14 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte-
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 11 kDa that was almost identical with the molecular
weight of 10,923 predicted from the ORF.
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA477156) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP10447> (SEQ ID Nos. 35, 45, and 55)
Determination of the whole base sequence of the cDNA
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61
insert of clone HP10447 obtained from cDNA library of human
liver revealed the structure consisting of a 271-by 5~-
untranslated region, a 570-by ORF, and a 34-by 3~-
untranslated region. The ORF codes for a protein consisting
of 189 amino acid residues and there existed five putative
transmembrare domains. Figure 15 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of high molecular weight.
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA296976) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP10477> (SEQ ID Nos. 36, 46, and 56)
Determination of the whole base sequence of the cDNA
insert of clone HP10477 obtained from cDNA library of human
liver revealed the structure consisting of a 149-by 5~-
untranslated region, a 1092-by ORF, and a 15-by 3~-
untranslated region. The ORF codes for a protein consisting
of 363 amino acid residues and there existed one putative
transmembrane domain at the N-terminus. Figure 16 depicts
the hydrophobicity/hydrophilicity profile, obtained by the
Kyte-Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 40 kDa that was almost identical with the molecular
weight of 39,884 predicted from the ORF.
The search of the protein data base using the amino
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62
acid sequence of the present protein revealed that the
protein was similar to the human peptidoglycan recognition
protein (GenBank Accession No. AF076483). Table 9 shows the
comparison between amino acid sequences of the human protein
of the present invention (HP) and the human peptidoglycan
recognition protein (PG}. Therein, the marks of -, *, and .
represent a gap, an amino acid residue identical with that
of the protein of the present invention, and an amino acid
residue similar to that of the protein of the present
invention, respectively. The both proteins shared a homology
of 54.8% in the entire region.
Table 9
HP MVDSLLAVTLAGNLGLTFLRGSQTQSHPDLGTEGCWDQLSAPRTFTLLDPKASLLTKAFL
HP NGALDGVILGDYLSRTPEPRPSLSHLLSQYYGAGVARDPGFRSNFRRQNGAALTSASILA
HP QQVWGTLVLLQRLEPVHLQLQCMSQEQLAQVAANATKEFTEAFLGCPAIHPRCRWGAAPY
*" * ** * * ,
PG MSRRSMLLAWALPSLLRLGAAQETEDPACCSPIVPRNEWKALA-
HP RGRPRLLQLPLGFLYVHHTYVPAPPCTDFTRCAANMRSMQRYHQDTQGWGDIGYSFWGS
.. .. * *** ., * ** ....*.. ..*... *..*.** ,* ** *,**,*" *.
PG SECAQHLSLPLRYVWSHT--AGSSCNTPASCQQQARNVQHYHMKTLGWCDVGYNFLIGE
HP DGYVYEGRGWHWVGAHTLGH-NSRGFGVAIVGNYTAALPTEAALRTVRDTLPSCAVRAGL
** *******...***, *....*....*** . .** .*.*.... * .*,* .*
PG DGLVYEGRGWNFTGAHSGHLWNPMSIGISFMGNYMDRVPTPQAIRAAQGLL-ACGVAQGA
HP LRPDYALLGHRQLVRTDCPGDALFDLLRTWPHFTATVKPRPARSVSKRSRREPPPRTLPA
**"*,* ***" ** ,**"*..*...***,
PG LRSNYVLKGHRDVQRTLSPGNQLYHLIQNWPHYRSP
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
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63
of sequences that shared a homology of 90% or more (for
example, Accession No. AA424759) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP10513> (SEQ ID Nos. 37, 47, and 57)
Determination of the whole base sequence of the cDNA
insert of clone HP10513 obtained from cDNA library of human
stomach cancer revealed the structure consisting of a 134-by
5'-untransiated region, a 750-by ORF, and a 0-by 3'-
untranslated region. The ORF codes for a protein consisting
of 249 amino acid residues and there existed one putative
transmembrane domain at the N-terminus. Figure 17 depicts
the hydrophobicity/hydrophilicity profile, obtained by the
Kyte-Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 29 kDa that was almost identical with the molecular
weight of 27,373 predicted from the ORF.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the human hypothetical protein
KIAA0512 (GenHank Accession No. AB011084). Table 10 shows
the comparison between amino acid sequences of the human
protein of the present invention (HP) and the human
hypothetical protein KIAA0512 (KI). Therein, the marks of -,
*, and . represent a gap, an amino acid residue identical
with that of the protein of the present invention, and an
amino acid residue similar to that of the protein of the
present invention, respectively. The both proteins shared a
homology of 31.6% in the C-terminal region of 196 amino acid
residues.
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Table 10
HP MGGPRGAGWVAAGLLLGAGACYCIYRLTRGRRRG
KI RGRGRRPVAMQKRPFPYEIDEILGVRDLRKVLALLQKSDDPFIQQVALLTLSNNANYSCN
HP DRELGIRSSKSAEDLTDGSYDDVLNAEQLQKLLYLLESTEDPVIIERALITLGNNAAFSV
* .....* . * *. *.. .. . .. ..
KI QETIRKLGGLPIIANMINKTDPHIKEKALMAMNNLSENYENQGRLQVYMNRVMDDIMASN
HP NQAIIRELGGIPIVANKINHSNQSIKEKALNALNNLSVNVENQIKIKVQVLRLLLNLSEN
.. .. .* ... .*... * . ...... ... .. **** " **,* * " **
KI LNSAVQWGLKFLTNMTITNDYQHLLVNSIANF--FRLLSQGGGKIKVEILKILSNFAEN
HP PAMTEGLLRAQVDSSFLSLYDSHVAKEILLRVLTLFQNIKNCLKIEGHLAVQPTFTEGSL
*,* , ** " ** ,** ***,*,* " ***,..****, * , *, * , ..*..***
KI PDMLKRLLSTQVPASFSSLYNSYVESEILINALTLFEIIYDNLRAE--VFNYREFNKGSL
HP FFL-LHGEECAQKIRALVDHHDAEVKEKWTIIPKI
*.* .. *..*****,.*** ** **.... *.
KI FYLCTTSGVCVRKIRALANHHDLLVRVKVIKLVNRF
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession .No. N92228) in ESTs, but, since they are
partial sequences, it can not be judged whether or not any
of these sequences codes for the same protein as the protein
of the present invention.
<HP10540> (SEQ ID Nos. 38, 48, and 58)
Determination of the whole base sequence of the cDNA
insert of clone HP10540 obtained from cDNA library of human
osteosarcoma cell line Saos-2 revealed the structure
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consisting of a 47-by 5'-untranslated region, a 297-by ORF,
and a 245-by 3'-untranslated region. The ORF codes for a
protein consisting of 98 amino acid residues and there
existed two putative transmembrane domains. Figure 18
5 depicts the hydrophobicity/hydrophilicity profile, obtained
by the Kyte-Doolittle method, of the present protein. In
vitro translation resulted in formation of a translation
product of high molecular weight.
The search of the protein data base using the amino
10 acid sequence of the present protein revealed that the
protein was similar to the Caenorhabditis elegans
hypothetical protein CEF49CI2.12 (GenHank Accession No.
Z68227). Table 11 shows the comparison between amino acid
sequences of the human protein of the present invention (HP)
15 and the C. elegans hypothetical protein CEF49C12.12 (CE).
Therein, the marks of -, *, and . represent a gap, an amino
acid residue identical with that of the protein of the
present invention, and an amino acid residue similar to that
of the protein of the present invention, respectively. The
20 both proteins shared a homology of 36.1% in the entire
region.
Table 11
25 HP M-ASLLCCGPKLAACGIVLSAWGVIMLIMLGIFFNVHSAVLIEDVPFTERDFENGPQNIY
* *** * * * **** * ** **
CE MGKICPLMGPKMSAFCMVMSVWGVIFLGLLGVFFYIQAVTLFPDLHF-EGHGKVPSSVID
HP NLYEQVSYNCFIAAGLYLLLGGFSFCQVRLNKRKEYMVR
* * ****** * * **
30 CE AKYNEKATQCWIAAGLYAVTLIAVFWQ---NKYNTAQIF
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Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA420715) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP10557> (SEQ ID Nos. 39, 49, and 59)
Determination of the whole base sequence of the cDNA
insert of clone FiP10557 obtained from cDNA library of human
stomach cancer revealed the structure consisting of a 24-by
5'-untranslated region, a 519-by ORF, and a 130-by 3'-
untranslated region. The ORF codes for a protein consisting
of 172 amino acid residues and there existed a putative
secretory signal at the N-terminus. Figure 19 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte-
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 32 kDa that was larger than the molecular weight of
18,844 predicted from the ORF. In this case, the addition of
a microsome led to the formation of a product of 39 kDa
which is considered to have been subjected to some
modification after secretion. In addition, there exist in
the amino acid sequence of this protein no site at which N-
glycosylation may occur. Application of the (-3,-1) rule, a
method for predicting the cleavage site of the secretory
signal sequence, allows to expect that the mature protein
starts from glycine at position 32. When expressed in COS7
cells, an expression product of about 20 kDa was observed in
the supernatant fraction and the membrane fraction.
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The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the human progesterone binding
protein (EMBL Accession No. AJ002030). Table 12 shows the
comparison between amino acid sequences of the human protein
of the present invention (HP) and the human progesterone
binding protein (PG). Therein, the marks of -, *, and
represent a gap, an amino acid residue identical with that
of the protein of the present invention, and an amino acid
residue similar to that of the protein of the present
invention, respectively. The both proteins shared a homology
of 30.5% in the C-terminal region of 151 amino acid residues.
Table 12
HP MVGPAP
PG MAAGDGDVKLGTLGSGSESSNDGGSESPGDAGAAAEGGGWAAAALALLTGGGEMLLNVAL
HP RRRLRPLA,ALALVLALAPGLPTARAGQTPRPAERGPPV--RLFTEEELARYGGEEEDQPI
** .. .. . .**.. *.. * *. *.* .*.* . ...*
PG VALVLLGAYRLWRWGRRGLGAGAGAGEESPATSLPRMKKRDFSLEQLRQYDG-SRNPRI
HP YLAVKGWFDVTSGKEFYGRGAPYNALTGKDSTRGVAKMSLDPADLTHDTTGLTAKELEA
***,* *****.*..***...**. ..*.*..**.*...** ..* .. ..*.. .
PG LLAVNGKVFDVTKGSKFYGPAGPYGIFAGRDASRGLATFCLDKDALRDEYDDLSDLNAVQ
HP LDEV--FTKVYKAKYPIVGYTARRILNEDGSPNLDFKPEDQPHFDIKDEF
...* ... .*.** .*.. *.*. ...*. ... *.... . *..
PG MESVREWEMQFKEKY---DYVG-RLLKPGEEPS-EYTDEEDTKDHNKQD
Furthermore, the search of the GenHank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (far
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example, Accession No. AA101709) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP10563> (SEQ ID Nos. 40, 50, and 60)
Determination of the whole base sequence of the cDNA
insert of clone HP10563 obtained from cDNA library of human
osteosarcoma cell line Saos-2 revealed the structure
consisting of a 126-by 5'-untranslated region, a 363-by ORF,
and a 936-by 3'-untranslated region. The ORF codes for a
protein consisting of 120 amino acid residues and there
existed two putative transmembrane domains. Figure 20
depicts the hydrophobicity/hydrophilicity profile, obtained
by the Kyte-Doolittle method, of the present protein. In
vitro translation resulted in formation of a translation
product of 18.5 kDa that was larger than the molecular
weight of 13,180 predicted from the ORF.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the Arabidopsis thaliana hypothetical
protein F27F23.15 (GenBank Accession No. AC003058). Table 13
shows the comparison between amino acid sequences of the
human protein of the present invention (HP) and the A.
thaliana hypothetical protein F27F23.15 (AT). Therein, the
marks of -, *, and . represent a gap, an amino acid residue
identical with that of the protein of the present invention,
and an amino acid residue similar to that of the protein of
the present invention, respectively. The both proteins
shared a homology of 35.5% in the entire region.
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Table 13
HP MMPSRTNLATGIPSSKVKYSRLSSTDDGYIDLQFKRTPPKIPYKAIALATVLFLIGAFLI
*..* ~*. . ... . * *.*_**_ *___*
AT MAYVDHAFSISDEDLMIGTSY-TVSNRPPVKEISLAVGLLVFGTLGI
HP IIGSLLLSGYISKGGADRAVPVLIIGILVFLPGFYHLRIAYYASKGYRGYSYDDIPDFDD
..* .. . .. *. .... ...* *.*.****, ****** ***,*,*,..**
AT VLGFFMAYNRVG-GDRGHGIFFIVLGCLLFIPGFYYTRIAYYAYRGYKGFSFSNIPSV
Furthermore, the search of the GenBank using the base
seguences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA083574) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP01467> (SEQ ID Nos. 61, 71, and 81)
Determination of the whole base sequence of the cDNA
insert of clone HP01467 obtained from cDNA library of human
fibrosarcoma cell line HT-1080 revealed the structure
consisting of a 65-by 5'-untranslated region, a 924-by ORF,
and a 447-by 3'-untranslated region. The ORF codes for a
protein consisting of 307 amino acid residues and there
existed three putative transmembrane domains. Figure 21
depicts the hydrophobicity/hydrophilicity profile, obtained
by the Kyte-Doolittle method, of the present protein. In
vitro translation resulted in formation of a translation
product of high molecular weight.
The search of the protein data base using the amino
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acid sequence of the present protein revealed that the
protein was similar to the rat Sec22 homologue (GenHank
Accession No. U42209). Table 14 shows the comparison between
amino acid sequences of the human protein of the present
invention (HP) and the rat Sec22 homologue (RN). Therein,
the marks of -, *, and . represent a gap, an amino acid
residue identical with that of the protein of the present
invention, and an amino acid residue similar to that of the
protein of the present invention, respectively. The both
proteins shared a homology of 94.6% in the N-terminal region
of 241 amino acid residues. The protein of the present
invention was longer .by 53 amino acids at the C-terminus
than the rat Sec22 homologue.
Table 14
HP MSMILSASVIRVRDGLPLSASTDYEQSTGMQECRKYFKMLSRKLAQLPDRCTLKTGHYNI
*********,*************,***,*.****************,********* " **
RN MSMILSASVVRVRDGLPLSASTDCEQSAGVQECRKYFKMLSRKLAQFPDRCTLKTGRHNI
HF NFISSLGVSYMMLCTENYPNVLAFSFLDELQKEFITTYNMMKTNTAVRPYCFIEFDNFIQ
************************************************************
RN NFISSLGVSYMMLCTENYPNVLAFSFLDELQKEFITTYNMMKTNTAVRPYCFIEFDNFIQ
HP RTKQRYNNPRSLSTKINLSDMQTEIKLRPPYQISMCELGSANGVTSAFSVDCKGAGKISS
********************** **********,**************************
RN RTKQRYNNPRSLSTKINLSDMQMEIKLRPPYQIPMCELGSANGVTSAFSVDCKGAGKISS
HP AHQRLEPATLSGIVGFILSLLCGALNLIRGFHAIESLLQSDGDDFNYIIAFFLGTAACLY
**************,***************************,**,*,************
RN AHQRLEPATLSGIVAFILSLLCGALNLIRGFHAIESLLQSDGEDFSYMIAFFLGTAACLY
HP QCYLLVYYTGWRNVKSFLTFGLICLCNMYLYELRNLWQLFFHVTVGAFVTLQIWLRQAQG
RN QMICLCLQGRKERT
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Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA421925) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP01956> (SEQ ID Nos. 62, 72, and 82)
Determination of the whole base sequence of the cDNA
insert of clone HP01956 obtained from cDNA library of human
liver revealed the structure consisting of a 86-by 5~-
untranslated region, a 552-by ORF, and a 359-by 3~-
untranslated region. The ORF codes for a protein consisting
of 183 amino acid residues and there existed one putative
transmembrane domain. Figure 22 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte-
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 20.5 kDa that was almost identical with the molecular
weight of 20,073 predicted from the ORF.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the yeast hypothetical protein 21.5
kDa (SWISS-PROT Accession No. P53073). Table 15 shows the
comparison between amino acid sequences of the human protein
of the present invention (HP) and the yeast hypothetical
protein 21.5 kDa (SC). Therein, the marks of -, *, and
represent a gap, an amino acid residue identical with that
of the protein of the present invention, and an amino acid
residue similar to that of the protein of the present
invention, respectively. The both proteins shared a homology
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of 34.3% in the C-terminal region of 108 amino acid residues.
Table 15
HP MTAQGGLVANRGRRFRWAIELSGPGGGSRGRSDRGSGQGDSLYPVGYLDKQVPDTS
SC MSEQEPYEWAKHLLDTKYIEKYNIQNSNTLPSPPGFEGNSSKGNVTRKQQDATSQTTSLA
HP VQETDRILVEKRCWDIALGPLKQIPMNLFIMYMAGNTISIFPTMMVCMMAWRpIQALMAI
.* .. *.*** * * ****,*. **,*... *.*.* . *. ** *,...
SC QKNQITVLQVQKAWQIALQPAKSIPMNIFMSYMSGTSLQIIPIMTALMLLSGPIKAIFST
HP SATFK--MLESSSQKFLQGLVYLIGNLMGLALAV-Y-KCQSMGLLPTHASDWLAFIEPPE
...** . ....*. .*. ... . *. . . * * ,****.*, ,***,
SC RSAFKPVLGNKATQSQVQTAMFMYIVFQGVLMYIGYRKLNSMGLIPNAKGDWLPWERIAH
HP RMEFSGGGLLL
SC YNNGLQWFSD
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AAI59753) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP02545> (SEQ ID Nos. 63, 73, and 83)
Determination of the whole base sequence of the cDNA
insert of clone HP02545 obtained from cDNA library of human
osteosarcoma cell line Saos-2 revealed the structure
consisting of a 133-by 5'-untranslated region, a 984-by ORF,
and a 636-by 3'-untranslated region. The ORF codes for a
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protein consisting of 327 amino acid residues and there
existed a putative secretory signal at the N-terminus and
one putative transmembrane domain at the C-terminus. Figure
23 depicts the hydrophobicity/hydrophilicity profile,
obtained by the Kyte-Doolittle method, of the present
protein.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the rat embigin (E1~L Accession No.
AJ009698). Table 16 shows the comparison between amino acid
sequences of the human protein of the present invention (HP)
and the rat embigin (RN). Therein, the marks of -, *, and .
represent a gap, an amino acid residue identical with that
of the protein of the present invention, and an amino acid
residue similar to that of the protein of the present
invention, respectively. The both proteins shared a homology
of 65.4% in the entire region.
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Table 16
HP MRALPGLLEARARTPRLLLLQCLLAAARPSSADGSAPDSPFTSPPLREEIMAN--NFSLE
**, ,** , *,. ,**** ,****,**" * *,..**,*** *,***,**, *,***
RN MRSHTGLRALVAPGCSLLLL-YLLAATRPDRAVGDPADSAFTSLPVREEMMAKYANLSLE
HP SHNISLTEHSSMPVEKNITLERPSNVNLTCQFTTSGDLNAVNVTWKKDGEQLE--NNYLV
..******..... *.********,..*.* **...*. ..*******., ** ,.. .
RN TYNISLTEQTRVS-EQNITLERPSHLELECTFTATEDVMSMNVTWKKDDALLETTDGFNT
HP SATGSTLYTQYRFTIINSKQMGSYSCFFREEKEQRGTFNFKVPELHGKNRpLISYVGDST
. *,***,***** " ******,****, ** ***** " ** " ********,******
RN TKMGDTLYSQYRFTVFNSKQMGKYSCFLGEE--LRGTFNIRVPRVHGKNKPLITYVGDST
HP VLTCKCQNCFPLNWTWYSSNGSVKVPVGVQM-NKYVINGTYANETKLKITQLLEEDGESY
**,*,****,******* ***,..**..*.. .*. ***,********,..******,**
RN VLKCECQNCLPLNWTWYMSNGTAQVPIDVHVNDKFDINGSYANETKLKVKHLLEEDGGSY
HP WCRALFQLGESEEHIELWLSYLVPLKPFLVIVAEVILLVATILLCEKYTQKKKKHSDEG
**** *,********,***** " *******,*,********,***** ******,..*.*
RN WCRAAFPLGESEEHIKLWLSFMVPLKPFLAIIAEVILLVAIILLCEVYTQKKRNDPDDG
HP KEFEQIEQLKSDDSNGIENNVPRHRKNESLGQ
*********************** **
RN KEFEQIEQLRSDDSNGIENNVPRYRKTDSGDQ
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA312629) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP02551> (SEQ ID Nos. 64, 74, and 84)
Determination of the whole base sequence of the cDNA
insert of clone HP02551 obtained from cDNA library of human
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osteosarcoma cell line Saos-2 revealed the structure
consisting of a 61-by 5~-untranslated region, a 672-by ORF,
and a 384-by 3'-untranslated region. The ORF codes for a
protein consisting of 223 amino acid residues and there
5 existed a putative secretory signal at the N-terminus.
Figure 24 depicts the hydrophobicity/hydrophilicity profile,
obtained by the Kyte-Doolittle method, of the present
protein. In vitro translation resulted in formation of a
translation product of 27 kDa that was somewhat larger than
10 the molecular weight of 24,555 predicted from the ORF. In
this case, the addition of a microsome led to the formation
of a product of 26 kDa from which the secretory signal is
considered to have been cleaved. Application of the (-3,-1)
rule, a method for predicting the cleavage site of the
15 secretory signal sequence, allows to expect that the mature
protein starts from glutamine at position 20.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the mouse FGF binding protein
20 (GenBank Accession No. U49641). Table 17 shows the
comparison between amino acid sequences of the human protein
of the present invention (HP) and the mouse FGF binding
protein (lei) . Therein, the marks of -, *, and . represent a
gap, an amino acid residue identical with that of the
25 protein of the present invention, and an amino acid residue
similar to that of the protein of the present invention,
respectively. The both proteins shared a homology of 21.2%
in the entire region other than the N-terminal region. In
particular, all the eight cysteine residues contained in the
30 both proteins were conserved.
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Table 17
HP MKFVPCLLLVTLSCLGTLGQAPRQKQGST
..**. . .* . ...
MM MRLHSLILLSFLLLATQAFSEKVRKRAKNAPHSTAEEGVEGSAPSLGKAQNKQRSRTSKS
HP GEEFHFQTGGRDSCTMRPSSLGQGAGEVWLRVDCRNTDQTYWCEYRGQPSMCQAFAADPK
.. .* * ....* . ...... .. * *.* ..**.. * . *.*. * . * .
MM LTHGKFVTKDQATC---RWAVTEEEQGISLKVQCTQADQEFSCVFAGDPTDCLRHDKD-Q
HP SYWNQALQELRRLHHACQGA-PVLRPSVCREAGPQAHMQQVTSSLKGSPEPNQQPEAGTP
**.*. ..**. .. *..* .**...***, *..... *... .*...*... .. ..
MM IYWKQVARTLRKQKNICRDAKSVLKTRVCRKRFPESNLKLVNPNARGNTKPRKEKAEVSA
HP SLRPKATVKLTEATQLGKDSMEELGKAKPTTRPTAKPTQPGPRPGGNEEAKKKAWEHCWK
. . *. ...... *... .*. * . *. * . .. *. .. .*.* * * .
MM REHNKVQEAVSTEPNRIKEDI-TLNPAATQTM-TIRDPECLEDPDVLNQ-RKTALEFCGE
HP PFQALCAFLISFFRG
.. ..*.*.......
MM SWSSICTFFLNMLQATSC
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA317400} in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP02631> (SEQ ID Nos. 65, 75, and 85)
Determination of the whole base sequence of the cDNA
insert of clone HP02631 obtained from cDNA library of human
osteosarcoma cell line Saos-2 revealed the structure
consisting of a 42-by 5'-untranslated region, a 147-by ORF,
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and a 1191-by 3'-untranslated region. The ORF codes for a
protein consisting of 48 amino acid residues and there
existed a putative secretory signal at the N-terminus.
Figure 25 depicts the hydrophobicity/hydrophilicity profile,
obtained by the Kyte-Doolittle method, of the present
protein. In vitro translation resulted in formation of a
translation product of 10 kDa or less.
Furthermore, the search of the GenHank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA156969) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP02632> (SEQ ID Nos. 66, 76, and 86)
Determination of the whole base sequence of the cDNA
insert of clone HP02632 obtained from cDNA library of human
fibrosarcoma cell line HT-1080 revealed the structure
consisting of a 50-by 5'-untranslated region, a 1116-by ORF,
and a 337-by 3'-untranslated region. The ORF codes for a
protein consisting of 371 amino acid residues and there
existed eight putative transmembrane domains. Figure 26
depicts the hydrophobicity/hydrophilicity profile, obtained
by the Kyte-Doolittle method, of the present protein. In
vitro translation resulted in formation of a translation
product of high molecular weight.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the Caenorhabditis elegans
hypothetical protein CELC2H12 (GenBank Accession No. U23169).
Table 18 shows the comparison between amino acid sequences
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of the human protein of the present invention (HP) and the C.
elegans hypothetical protein CELC2H12 (CE). Therein, the
marks of -, *, and . represent a gap, an amino acid residue
identical with that of the protein of the present invention,
and an amino acid residue similar to that of the protein of
the present invention, respectively. The both proteins
shared a homology of 51.4% in the entire region.
Table 18
HP MAWTKYQLFLAGLMLVTGSINTLSAKWADNFMAEGCGGSKEHSFQHPFLQAVGMFLGEFS
...... .*.****,** " *****,..*. . .*,******, **,***
CE MVAFAVIISVMMWTGSLNTICAKWADSIKAD------GVPFNHPFLQATCMFFGEFL
HP CLAAFYL---------LRCRAAGQSDS-------SVDPQQPFNPLLFLPPALCDMTGTSL
**..*.* * ...*.*.* . . ,****,**,******, ***,
CE CLWFFLIFGYKRYVWNRANVQGESGSVTEITSEEKPTLPPFNPFLFFPPALCDILGTSI
HP MYVALNMTSASSFQMLRGAVIIFTGLFSVAFLGRRLVLSQWLGILATIAGLVWGLADLL
** " **~*~*****************,** " *. .. .*.*.* .. ***,** " *.
CE MYIGLNLTTASSFQMLRGAVIIFTGLLSVGMLNAQIKPFKWFGMLFVMLGLVIVGVTDIY
HP SKHDSQHKLSEVITGDLLIIMAQIIVAIQMVLEEKFVYKHNVHPLRAVGTEGLFGFVILS
..*. .. ...***,***,*********** *,* " *..*..* *** *****,*,**
CE YDDDPLDDKNAIITGNLLIVMAQIIVAIQMVYEQKYLTKYDVPALFAVGLEGLFGMVTLS
HP LLLVPMYYIpAG-SFSGNPRGTLEDALDAFCQVGQQPLIAVALLGNISSIAFFNFAGISV
.*..*.***,. .**.** * *** " *. .....* **,** *~~ *********,**
CE ILMIPFYYIHVPRTFSTNPEGRLEDVFYAWKEITEEPTIALALSGTWSIAFFNFAGVSV
HP TKELSATTRMVLDSLRTWIWALSLALGWEAFHALQILGFLILLIGTALYNGLHRPLLGR
'**************,**,*** " *..* * * *,*, ** ,* " ** ,**,.
CE TKELSATTRMVLDSVRTLVIWWSIPLFHEKFIAIQLSGFAMLILGTLIYNDILIGPWFR
HP LSRGRPLAEESEQERLLGGTRTPINDAS
CE RNILPNLSSHANCARCWLCICGGDSELIEYEQEDQEHLMEA
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Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. N50907) in ESTs, but, since they are
partial sequences, it can not be judged whether or not any
of these sequences codes for the same protein as the protein
of the present invention.
<HP10488> (SEQ ID Nos. 67, 77, and 87)
Determination of the whole base sequence of the cDNA
insert of clone HP10488 obtained from cDNA library of human
liver revealed the structure consisting of a 39-by 5~-
untranslated region, a 273-by ORF, and a 421-by 3~-
untranslated region. The ORF codes for a protein consisting
of 90 amino acid residues and there existed one putative
transmembrane domain at the N-terminus. Figure 27 depicts
the hydrophobicity/hydrophilicity profile, obtained by the
Kyte-Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 10 kDa that was almost identical with the molecular
weight of 10,151 predicted from the ORF. When expressed in
COS7 cells, an expression product of about 6 kDa was
observed in the membrane fraction.
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. H73534) in ESTs, but, since they are
partial sequences, it can not be judged whether or not any
of these sequences codes for the same protein as the protein
of the present invention.
<HP10538> (SEQ ID Nos. 68, 78, and 88)
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Determination of the whole base sequence of the cDNA
insert of clone HP10538 obtained from cDNA library of human
osteosarcoma cell line Saos-2 revealed the structure
consisting of a 357-by 5'-untranslated region, a 1500-by ORF,
5 and a 1911-by 3'-untranslated region. The ORF codes for a
protein consisting of 499 amino acid residues and there
existed at least four putative transmembrane domains. Figure
28 depicts the hydrophobicity/hydrophilicity profile,
obtained by the Kyte-Doolittle method, of the present
10 protein. In vitro translation resulted in formation of a
translation product of high molecular weight.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the mouse pore-forming K+ channel
15 subunit (GenBank Accession No. AF056492). Table 19 shows the
comparison between amino acid sequences of the human protein
of the present invention ( HP ) and the mouse pore-forming K'
channel subunit (MM). Therein, the marks of -, *, and
represent a gap, an amino acid residue identical with that
20 of the protein of the present invention, and an amino acid
residue similar to that of the protein of the present
invention, respectively. The both proteins shared a homology
of 32.4% in the N-terminal region of 241 amino acid residues.
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Table 19
HP MVDRGPLLTSAIIFYLAIGAAIFEVLEEPHWKEAKKNYYTQKLHLLKEFPCLGQEGLDK
* . ...**. ** ,*" **,** .,*,*. . ..*.. **..*..*..
MM MRSTTLLALLALVLLYLVSGALVFQALEQPHEQQAQKKMDHGRDQFLRDHPCVSQKSLED
HP ILEWSDAAGQG-----VAITGNQTFNNWNWPNAMIFAATVITTIGYGNVAPKTPAGRLF
..... .* * * ..... ..** .*..*..*.********,. .* *****
MM FIKLLVEALGGGANPETSWTNSSNHSSAWNLGSAFFFSGTIITTIGYGNIVLHTDAGRLF
HP CVFYGLFGVPLCLTWISALGKFFGGRAKR----LGQFLTKRGVSLRKAQITCTVIFIVWG
*,**.* *.** ....*. .*.. .* ..... *. *. .. ..*.*..
MM CIFYALVGIPLFGMLLAGVGDRLGSSLRRGIGHIEAIFLKWHVPPGLVRSLSAVLFLLIG
HP VLVHLVIPPFVFMVTEGWNYIEGLYYSFITISTIGFGDFVAGVNPSANYHALYRYFVELW
*. ...*.*** *,*, ,*..*. ..*..*.****,*.* , ... . *. .* .*
MM CLLFVLTPTFVFSYMESWSKLEAIYFVIVTLTTVGFGDYVPG-DGTGQNSPAYQPLVWFW
HP IYLGLAWLSLFVNWKVSMFVEVHKAIKKRRRRRKESFESSPHSRKALQVKGSTASKDVNI
* ,***,..
MM ILFGLAYFASVLTTIGNWLRAVSRRTRAEMGGLTAQAASWTGTVTARVTQRTGPSAPPPE
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. 825184) in ESTs, but, since they are
partial sequences, it can not be judged whether or not any
of these sequences codes for the same protein as the protein
of the present invention.
<HP10542> (SEQ ID Nos. 69, 79, and 89)
Determination of the whole base sequence of the cDNA
insert of clone HP10542 obtained from cDNA library of human
stomach cancer revealed the structure consisting of a 23-by
5'-untranslated region, a 321-by ORF, and a 426-by 3'
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untranslated region. The ORF codes for a protein consisting
of 106 amino acid residues and there existed one putative
transmembrane domain. Figure 29 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte-
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 12 kDa that was almost identical with the molecular
weight of 11,724 predicted from the ORF. When expressed in
COS7 cells, an expression product of about 13 kDa was
observed in the membrane fraction.
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA029683) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP10571> (SEQ ID Nos. 70, 80, and 90)
Determination of the whole base sequence of the cDNA
insert of clone HP10571 obtained from cDNA library of human
stomach cancer revealed the structure consisting of a 95-by
5'-untranslated region, a 459-by ORF, and a 675-by 3'-
untranslated region. The ORF codes for a protein consisting
of 152 amino acid residues and there existed one putative
transmembrane domain. Figure 30 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte-
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 20 kDa that was larger than the molecular weight of
17,062 predicted from the ORF. In this case, the addition of
a microsome led to the formation of a product of 23 kDa
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which is considered to have a sugar chain being attached
after secretion. In addition, there exists in the amino acid
sequence of this protein one site at which N-glycosylation
may occur (Asn-Ile-Thr at position 10).
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA105822) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP01470> (SEQ ID Nos. 91, 101, and 111)
Determination of the whole base sequence of the cDNA
insert of clone HP01470 obtained from cDNA library of human
stomach cancer revealed the structure consisting of a 157-by
5'-untranslated region, a 1077-by ORF, and a 385-by 3'
untranslated region. The ORF codes for a protein consisting
of 358 amino acid residues and there existed one putative
transmembrane domain. Figure 31 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte-
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 43 kDa that was somewhat larger than the molecular weight
of 40,489 predicted from the ORF. In this case, the addition
of a microsome led to the formation of a product of 40 kDa
from which the secretory signal is considered to have been
cleaved and a product of 43.5 kDa which is considered to
have been subjected to some modification. Application of the
(-3,-1) rule, a method for predicting the cleavage site of
the secretory signal sequence, allows to expect that the
mature protein starts from glycine at position 23. When
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expressed in COS7 cells, an expression product of about 44
kDa was observed in the supernatant fraction.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the Caenorhabditis elegans
hypothetical protein 39.9 kDa (SWISS-PROT Accession No.
Q10005). Table 20 shows the comparison between amino acid
sequences of the human protein of the present invention (HP)
and the C. elegans hypothetical protein 39.9 kDa (CE).
20 Therein, the marks of -, *, and . represent a gap, an amino
acid residue identical with that of the protein of the
present invention, and an amino acid residue similar to that
of the protein of the present invention, respectively. The
both proteins shared a homology of 58.9$ in the entire
region .
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Table 20
HP MAPQNLSTFCLLLLYLIGAVIAGRDFYKILGVPRSASIKDIKKAYRKLALQLHPDRNPDD
* " * **********,..*. ..********* _********
5 CE MRILNVSLLVLASSLVAFVECGRDFYKILGVAKNANANQIKKAYRKLARELHPDRNQDD
HP PQAQEKFQDLGAAYEVLSDSEKRKQYDTYGEEGL--KDGHQSSHGDIFSHFFGDFGFMFG
*,****** " *******,*** ** ,****, ..* .. * ** *****
CE EMANERFQDLSSAYEVLSDKEKRAMYDRHGEEGVAKMGGGGGGGHDPFSSFFGDF-FG-G
HP GTPRQQDRNIPRGSDIIVDLEVTLEEVYAGNFVEVVRNRPVARQAPGKRRCNCRQEMRTT
10 *. . . ..*.*.*...** *******,*,***, *,*,* ,* " *,*,****,****,
CE GGGHGGEEGTPKGADVTIDLFVTLEEVYNGHFVEIKRKKAVYRQTSGTRQCNCRHEMRTE
HP QLGPGRFQMTQEWCDECFNVKLVNEERTLEVEIEPGVRDGMEYPFIGEGEPHVDGEPGD
*,*,***** * ***********,*,..****,* *, ,* , * ****** " *,***
CE QMGQGRFQMFQVKVCDECPNVKLVQENKVLEVEVEVGADNGHQQIFHGEGEPHIEGDPGD
15 HP LRFRIKWKHPIFERRGDDLYTNVTISLVESLVGFEMDITHLDGHKVHISRDKITRPGAK
*,*,* " *** ***,************ " * ****,* ***** * " ***,*,***,
CE LRFKIRIQKHPRFERKGDDLYTNVTISLQDALNGFEMEIQHLDGHIVKVQRDKVTWPGAR
HP LWRKGEGLPNFDNNNIKGSLIITFDVDFPKEQLTEEAREGIKQLLKQGSVQ-KVYNGLQG
*,**,**,*,...** ** * " ****,*** " *..*... * ..*.*..*. *,****
20 CE LRKKDEGMPSLEDNNKKGMLWTFDVEFPKTELSDEQKAQIIEILQQNTVKPKAYNGL
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
25 example, Accession No. AA282838) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
30 <HP002419> (SEQ ID Nos. 92, 102, and 112}
Determination of the whole base sequence of the cDNA
insert of clone HP02419 obtained from cDNA library of human
stomach cancer revealed the structure consisting of a 253-by
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5'-untranslated region, a 681-by ORF, and a 1120-by 3'-
untranslated region. The ORF codes for a protein consisting
of 226 amino acid residues and there existed four putative
transmembrane domains. Figure 32 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte-
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of high molecular weight.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the human hypothetical protein
KIAA0108 (SWISS-PROT Accession No. Q15012). Table 21 shows
the comparison between amino acid sequences of the human
protein of the present invention (AP) and the human
hypothetical protein KIAA0108 (KI). Therein, the marks of -,
*, and . represent a gap, an amino acid residue identical
with that of the protein of the present invention, and an
amino acid residue similar to that of the protein of the
present invention, respectively. The both proteins shared a
homology of 43.9% in the entire region.
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Table 21
HP MKMVAPWTRFYSNSCCLCCHVRTGTILLGVWYLIINAWLLILLSALADPD---QY
**** " ** *********,**,**...* .. ..* ..
KI MVSMSFKRNRSDRFYSTRCCGCCHVRTGTIILGTWYMVVNLLMAILLTVEVTHFNSMPAV
HP NFSSSELGGDFEF-MDDANMCIAIAISLLMILICAMATYGAYKQRAAWIIPFFCYQIFDF
*. . .*. .. . ..* *. .*.*.**..*..* .*** . ...*.******..***
KI NIQYEVIGNYYSSERMADNACVLFAVSVLMFIISSMLVYGAISYQVGWLIPFFCYRLFDF
HP ALNMLVAITVLIYPNSIQEYIRQLPPNFPYRDDVMSVNPTCLVLIILLFISIILTFKGYL
.*. ****. *.* .*.**. ** *.***.**.......**..*.*.*......**.**
KI VLSCLVAISSLTYLPRIKEYLDQL-PDFPYKDDLLALDSSCLLFIVLVFFALFIIFKAYL
HP ISCVWNCYRYINGRNSSDVLVYVT-SNDTTVLLPPYDDATVNGAAKEPPPPYVSA
*.******.***.** ... ** . .. . .**.* . .*. ..*******.,*
KI INCVWNCYKYINNRNVPEIAVYPAFEAPPQYVLPTY-EMAVKMPEKEPPPPYLPA
I5
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA173214) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP02631> (SEQ ID Nos. 93, 103, and 113)
Determination of the whole base sequence of the cDNA
insert of clone HP02631 obtained from cDNA library of human
osteosarcoma cell line Saos-2 revealed the structure
consisting of a 42-by 5 ~-untranslated region, a 588-by oRF,
and a 750-by 3'-untranslated region. Although the 49th amino
acid residue is encoded by a stop codon, it is likely that
this codon encodes selenocysteine from the molecular weight
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of the translation product and the sequence comparison data
with the Caenorhabditis elegans homologue. The ORF codes for
a protein consisting of 195 amino acid residues and there
existed a putative secretory signal at the N=terminus and
one putative transmembrane domain in the intermediate region.
Figure 33 depicts the hydrophobicity/hydrophilicity profile,
obtained by the Kyte-Doolittle method, of the present
protein. In vitro translation resulted in formation of a
translation product of 58 kDa. In this case, the addition of
a microsome led to the formation of a product of 56. kDa from
which the secretory signal is considered to have been
cleaved. Since both of these products are larger than the
molecular weight of 22 kDa predicted from the ORF, it is
likely that the protein interacts with another protein.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the Caenorhabditis elegans
hypothetical protein C35C5.3 (EMBL Accession No. 278417).
Table 22 shows the comparison between amino acid sequences
of the human protein of the present invention (HP) and the C.
elegans hypothetical protein C35C5.3 (CE). U at position 49
in the amino acid sequence of the protein of the present
invention represents selenocysteine. Therein, the marks of -,
*, and . represent a gap, an amino acid residue identical
with that of the protein of the present invention, and an
amino acid residue similar to that of the protein of the
present invention, respectively. The both proteins shared a
homology of 37.9% in the entire region other than the N-
terminal region. Cystein was found in the sequence of the C.
elegans protein at the posistion corresponding to position
49 encoded by the stop codon (selenocysteine) of the protein
of the present invention.
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Table 22
HP MRLLLL
CE MRIHDELQKQDMSRFGVFIIGVLFFMSVCDVLRTEEHSHDENHVHERDDFEAEFGDETDS
HP LLVAASAMVRSEASANLGGVPSKRLKMQYATGPLLKFQIGVSUGYRRVFEEYMRVISQRY
* * " *** **,..*... ...*
CE QSFSQGTEEDHIEVREQSSFVKPTAVHHAKDLPTLRIFYCVSCGYKQAFDQFTTFAKERY
HP PDIRIEGENYLPQPIYRHIASFLSVFKLVLIGLIIVGKDPFAFFGMQAPSIWQWGQENKV
*...***,*, * .,* ** *,... *.. * ,.**, **. * * * ...**.
CE PNMPIEGANFAPVLWKAYVAQALSFVKMAVLVLVLGGINPFERFGLGYPQILQHAHGNKM
HP YACMMVFFLSNMIENQCMSTGAFEITLNDVPVWSKLESGHLPSMQQLVQILDNEMKLNVH
.**,**,*,* " *, ~.******, *.. ..***,*** " ** *,..*..*... .
CE SSCMLVFMLGNLVEQSLISTGAFEVYLGNEQIWSKIESGRVPSPQEFMQLIDAQLAVLGK
HP MDSIPHHRS
CE APVNTESFGEFQQTV
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA156969) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP02695> (SEQ ID Nos. 94, 104, and 114)
Determination of the whole base sequence of the cDNA
insert of clone HP02695 obtained from cDNA library of human
stomach cancer revealed the structure consisting of a 112-by
5'-untranslated region, a 1020-by ORF, and a 160-by 3'
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untranslated region. The ORF codes for a protein consisting
of 339 amino acid residues and there existed three putative
transmembrane domains. Figure 34 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte-
5 Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 38 kDa that was almost identical with the molecular
weight of 38,274 kDa predicted from the ORF.
The search of the protein data base using the amino
10 acid sequence of the present protein revealed that the
protein was similar to the rat hypertension-induced protein
S-2 fragment (PIR Accession No. 539959). Table 23 shows the
comparison between amino acid sequences of the human protein
of the present invention (HP) and the rat hypertension
15 induced protein S-2 fragment (RN). Therein, the marks of -,
*, and . represent a gap, an amino acid residue identical
with that of the protein of the present invention, and an
amino acid residue similar to that of the protein of the
present invention, respectively. The both proteins shared a
20 homology of 74.3% in the entire region.
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Table 23
HP MNWELLLWLLVLCALLLLLVQLLRFLRADGDLTLLWAEWQGRRPEWELTDMWWVTGASS
HP GIGEELAYQLSKLGVSLVLSARRVHELERVKRRCLENGNLKEKDILVLPLDLTDTGSHEA
****,******************,**,**,
RN VKRRSLENGNLKEKDILVLPLDLADTSSHDI
HP ATKAVLQEFGRIDILVNNGGMSQRSLCMDTSLDVYRKLIELNYLGTVSLTKCVLPHMIER
***,****************,.. ** .*..*... ***,*********** ****,**
RN ATKTVLQEFGRIDILVNNGGVAHASLVENTNMDIFKVLIEVNYLGTVSLTKCFLPHMMER
HP KQGKIVTVNSILGIISVPLSIGYCASKHALRGFFNGLRTELATYPGIIVSNICPGPVQSN
*****,..*
RN NQGKIVVMKS
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. T84331) in ESTs, but, since they are
partial sequences, it can not be judged whether or not any
of these sequences codes for the same protein as the protein
of the present invention.
<HP10031> (SEQ ID Nos. 95, 105, and 115)
Determination of the whole base sequence of the cDNA
insert of clone HP10031 obtained from cDNA library of human
osteosarcoma cell line Saos-2 revealed the structure
consisting of a 55-by 5'-untranslated region, a 1464-by ORF,
and a 649-by 3'-untranslated region. The ORF codes for a
protein consisting of 487 amino acid residues and there
existed eleven putative transmembrane domains. Figure 35
depicts the hydrophobicity/hydrophilicity profile, obtained
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by the Kyte-Doolittle method, of the present protein. In
vitro translation resulted in formation of a translation
product of high molecular weight. When expressed in COS7
cells, an expression product of about 55 kDa was observed in
the membrane fraction.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the Caenorhabditis elegans
hypothetical protein CELK07H8 (GenBank Accession No.
AF047659). Table 24 shows the comparison between amino acid
sequences of the human protein of the present invention (HP)
and the C. elegans hypothetical protein CELK07H8 (CE).
Therein, the marks of -, *, and . represent a gap, an amino
acid residue identical with that of the protein of the
present invention, and an amino acid residue similar to that
of the protein of the present invention, respectively. The
both proteins shared a homology of 44.2% in the entire
region.
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Table 24
HP MDGTETRQRRLDSCGKPGELGLPHPLSTGGLPVAS
CE MKGGGGIGDGKKDYQSAVHEGLTTFDQLGIALEDVGKSMDAETATPGGSLFSRVIFRFRN
HP EDGALRAPESQSVTPKPLETEPSRETAWSIGLQVTVPFMFAGLGLSWAGMLLDYFQHWPV
*...*.... . . . . *... . .** ** ****, ,**..*. **,
CE ENSSLKSRTYDHSNDLVNMSVIPAESSYVLFFQVLFPFAVAGLGMVFAGLVLSIVVTWPL
HP FVEVKDLLTLVPPLVGLRGNLEMTLASRLSTAANTGQIDDPQEQHRVISSNLALIQVQAT
* *. ..*.***,*,**************** ** * " *...... *. ,****,*****
CE FEEIPEILILVPALLGLRGNLEMTLASRLSTLANLGHMDSSKQRKDWIANLALVQVQAT
HP WGLLAAVAALLLGWSREEVDVAKVELLCASSVLTAFLAAFALGVLMVCIVIGARKLGV
** " **.. * *, ..... * *. .*.****, ** *...*..*** .....** ..
CE WAFLASAFAAALAFIPSGDFDWAHGALMCASSLATACSASLVLSLLMVWIVTSRKYNI
HP NPDNIATPIAASLGDLITLSILALVSSFFYR-HKDSRYLTPLVCLSFAALTPVWVLIAKQ
****,***********,** " **, ,* * , *.....*. .* . * * * *, **,.
CE NPDNVATPIAASLGDLTTLTVLAFFGSVFLKAHNTESWLNVIVIVLFLLLLPFWIKIANE
HP SPPIVKILKFGWFPIILAMVISSFGGLILSKTVSKQQYKGMAIFTPVICGVGGNLVAIQT
. ..* ** *.*,.*,*** **.**...* ..*.......**. ******.*,*.
CE NEGTQETLYNGWTPVIMSMLISSAGGFILETAV--RRYHSLSTYGPVLNGVGGNLAAVQA
HP SRISTYLHMWSAPGVLPLQ--MKKFWPNPCSTFCTSEINSMSARVLLLLVVPGHLIF-FY
**.***.*, .. **** . ...* .. ..* ..* .*.*************,
CE SRLSTYFHKAGTVGVLPNEWTVSRF-TSVQRAFFSKEWDSRSARVLLLLVVPGHICFNFL
HP I-IYLVEGQSVINSQ--TFWLYLLAGLIQVTILLYLAEVMVRLTWHQALDPDNHCIPYL
* .. ..... .... *. **..*..***.***,. ...* * *, .**** ****
CE IQLFTLTSKNNVTPHGPLFTSLYMIAAIIQWILLFVCQLLVALLWKWKIDPDNSVIPYL
HP TGLGDLLGTGLLALCFFTDWLLKSKAELGGISELASGPP
*,********** , *,*
CE TALGDLLGTGLLFIVFLTTDHFDPKELTSS
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
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example, Accession No. AA334000) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP10530> (SEQ ID Nos. 96, 106, and 116)
Determination of the whole base sequence of the cDNA
insert of clone HP10530 obtained from cDNA library of human
osteosarcoma cell line Saos-2 revealed the structure
consisting of a 80-by 5'-untranslated region, a 1182-by ORF,
and a 95-by 3'-untranslated region. The ORF codes for a
protein consisting of 393 amino acid residues and there
existed a putative secretory signal at the N-terminus.
Figure 36 depicts the hydrophobicity/hydrophilicity profile,
obtained by the Kyte-Doolittle method, of the present
protein. In vitro translation resulted in formation of a
translation product of 46 kDa that was somewhat larger than
the molecular weight of 44,912 predicted from the ORF. In
this case, the addition of a microsome led to the formation
of a product of 45.5 kDa from which the secretory signal is
considered to have been cleaved. Application of the (-3,-1)
rule, a method for predicting the cleavage site of the
secretory signal sequence, allows to expect that the mature
protein starts from lysine at position 23. When expressed in
COS7 cells, an expression product of about 43 kDa was
observed in the supernatant fraction and the membrane
fraction.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the Arabidopsis thaliana hypothetical
protein IG002N01 (GenBank Accession No. AF007269). Table 25
shows the comparison between amino acid sequences of the
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human protein of the present invention (HP) and the A.
thaliana hypothetical protein IG002N01 (AT). Therein, the
marks of -, *, and . represent a gap, an amino acid residue
identical with that of the protein of the present invention,
5 and an amino acid residue similar to that of the protein of
the present invention, respectively. The both proteins
shared a homology of 27.0% in the N-terminal region of 355
amino acid residues.
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Table 25
HP MRTLFNLLWL
AT MELTSFQKSPSSNDWSFSVSLVRNSMARRRRSSAAESLKRRNDGYESLCQWQQDSDRR
HP ALACSPVHTTLSKSDAKKAASKTLLEKSQFSDKPVQDRGLWTDLKAESVVLEHRSYCSA
........*.* **,. .... **.. ..
AT LITIFVIFFIVIPAVSIAVYKVKFADRVIQTESSIRQKGIVKTDINFQEILTEHSK--AS
HP KARDRHFAGDVLGYVTPWNSHGYDVTKVFGSKFTQISPVWLQ-LKRRGREMFEVTGLHDV
....**.. **.*,** " * .. *.... . . *.* *..**... . .**.
AT ENSTRHYDYPVLAYITP--CQGSGL--VLEGR-HNADKGWIQELRSRGNALSASKGLPRL
HP DQGWMRAVRKHAKGLHIVPRLLFEDWTYDDFRNVLDSEDEIEELSKTWQVAKNQHFDGF
. . . . * ... . * . ** .. .*.* *.* . .. .. . .. .
AT ---YNSCIFHALKRMNFFTLELVNFNTYLVIMFALNS-REMEYNGIVLESWSRWAAYGVL
HP WEVWNQLLSQKRVGLIHMLTHLAEALHQARLLALLVIPPAITPGTDQLGMFTHKEFEQL
... . * . * ... .... .... . . ... *. *......
AT HDPDLRKMALKFVKQLGDALHSTSSPRNNQQHMQFMYWGPPRSEKLQMYDFGPEDLQFL
HP APVLDGFSLMTYDYSTAHQPGPNAPLSWVRACVQ-VLDPKSK----WRSKILLGLNFYGM
*********,*,...****** " *. .. .*..... .*.***,****
AT KDSVDGFSLMTYDFSNPQNPGPNAPVKWIDLTLKLLLGSSNNIDSNIARKVLLGINFYGN
HP DYATSKDAREPWGARYIQTLKDHRPRMVWDSQASEHFFEYKKSRSGRHWFYPTLKSLQ
*...* .. ....* *.. *..*.* . **....**.* *..... .*.******.*,
AT DFVISGGGGGAITGRDYLALLQKHKPTFRWDKESGEHLFMYRDDKNIKHAVFYPTLMSIL
HP VRLELARELGVGVSIWELGQGLDYFYDLL
,*** ** *,*,****,**, ..*
AT LRLENARLWGIGISIWEIGQDKGHFGKYAEASLEASSIFSGHTFDMQFRTNPRQLSRNGS
Furthermore, the search of the GenHank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA302913) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
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protein of the present invention.
<HP10541> (SEQ ID Nos. 97, 107, and 117)
Determination of the whole base sequence of the cDNA
insert of clone HP10541 obtained from cDNA library of human
stomach cancer revealed the structure consisting of a 7-by
5'-untranslated region, a 591-by ORF, and a 113-by 3~
untranslated region. The ORF codes for a protein consisting
of 196 amino acid residues and there existed a putative
secretory signal at the N-terminus. Figure 37 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte-
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 23 kDa that was somewhat larger than the molecular weight
of 21,553 predicted from the ORF. In this case, the addition
of a microsome led to the formation of a product of 20 kDa
from which the secretory signal is considered to have been
cleaved and a product of 23 kDa which is considered to have
a sugar chain being attached. Application of the (-3,-1}
rule, a method for predicting the cleavage site of the
secretory signal sequence, allows to expect that the mature
protein starts from glycine at position 41. In addition,
there exists in the amino acid sequence of this protein one
site at which N-glycosylation may occur (Asn-Leu-Thr at
position 185).
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the human zymogen membrane protein
(GenHank Accession No. AF056492). Table 26 shows the
comparison between amino acid sequences of the human protein
of the present invention (HP) and the human zymogen membrane
protein (ZM). Therein, the marks of -, *, and . represent a
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9$
gap, an amino acid residue identical with that of the
protein of the present invention, and an amino acid residue
similar to that of the protein of the present invention,
respectively. The both proteins shared a homology of 37.6%
in the C-terminal region of 133 amino acid residues.
Table 26
HP MWRVPGTTRRPVTGESPGMHRPEAMLLLLTLALLGGPTWAGKMYGPGGGKYFS-TTEDYD
**,**** ** ....
ZM MLTVALLALLCASASGNAIQARSSSYSGEYGSGGGKRFSHSGNQLD
HP HEITGLRVSVGLLLVKSVQVKLGDSWDVKLGALGGNTQEVTLQPGEYITKVFVAFQAFLR
**,***,*, . ..**. *. *. .*. .*. .*. *,*** ,..* .. .*.
ZM GPITALRVRVNTYYIVGLQVRYGKVWSDYVGGRNGDLEEIFLHPGESVIQVSGKYKWYLK
HP GMVMYTSKDRYFYFGKLDGQISSAYPSQEGQVLVGIYGQYQLLGIKSIGFEWN-YPLEEP
*, *,*,**, *** ,* ,* * . . ** * *, * * " ** " *, **
ZM KLVFVTDKGRYLSFGKDSGTSFNAVPLHPNTVLRFISGRSGSL-IDAIGLHWDVYPTSCS
HP TTEPPVNLTYSANSPVGR
ZM RC
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA340605) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP10550> (SEQ ID Nos. 98, 108, and 118)
Determination of the whole base sequence of the cDNA
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insert of clone HP10550 obtained from cDNA library of human
stomach cancer revealed the structure consisting of a 241-by
5'-untranslated region, a 324-by ORF, and a 86-by 3'-
untranslated region. The ORF codes for a protein consisting
of 107 amino acid residues and there existed one putative
transmembrane domain. Figure 38 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of high molecular weight.
Furthermore, the search of the GenHank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA348310) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP10590> (SEQ ID Nos. 99, 109, and 119)
Determination of the whole base sequence of the cDNA
insert of clone HP10590 obtained from cDNA library of human
fibrosarcoma cell line HT-1080 revealed the structure
consisting of a 77-by 5'-untranslated region, a 1053-by ORF,
and a 180-by 3'-untranslated region. The ORF codes for a
protein consisting of 350 amino acid residues and there
existed one putative transmembrane domain. Figure 39 depicts
the hydrophobicity/hydrophilicity profile, obtained by the
Kyte-Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 40 kDa that was almost identical with the molecular
weight of 39, 285 predicted from the ORF. In this case, the
addition of a microsome led to the formation of a product of
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43 kDa which is considered to have a sugar chain being
attached. In addition, there exist in the amino acid
sequence of this protein two sites at which N-glycosylation
may occur (Asn-Asn-Ser at position 144 and Asn-Leu-Thr at
position 328).
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA461346) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP10591> (SEQ ID Nos. 100, 1I0, and 120)
Determination of the whole base sequence of the cDNA
insert of clone HP10591 obtained from cDNA library of human
fibrosarcoma cell line HT-1080 revealed the structure
consisting of a 232-by 5'-untranslated region, a 324-by ORF,
and a 844-by 3'-untranslated region. The ORF codes for a
protein consisting of 107 amino acid residues and there
existed one putative transmembrane domain. Figure 40 depicts
the hydrophobicity/hydrophilicity profile, obtained by the
Kyte-Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 12 kDa that was almost identical with the molecular
weight of 11,328 predicted from the ORF.
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. H09424) in ESTs, but, since they are
partial sequences, it can not be judged whether or not any
of these sequences codes for the same protein as the protein
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of the present invention.
<HP01462> (SEQ ID Nos. 121, 131, and 141)
Determination of the whole base sequence of the cDNA
insert of clone HP01462 obtained from cDNA library of human
fibrosarcoma cell line HT-1080 revealed the structure
consisting of a 121-by 5'-untranslated region, a 1452-by ORF,
and a 477-by 3'-untranslated region. The ORF codes for a
protein consisting of 483 amino acid residues and there
existed a putative secretory signal at the N-terminus.
Figure 41 depicts the hydrophobicity/hydrophilicity profile,
obtained by the Kyte-Doolittle method, of the present
protein. In vitro translation resulted in formation of a
translation product of 72 kDa that was larger than the
molecular weight of 55,838 predicted from the ORF.
Application of the (-3,-1) rule, a method for predicting the
cleavage site of the secretory signal sequence, allows to
expect that the mature protein starts from lysine at
position 2l.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the Caenorhabditis elegans
hypothetical protein ZR1058.4 (EMBL Accession No. Z35604).
Table 27 shows the comparison between amino acid sequences
of the human protein of the present invention (HP} and the C.
elegans hypothetical protein ZK1058.4 (CE}. Therein, the
marks of -, *, and . represent a gap, an amino acid residue
identical with that of the protein of the present invention,
and an amino acid residue similar to that of the protein of
the present invention, respectively. The both proteins
shared a homology of 35.6$ in the entire region.
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Table 27
HP MKAFHTFCWLLVFGSVSEAKFDDFEDEEDIVEYDDNDFAEFEDVMEDSVTESPQRVIIT
CE MKIVWIFLIFFIGFAIST
HP EDDE-DETTVELEGQDENQEGDFEDADTQEGDTESEPYDDEEFEGYEDKP---------D
.*.* .* . *. * ...*. ... .... .... ...*.*. *..*
CE DDNEFAEFEDEFVGSSATQAPEIQREGEPPVLKQKDDFEEEDFGWEEEPEEAEKVREAD
HP TSSSRNKDPITIVDVPAHLQNSWESYYLEILMVTGLLAYIMNYIIGRNKNSRLAQAWFNT
.... .*....*****,...*.** .* ..* .* *. **,*** " *...**. *.
CE SDDAAPAQPLKFADVPAHFRSNWASYQVEGIWLIILIYMTNYLIGKTTNASIAQTIFDM
HP HRELLESNFTLVGDDGTNKEATSTGKLNQENEHIYNLWCSGRVCCEGMLIQLRFLKRQDL
* ** " *..******,. .. . .*..... ... **,*** .....*....****,
CE CRPTLEEQFAWGDDGTTDLDKMIPSLKHDTDSTFSAWCTGRVNVNSLFLQMKMVKRQDV
HP LNVLARMMRPVSDQVQIKVTMN-DEDMDTYVFAVGTRKALVRLQKEMQDLSEFCSDKPKS
.. . *. * .*.. **.... ..* *. .****..* , *** ** " * *,. ..
CE VSRIMEMFTPSGDKMTIKASLETTNDTDPLIFAVGEKKIASKYFKEMLDLNSFASERRQA
HP GARYGLPDSLAILSEMGEVTDGMMDTKMVHFLTHYADKIESVHFSDQFSGPKIMQEEGQP
.....**.* .. .. .**. ...*. .* .*....* ** .*,****,*** .,*. .
CE AQQFNLPASWQVYADQNEWFSILDPGWSLLKKHEDAIEFIHISDQFTGPKPAEGESYT
HP LKLPDTKRTLLFTFNVPGSGNTYPKDMEALLPLMNMVIYSIDKAKKFRLNREGKQKADKN
.**...* .. ..*.. * .* *... ..*.*.* ****,*" *....* **,..
CE -RLPEAQRYMFVSLNLQYLG----QDEESVMEILNLVFYLIDKARKMKLSKDAKVKAERR
HP RARVEENFLKLTHVQRQEAAQSRREEKKRAEKERIMNEEDPEKQRRLEEAALRREQKKLE
* * " *** ** ******,*****,*, *,..*.*.***,*,***, ,*,**,*
CE RKEFEDAFLKQTHQFRQEAAQARREEKTRERKQKLMDESDPERQKRLEAKELKREAKA--
HP KKQMKMKQIRVKAM
* **** ***
CE -KSPKMKQLKVK
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
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example, Accession No. AA307793) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP02485> (SEQ ID Nos. 122, 132, and 142)
Determination of the whole base sequence of the cDNA
insert of clone HP02485 obtained from cDNA library of human
stomach cancer revealed the structure consisting of a 69-by
5'-untranslated region, a 1005-by ORF, and a 1672-by 3~-
untranslated region. The ORF codes for a protein consisting
of 334 amino acid residues and there existed one putative
transmembrane domain. Figure 42 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte-
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 36 kDa that was almost identical with the molecular
weight of 38,1?1 predicted from the ORF. When expressed in
COS7 cells, an expression product of about 23 kDa was
observed in the membrane fraction.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the Caenorhabditis elegans
hypothetical protein WOlAll.2 (GenBank Accession No. U64852).
Table 28 shows the comparison between amino acid sequences
of the human protein of the present invention (HP) and the C.
elegans hypothetical protein WOlAll.2 (CE). Therein, the
marks of -, *, and . represent a gap, an amino acid residue
identical with that of the protein of the present invention,
and an amino acid residue similar to that of the protein of
the present invention, respectively. The both proteins
shared a homology of 45.5% in the entire region.
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Table 28
HP MVEFAPLFMPWERRLQTLAVLQFVFSFLALAEICT-V
,*** " **,***,****, *,* " *. .
CE MRLRLSSISGKAKLPDKEICSSVSRILAPLLVPWKRRLETLAVMGFIFMWVILPIMDLWV
HP GFIALLFTRFWLLTVLYAAWWYLDRDKPRQGGRHIQAIRCWTIWKYMKDYFPISLVKTAE
* ,*, **,*,*, ***,*,* * *,*,...*. . * , ***, ,*** " *,***,
CE PFHVLFNTRWWFLVPLYAVWFYYDFDTPKRASRRWNWARRHVAWKYFASYFPLRLIKTAD
HP LDPSRNYIAGFHPHGVLAVGAFANLCTESTGFSSIFPGIRPHLMMLTLWFRAPFFRDYIM
* " **** * ****,..**.*....*..***" **** " *,* *, * ** *,. .
CE LPADRNYIIGSHPHGMFSVGGFTAMSTNATGFEDKFPGIKSHIMTLNGQFYFPFRREFGI
HP SAGLVTSEKESAAHILNRKGGGNLLGIIVGGAQEALDARPGSFTLLLRNRKGFVRLALTH
* .. .*** ...*.. * *. .*..*** ***.*.*.. ** * **.** . **.
CE MLGGIEVSKESLEYTLTKCGKGRACAIVIGGASEALEAHPNKNTLTLINRRGFCKYALKF
HP GAPLVPIFSFGENDLFDQIPNSSGSWLRYIQNRLQKIMGISLPLFHGRGVF-QYSFGLIP
** ***,..****** " * * " **,** ,*,......*.. **..**..* ** ,**,*
CE GADLVPMYNFGENDLYEQYENPKGSRLREVQEKIKDMFGLCPPLLRGRSLFNQYLIGLLP
HP YRRPITTWGKPIEVQKTLHPSEEEVNQLHQRYIKELCNLFEAHKLKFNIPADQHLEFC
*,*,***,*,** * ,* ,*, *,...**..* ..*.**** " * ,**,* **
CE FRKPVTTVMGRPIRVTQTDEPTVEQIDELHAKYCDALYNLFEEYKHLHSIPPDTHLIFQ
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. D25664) in ESTs, but, since they are
partial sequences, it can not be judged whether or not any
of these sequences codes for the same protein as the protein
of the present invention.
<HP02798> (SEQ ID Nos. 123, 133, and 143)
Determination of the whole base sequence of the cDNA
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insert of clone HP02798 obtained from cDNA library of human
fibrosarcoma cell line HT-1080 revealed the structure
consisting of a 31-by 5~-untranslated region, a 804-by ORF,
and a 301-by 3'-untranslated region. The ORF codes for a
protein consisting of 267 amino acid residues and there
existed four putative transmembrane domains. Figure 43
depicts the hydrophobicity/hydrophilicity profile, obtained
by the Kyte-Doolittle method, of the present protein. In
vitro translation resulted in formation of a translation
product of 29 kDa that was almost identical with the
molecular weight of 30,778 predicted from the ORF. When
expressed in COS7 cells, an expression product of about 26
kDa was observed in the membrane fraction.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the human DHHC-containing cysteine
rich protein (GenBank Accession No. U90653). Table 29 shows
the comparison between amino acid sequences of the human
protein of the present invention (HP) and the human DHHC
containing cysteine-rich protein (DH). Therein, the marks of
-, *, and . represent a gap, an amino acid residue identical
with that of the protein of the present invention, and an
amino acid residue similar to that of the protein of the
present invention, respectively. The both proteins shared a
homology of 35.0% in the intermediate region of 100 amino
acid residues. The positions of seven cysteines were
conserved between the two proteins. The protein of the
present invention also had the DHHC (Asp-His-His-Cys)
sequence.
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Table 29
HP MAPWALLSPGVLVRTGHTVLTWGI
DH MYRMNICNKPSNKTAPEKSVWTAPAQPSGPSPELQGQRSRRNGWSWPPHPLQIVAWLLYL
HP TLVLFLHDTELRQWEEQGELLLPLTFLLLVLGSLLLYLAVSLMDPGYVNVQPQP-QEELR
* *...*.. .**. **, .. ..
DH FFAVIGFGILVPLLPHHWVPAGYACMGAIFAGHLWHLTAVSIDPADDNVRDKSYAGPLP
HP.EEQTAMVPPAIPLRRCRYCLVLQPLRARHCRECRRCVRRYDHHCPWMENCVGERNHPLFV
. . ...* .*. * * . *..**..*..** .**** *..******* " **,
DH IFNRSQHAHVIEDLHCNLCNVDVSARSKHCSACNKCVCGFDHHCKWLNNCVGERNYRLFL
HP VYLALQLWLLWGLYLAWSGLRFFQPWGLWLRSSGLLFATFLLLSLFSLVASLLLVSHLY
.* .*. .*
DH HSVASALLGVLLLVLGGHICLRGVLCQPHASAHQPTL
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. D79050) in ESTs, but, since they are
partial sequences, it can not be judged whether or not any
of these sequences codes for the same protein as the protein
of the present invention.
<HP10041> (SEQ ID Nos. 124, 134, and 144)
Determination of the whole base sequence of the cDNA
insert of clone HP10041 obtained from cDNA library of human
osteosarcoma cell line Saos-2 revealed the structure
consisting of a 12-by 5'-untranslated region, a 321-by ORF,
and a 286-by 3'-untranslated region. The ORF codes for a
protein consisting of 106 amino acid residues and there
existed one putative transmembrane domain. Figure 44 depicts
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the hydrophobicity/hydrophilicity profile, obtained by the
Ryte-Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 12 kDa that was almost identical with the molecular
weight of 12,060 predicted from the ORF. When expressed in
COS7 cells, an expression product of about 13 kDa was
observed in the membrane fraction.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the Caenorhabditis elegans
hypothetical protein K10B2.4 (GenBank Accession No. U28730).
Table 30 shows the comparison between amino acid sequences
of the human protein of the present invention (HP) and the C.
elegans hypothetical protein K10B2.4 (CE). Therein, the
marks of -, *, and . represent a gap, an amino acid residue
identical with that of the protein of the present invention,
and an amino acid residue similar to that of the protein of
the present invention, respectively. The both proteins
shared a homology of 62.1% in the entire region.
Table 30
HP MSTNNMSDPRRPNKVLRYKP---PPSECNPALDDPTPDYMNLLGMIFSMCGLMLKLRWCA
,****,*,..**** .... .. .** *,***,***********,..***,
CE MQQNGDPRRTNRIVRYKPLDSTANQQQAISEDPLPEYMNVLGMIFSMCGLMIRMKWCS
HP WVAVYCSFISFANSRSSEDTKQMMSSFMLSISAVVMSYLQNPQPMTPPW
*,*, ** *****,*,*,*,** " ******,*********** * " ***
CE WLALVCSCISFANTRTSDDAKQIVSSFMLSVSAWMSYLQNPSPIIPPWVTLLQS
Furthermore, the search of the GenBank using the base
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sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. H20098) in ESTs, but, since they are
partial sequences, it can not be judged whether or not any
of these sequences codes for the same protein as the protein
of the present invention.
<HP10246> (SEQ ID Nos. I25, 135, and 145)
Determination of the whole base sequence of the cDNA
insert of clone HP10246 obtained from cDNA library of human
epidermoid carcinoma cell line KB revealed the structure
consisting of a 110-by 5'-untranslated region, a 675-by ORF,
and a 79-by 3'-untranslated region. The ORF codes for a
protein consisting of 224 amino acid residues and there
existed five putative transmembrane domains. Figure 45
depicts the hydrophobicity/hydrophilicity profile, obtained
by the Kyte-Doolittle method, of the present protein. In
vitro translation resulted in formation of a translation
product of 23 kDa that was somewhat smaller than the
molecular weight of 25,244 predicted from the ORF. When
expressed in COS7 cells, an expression product of about 21
kDa was observed in the membrane fraction.
The search 'of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the human putative seven
transmembrane domain protein (GenBank Accession No. Y18007}.
Table 31 shows the comparison between amino acid sequences
of the human protein of the present invention (HP) and the
human putative seven transmembrane domain protein (TM).
Therein, the marks of -, *, and . represent a gap, an amino
acid residue identical with that of the protein of the
present invention, and an amino acid residue similar to that
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of the protein of the present invention, respectively. The
both proteins shared a homology of 93.3% in the entire
region.
Table 31
HP MTLFHFGNCFALAYFPYFITYKCSGLSEYNAFWKCVQAGVTYLFVQLCKMLFLATFFPTW
***********************.,***********************************
TM MTLFHFGNCFALAYFPYFITYKCTDLSEYNAFWKCVQAGVTYLFVQLCKMLFLATFFPTW
HP EGGIYDFIGEFMKASVDVADLIGLNLVMSRNAGKGEYKIMVAALGWATAELIMSRCIPLW
************************************************************
TM EGGIYDFIGEFMKASVDVADLIGLNLVMSRNAGKGEYKIMVAALGWATAELIMSRCIPLW
HP VGARGIEFDWKYIQMSIDSNISLVHYIVASAQVWMITRYDLYHTFRPAVLLLMFLSVYKA
*********************** ,******************************,****
TM VGARGIEFDWKYIQMSIDSNISLGPYIVASAQVWMITRYDLYHTFRPAVLLLMFLRVYKA
HP FVMETFVHLCSLGSWAALLARAVVTGLLALSTLALYVAWNVHS
****************,*.* .**,***,...**,*********
TM FVMETFVHLCSLGSWAVLMAGVWKGLLVIRNLAMYVAVVNVHS
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA453931) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP10392> (SEQ ID Nos. I26, 136, and 146)
Determination of the whole base sequence of the cDNA
insert of clone HP10392 obtained from cDNA library of human
osteosarcoma cell line U-2 OS revealed the structure
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consisting of a 24-by 5'-untranslated region, a ?77-by ORF,
and a 726-by 3'-untranslated region. The ORF codes for a
protein consisting of 258 amino acid residues and there
existed a putative secretory signal at the N-terminus.
Figure 46 depicts the hydrophobicity/hydrophilicity profile,
obtained by the Kyte-Doolittle method, of the present
protein. In vitro translation resulted in formation of a
translation product of 34 kDa that was somewhat larger than
the molecular weight of 29,623 predicted from the ORF.
Application of the (-3,-1) rule, a method for predicting the
cleavage site of the secretory signal sequence, allows to
expect that the mature protein starts from leucine at
position 49.
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. H15999) in ESTs, but, since they are
partial sequences, it can not be judged whether or not any
of these sequences codes for the same protein as the protein
of the present invention. In addition, partial identity with
the hypothetical protein KIAA0384 (Accession No. AB002382)
was observed, although the hypothetical protein had a
different ORF.
<HP10489> (SEQ ID Nos. 127, 137, and 147)
Determination of the whole base sequence of the cDNA
insert of clone HP10489 obtained from cDNA library of human
stomach cancer revealed the structure consisting of a 137-by
5'-untranslated region, a 333-by ORF, and a 189-by 3'-
untranslated region. The ORF codes for a protein consisting
of 110 amino acid residues and there existed two putative
transmembrane domains. Figure 47 depicts the
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hydrophobicity/hydrophilicity profile, obtained by the Ryte-
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 19 kDa that was somewhat larger than the molecular weight
of 12,010 predicted from the ORF.
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA262162) in ESTs, but, since they
are partial sequences, it can not be judged whether or not
any of these sequences codes for the same protein as the
protein of the present invention.
<HP10519> (SEQ ID Nos. 128, 138, and 148)
Determination of the whole base sequence of the cDNA
insert of clone HP10519 obtained from cDNA library of human
stomach cancer revealed the structure consisting of a 67-by
5'-untranslated region, a 276-by ORF, and a 367-by 3~-
untranslated region. The ORF codes for a protein consisting
of 91 amino acid residues and there existed one putative
transmembrane domain. Figure 48 depicts the
hydrophobicity/hydrophilicity profile, obtained by the Kyte-
Doolittle method, of the present protein. In vitro
translation resulted in formation of a translation product
of 10 kDa that was almost identical with the molecular
weight of 10,275 predicted from the ORF.
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. W16639) in ESTs, but, since they are
partial sequences, it can not be judged whether or not any
of these sequences codes for the same protein as the protein
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of the present invention.
<HP10531> (SEQ ID Nos. 129, 139, and 149)
Determination of the whole base sequence of the cDNA
insert of clone HP10531 obtained from cDNA library of human
osteosarcoma cell line Saos-2 revealed the structure
consisting of a 55-by 5'-untranslated region, a 1035-by ORF,
and a 1092-by 3'-untranslated region. The ORF codes for a
protein consisting of 344 amino acid residues and there
existed five putative transmembrane domains.' Figure 49
depicts the hydrophobicity/hydrophilicity profile, obtained
by the Kyte-Doolittle method, of the present protein. In
vitro translation resulted in formation of a translation
product of high molecular weight.
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. 850695) in ESTs, but, since they are
partial sequences, it can not be judged whether or not any
of these sequences codes for the same protein as the protein
of the present invention.
<HP10574> (SEQ ID Nos. 130, 140, and 150)
Determination of the whole base sequence of the cDNA
insert of clone HP10574 obtained from cDNA library of human
stomach cancer revealed the structure consisting of a 210-by
5'-untranslated region, a 1287-by ORF, and a 1276-by 3'
untranslated region. The ORF codes for a protein consisting
of 428 amino acid residues and there existed a putative
secretory signal at the N-terminus and one putative
transmembrane domain in the intermediate region. Figure 50
depicts the hydrophobicity/hydrophilicity profile, obtained
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by the Kyte-Doolittle method, of the present protein. In
vitro translation resulted in formation of a translation
product of high molecular weight. Application of the (-3,-1)
rule, a method for predicting the cleavage site of the
secretory signal sequence, allows to expect that the mature
protein starts from serine at position 36.
The search of the protein data base using the amino
acid sequence of the present protein revealed that the
protein was similar to the Drosophila melanogaster GOLIATH
protein (SWISS-PROT Accession No. Q06003). Table 32 shows
the comparison between amino acid sequences of the human
protein of the present invention (HP) and the D.
melanogaster GOLIATH protein (DM). Therein, the marks of -,
*, and . represent a gap, an amino acid residue identical
with that of the protein of the present invention, and an
amino acid residue similar to that of the protein of the
present invention, respectively. The intermediate region of
169 amino acids of the protein of the present invention
shared a homology of 41.4% with the N-terminal region of the
D. melanogaster GOLIATH protein.
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Table 32
HP MGPPPGAGVSCRGGCGFSRLLAWCFLLALSPQAPGSRGAEAVWTAYLNVSWRVPHTGVNR
HP TVWELSEEGVYGQDSPLEPVAGVLVPPDGPGALNACNPHTNFTVPTVWGSTVQVSWLALI
HP QRGGGCTFADKIHLAYERGASGAVIFNFPGTRNEVIPMSHPGAVDIVAIMIGNLKGTKIL
.*.*... . * ..
DM MQLERMQIKGKTRNIAAVITYQNIGQDLS
HP QSIQRGIQVTMVIEVGKK---HGPWVNHYSIFFVSVSFFIITAATVGYFIFYSARRLRNA
....* .**. * *.. . .*. *..***.* **. .... ..*** .*,*
DM LTLDKGYNVTISIIEGRRGVRTISSLNRTSVLFVSIS-FIV-DDILCWLIFYYIQRFRYM
HP RAQSRKQRQLKADAKKAIGRLQLRTLKQGDKEIGPDGDSCAVCIELYKPNDLVRILTCNH
.*.... *.*' . .**** ... .* * ,* * , *,*,**,*** ***,* ,***,*,*
DM QARDQQSRNLCSVTKKAIMKIPTKTGKFSD-EKDLDSDCCAICIEAYRPTDTIRILPCRH
HP IFHKTCVDPWLLEHRTCPMCKCDILKALGIEVDVEDGSVSLQVPVSNEISNSASSHEEDN
***,*,****,********* *,** * *,
DM EFHKNCIDPWLIEHRTCPMCKLDVLKFYGYWGDQIYQTPSPQHTAPIASIEEVPVIWA
HP RSETASSGYASVQGTDEPPLEEHVQSTNESLQLVNHEANSVAVDVIPHVDNPTFEEDETP
DM VPHGPQPLQPLQASNMSSFAPSHYFQSSRSPSSSVQQQLAPLTYQPHPQQAASERGRRNS
HP NQETAVREIKS
DM APATMPHAITASHQVTDV
Furthermore, the search of the GenBank using the base
sequences of the present cDNA has revealed the registration
of sequences that shared a homology of 90% or more (for
example, Accession No. AA155685) in ESTs, but, since they
are partial sequences, it can not be judged whether or~not
any of these sequences codes for the same protein as the
protein of the present invention.
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The present invention provides human proteins having
hydrophobic domains, DNAs coding for these proteins, and
expression vectors for these DNAs as well as eucaryotic
cells expressing these DNAs. All of the proteins of the
present invention are secreted or exist in the cell membrane,
so that they are considered to be proteins controlling the
proliferation and/or the differentiation of the cells.
Accordingly, the proteins of the present invention can be
employed as pharmaceuticals such as carcinostatic agents
which act to control the proliferation and/or the
differentiation of the cells, or as antigens for preparing
antibodies against these proteins. The DNAs of the present
invention can be utilized as probes for the genetic
diagnosis and gene sources for the gene therapy. Furthermore,
the DNAs can be utilized for large-scale expression of these
proteins. Cells into which these genes are introduced to
express these proteins, can be utilized for detection of the
corresponding receptors and ligands, screening of novel low-
molecular pharmaceuticals, and so on.
The present invention also provides genes corresponding
to the polynucleotide sequences disclosed herein.
"Corresponding genes" are the regions of the genome that are
transcribed to produce the mRNAs from which cDNA
polynucleotide sequences are derived and may include
contiguous regions of the genome necessary for the regulated
expression of such genes. Corresponding genes may therefore
include but are not limited to coding sequences, 5' and 3'
untranslated regions, alternatively spliced exons, introns,
promoters, enhancers, and silencer or suppressor elements.
The corresponding genes can be isolated in accordance with
known methods using the sequence information disclosed
herein. Such methods include the preparation of probes or
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primers from the disclosed sequence information for
identification and/or amplification of genes in appropriate
genomic libraries or other sources of genomic materials. An
"isolated gene" is a gene that has been separated from the
adjacent coding sequences, if any, present in the genome of
the organism from which the gene was isolated.
Organisms that have enhanced, reduced, or modified
expression of the genes) corresponding to the
polynucleotide sequences disclosed herein are provided. The
IO desired change in gene expression can be achieved through
the use of antisense polynucleotides or ribozymes that bind
and/or cleave the mRNA transcribed from the gene (Albert and
Morris, 1994, Trends Pharmacol. Sci. 15(7): 250-254;
Lavarosky et al., 1997, Biochem. Mol. Med. 62(1): 11-22; and
Hampel, 1998, Prog. Nucleic Acid Res. Mol. Biol. 58: 1-39;
all of which are incorporated by reference herein).
Transgenic animals that have multiple copies of the genes)
corresponding to the polynucleotide sequences disclosed
herein, preferably produced by transformation of cells with
genetic constructs that are stably maintained within the
transformed cells and their progeny, are provided.
Transgenic animals that have modified genetic control
regions that increase or reduce gene expression levels, or
that change temporal or spatial patterns of gene expression,
are also provided (see European Patent No. 0 649 464 B1,
incorporated by reference herein). In addition, organisms
are provided in which the genes) corresponding to the
polynucleotide sequences disclosed herein have been
partially or completely inactivated, through insertion of
extraneous sequences into the corresponding genes) or
through deletion of all or part of the corresponding gene(s).
Partial or complete gene inactivation can be accomplished
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through insertion, preferably followed by imprecise excision,
of transposable elements (Plasterk, 1992, Bioessays 14(9):
629-633; Zwaal et al., 1993, Proc. Natl. Acad. Sci. USA
90(16): 7431-7435; Clark et al., 1994, Proc. Natl. Acad. Sci.
USA 91(2): 719-722; all of which are incorporated by
reference herein), or through homologous recombination,
preferably detected by positive/negative genetic selection
strategies (Mansour et al., 1988, Nature 336: 348-352; U.S.
Patent Nos. 5,464,764; 5,487,992; 5,627,059; 5,631,153;
5,614, 396; 5,616,491; and 5,679,523; all of which are
incorporated by reference herein). These organisms with
altered gene expression are preferably eukaryotes and more
preferably are mammals. Such organisms are useful for the
development of non-human models for the study of disorders
involving the corresponding gene(s), and for the development
of assay systems for the identification of molecules that
interact with the protein products) of the corresponding
gene(s). Where the protein of the present invention is
membrane-bound (e. g., is a receptor), the present invention
also provides for soluble forms of such protein. In such
forms part or all of the intracellular and transmembrane
domains of the protein are deleted such that the protein is
fully secreted from the cell in which it is expressed. The
intracellular and transmembrane domains of proteins of the
invention can be identified in accordance with known
techniques for determination of such domains from sequence
information.
Proteins and protein fragments of the present invention
include proteins with amino acid sequence lengths that are
at least 25%(more preferably at least 50%, and most
preferably at least 75%) of the length of a disclosed
protein and have at least 60% sequence identity (more
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preferably, at least 75% identity; most preferably at least
90% or 95% identity) with that disclosed protein, where
sequence identity is determined by comparing the amino acid
sequences of the proteins when aligned so as to maximize
overlap and identity while minimizing sequence gaps. Also
included in the present invention are proteins and protein
fragments that contain a segment preferably comprising 8 or
more (more preferably 20 or more, most preferably 30 or
more) contiguous amino acids that shares at least 75%
sequence identity (more preferably, at least 85% identity;
most preferably at least 95% identity) with any such segment
of any of the disclosed proteins.
Species homologs of the disclosed polynucleotides and
proteins are also provided by the present invention. As
used herein, a "species homologue" is a protein or
polynucleotide with a different species of origin from that
of a given protein or polynucleotide, but with significant
sequence similarity to the given protein or polynucleotide,
as determined by those of skill in the art. Species
homologs may be isolated and identified by making suitable
probes or primers from the sequences provided herein and
screening a suitable nucleic acid source from the desired
species.
The invention also encompasses allelic variants of the
disclosed polynucleotides or proteins; that is, naturally
occurring alternative forms of the isolated polynucleotide
which also encode proteins which are identical, homologous,
or related to that encoded by the polynucleotides.
The invention also includes polynucleotides with
sequences complementary to those of the polynucleotides
disclosed herein.
The present invention also includes polynucleotides
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capable of hybridizing under reduced stringency conditions,
more preferably stringent conditions, and most preferably
highly stringent conditions, to polynucleotides described
herein. Examples of stringency conditions are shown in the
table 33 below: highly stringent conditions are those that
are at least as stringent as, for example, conditions A-F;
stringent conditions are at least as stringent as, for
example, conditions G-L; and reduced stringency conditions
are at least as stringent as, for example, conditions M-R.
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Table 33
StringencyPolynucleotideHybridHybridization TemperatureWash
ConditionHybrid Lengthand Buffers Temperature
and Buffers
A DNA : DNA >_50 65C; lxSSC -or- 65C; 0.3xSSC
42C; lxSSC,50% formamide
B DNA : DNA <50 TB*; lxSSC TB*; IxSSC
C DNA : RNA >_50 67C; lxSSC -or- 67~C; 0.3xSSC
45C; lxSSC,50% formamide
D DNA : RNA <50 TD*; lxSSC To*; lxSSC
E RNA : RNA X50 70C; lxSSC -or- 70C; 0.3xSSC
50C; lxSSC,50% formamide
F RNA : RNA <50 TF*; lxSSC Tr*; lxSSC
G DNA : DNA Z50 65C; 4xSSC -or- 65C; lxSSC
42C; 4xSSC,50% formamide
H DNA : DNA <50 TH*; 4xSSC TH*; 4xSSC
I DNA : RNA X50 67~; 4xSSC -or- 67C; lxSSC
4590; 4xSSC,50% formamide
J DNA : RNA <50 TJ*; 4xSSC Td*; 4xSSC
K RNA : RNA >_50 70~; 4xSSC -or- 6790; lxSSC
50qC; 4xSSC,50% formamide
L RNA : RNA <50 TL*; 2xSSC TL*; 2xSSC
M DNA : DNA __>50 50~; 4xSSC -or- 50~C; 2xSSC
40C; 6xSSC,50% formamide
N DNA : DNA <50 TH*; 6xSSC TN*; 6xSSC
O DNA : RNA >_50 55C; 4xSSC -or- 55~; 2xSSC
42~; 6xSSC,50% formamide
P DNA : RNA <50 TP*; 6xSSC TP*; 6xSSC
Q RNA : RNA >_50 60C; 4xSSC -or- 60C; 2xSSC
45~; 6xSSC,50% formamide
R RNA : RNA <50 TR*; 4xSSC TR*; 4xSSC
$ : The hybrid length is that anticipated for the hybridized regions) of the
hybridizing polynucleotides. When hybridizing a polynucleotide to a target
polynucleotide of unknown sequence, the hybrid length is assumed to be that of
the
hybridizing polynucleotide. When polynucleotides of known sequencx are
hybridized,
the hybrid length can be determined by aligning the sequences of the
polynucleotides
and identifying the region or regions of optimal sequence complementarity.
f : SSPE (lxSSPE is 0.15M NaCI, lOmM NaH2P04, and 1.25mM EDTA, pH7.4)
can be substituted for SSC (lxSSG is 0.15M NaCI and lSmM sodium citrate) in
the
hybridization and wash buffers; washes are performed for 15 minutes after
hybridization is complete.
'"'TH - TR : The hybridization temperature for hybrids anticipated to be less
than
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50 base pairs in length should be 5-10°C less than the melting
temperature (T~ of the
hybrid, where T~, is determined according to the following equations. For
hybrids less
than 18 base pairs in length, T~,(°C)=2(#of A + T bases) + 4(# of G + C
bases). For
hybrids between 18 and 49 base pairs in length, Tm('C)=81.5 + 16.6(log,o[Na'])
+ 0.41
(%G+C) - (600/I~, where N is the number of bases in the hybrid, and [Na+] is
the
concentration of sodium ions in the hybridization buffer ([Na'] for
lxSSC~.1651V1).
Additional examples of stringency conditions for
polynucleotide hybridization are provided in Sambrook, J.,
E.F. Fritsch, and T. Maniatis, 1989, Molecular Cloning: A
Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold
Spring Harbor, NY, chapters 9 and 11, and Current Protocols
in Molecular Biology, 1995, F.M. Ausubel et al., eds., John
Wiley & Sons, Inc., sections 2.10 and 6.3-6.4, incorporated
herein by reference.
Preferably, each such hybridizing polynucleotide has a
length that is at least 25%(more preferably' at least 50%,
and most preferably at least 75%) of the length of the
polynucleotide of the present invention to which it
hybridizes, and has at least 60% sequence identity (more
preferably, at least 75% identity; most preferably at least
90% or 95% identity) with the polynucleotide of the present
invention to which it hybridizes, where sequence identity is
determined by comparing the sequences of the hybridizing
polynucleotides when aligned so as to maximize overlap and
identity while minimizing sequence gaps.
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Sequence listing
<110> Sagami Chemical Research Center; Protegene Inc.
<120> Human Proteins Having Hydrophobic Domains And DNAs Encoding These
Proteins
<130> 661102
<150> JP 10-208820
<151> 1998-07-24
<150> JP 10-224105
<151> 1998-08-07
<150> JP 10-238116
<151> 1998-08-25
<150> JP 10-254736
<151> 1998-09-09
<150> JP 10-275505
<I51> 1998-09-29
<160> 150
<170> Windows 95 (Word 98)
<210> 1
<211> 125
<212> PRT
<213> Homo Sapiens
<400> 1
Met Ala Lys Tyr Leu Ala Gln Ile Ile Val Met Gly Val Gln Val Val
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1 5 10 15
Gly Arg Ala Phe Ala Arg Ala Leu Arg Gln Glu Phe Ala Ala Ser Arg
' 20 25 30
Ala Ala Ala Asp Ala Arg Gly Arg Ala Gly His Arg Ser Ala Ala Ala
35 40 45
Ser Asn Leu Ser Gly Leu Ser Leu Gln Glu Ala Gln Gln Ile Leu Asn
50 55 60
Val Ser Lys Leu Ser Pro Glu Glu Val Gln Lys Asn Tyr Glu His Leu
65 70 75 80
Phe Lys Val Asn Asp Lys Ser Val Gly Gly Ser Phe Tyr Leu Gln Ser
85 90 g5
Lys Val Val Arg Ala Lys Glu Arg Leu Asp Glu Glu Leu Lys Ile Gln
100 105 110
Ala Gln Glu Asp Arg Glu Lys Gly Gln Met Pro His Thr
115 120 125
<210> 2
<211> 131
<212> PRT
<213> Homo sapiens
<400> 2
Met Ala Gly IIe Lys Ala Leu Ile Ser Leu Ser Phe Gly Gly Ala Ile
1 5 10 15
Gly Leu Met Phe Leu Met Leu Gly Cys Ala Leu Pro Ile Tyr Asn Lys
20 25 30
Tyr Trp Pro Leu Phe Val Leu Phe Phe Tyr Ile Leu Ser Pro Ile Pro
40 45
Tyr Cys Ile Ala Arg Arg Leu Val Asp Asp Thr Asp Ala Met Ser Asn
30 50 55 60
Ala Cys Lys Glu Leu Ala Ile Phe Leu Thr Thr Gly Ile Val Val Ser
65 70 75 80
Ala Phe Gly Leu Pro Ile Val Phe Ala Arg Ala His Leu Ile Glu Trp
85 90 95
35 Gly Ala Cys Ala Leu Val Leu Thr Gly Asn Thr Val Ile Phe Ala Thr
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I00 105 110
Ile Leu Gly Phe Phe Leu Val Phe Gly Ser Asn Asp Asp Phe Ser Trp
115 120 125
Gln Gln Trp
130
<210> 3
<211> 242
<212> PRT
<213> Homo sapiens
<400> 3
Met Ala Lys His Glu Gln Ile Leu Val Leu Asp Pro Pro Thr Asp Leu
1 5 10 15
Lys Phe Lys Gly Pro Phe Thr Asp Val Val Thr Thr Asn Leu Lys Leu
25 30
Arg Asn Pro Ser Asp Arg Lys Val Cys Phe Lys Val Lys Thr Thr Ala
35 40 45
Pro Arg Arg Tyr Cys Val Arg Pro Asn Ser Gly Ile Ile Asp Pro Gly
20 50 55 60
Ser Thr Val Thr Val Sex Val Met Leu Gln Pro Phe Asp Tyr Asp Pro
65 70 75 80
Asn Glu Lys Ser Lys His Lys Phe Met Val Gln Thr Ile Phe Ala Pro
B5 90 g5
Pro Asn Thr Ser Asp Met Glu Ala Val Trp Lys Glu Ala Lys Pro Asp
100 105 lI0
Glu Leu Met Asp Ser Lys Leu Arg Cys Val Phe Glu Met Pro Asn Glu
115 120 125
Asn Asp Lys Leu Asn Asp Met Glu Pro Ser Lys Ala Val Pro Leu Asn
130 135 140
Ala Ser Lys Gln Asp Gly Pro Met Pro Lys Pro His Ser Val Ser Leu
145 150 155 160
Asn Asp Thr Glu Thr Arg Lys Leu Met Glu Glu Cys Lys Arg Leu Gln
165 I70 175
Gly Glu Met Met Lys Leu Ser Glu Glu Asn Arg His Leu Arg Asp Glu
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180 185 190
Gly Leu Arg Leu Arg Lys Val Ala His Ser Asp Lys Pro Gly Ser Thr
195 200 205
Ser Thr Ala Ser Phe Arg Asp Asn Val Thr Ser Pro Leu Pro Ser Leu
210 215 220
Leu Val Val Ile Ala Ala Ile Phe Ile Gly Phe Phe Leu Gly Lys Phe
225 230 235 240
Ile Leu
<210> 4
<211> 264
<212> PRT
<213> Homo sapiens
<400> 4
Met Phe Val Pro Cys Gly Glu Ser Ala Pro Asp Leu Ala Gly Phe Thr
1 5 10 15
Leu Leu Met Pro Ala Val Ser Val Gly Asn Val Gly Gln Leu Ala Met
25 30
20 Asp Leu Ile Ile Ser Thr Leu Asn Met Sex Lys Ile Gly Tyr Phe Tyr
35 40 45
Thr Asp Cys Leu Val Pro Met Val Gly Asn Asn Pro Tyr Ala Thr Thr
50 55 60
Glu Gly Asn Ser Thr Glu Leu Ser Ile Asn Ala Glu Val Tyr Ser Leu
65 70 75 80
Pro Ser Arg Lys Leu Val Ala Leu Gln Leu Arg Ser Ile Phe Ile Lys
85 90 g5
Tyr Lys Ser Lys Pro Phe Cys Glu Lys Leu Leu Ser Trp Val Lys Ser
100 105 110
Ser Gly Cys Ala Arg Val Ile Val Leu Ser Ser Ser His Ser Tyr Gln
115 120 125
Arg Asn Asp Leu Gln Leu Arg Ser Thr Pro Phe Arg Tyr Leu Leu Thr
130 135 140
Pro Ser Met Gln Lys Ser Val Gln Asn Lys Ile Lys Ser Leu Asn Trp
145 150 155 160
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Glu Glu Met Glu Lys Ser Arg Cys Ile Pro Glu Ile Asp Asp Ser Glu
165 170 i~~
Phe Cys Ile Arg Ile Pro Gly Gly Gly Ile Thr Lys Thr Leu Tyr Asp
180 185 190
Glu Ser Cys Ser Lys Glu Ile Gln Met Ala Val Leu Leu Lys Phe Val
195 200 205
Ser Glu Gly Asp Asn Ile Pro Asp Ala Leu Gly Leu Val Glu Tyr Leu
210 215 220
Asn Glu Trp Leu Gln Ile Leu Lys Pro Leu Ser Asp Asp Pro Thr Val
225 230 235 240
Ser Ala Ser Arg Trp Lys Ile Pro Ser Ser Trp Arg Leu Leu Phe Gly
245 250 255
Ser Gly Leu Pro Pro Ala Leu Phe
260
<210> 5
<211> 112
<212> PRT
<213> Homo sapiens
<400> 5
Met Gly Ser Arg Leu Ser Gln Pro Phe Glu Ser Tyr Ile Thr Ala Pro
1 5 10 15
Pro Gly Thr Ala Ala Ala Pro Ala Lys Pro Ala Pro Pro Ale Thr Pro
20 25 30
Gly Ala Pro Thr Ser Pro Ala Glu His Arg Leu Leu Lys Thr Cys Trp
40 45
Ser Cys Arg Val Leu Ser Gly Leu Gly Leu Met Gly Ala Gly Gly Tyr
50 55 60
3U Val Tyr Trp Val Ala Arg Lys Pro Met Lys Met Gly Tyr Pro Pro Ser
65 70 75 80
Pro Trp Thr Ile Thr Gln Met Val Ile Gly Leu Ser Ile Ala Thr Trp
85 90 95
Gly Ile Val Val Met Ala Asp Pro Lys Gly Lys Ala Tyr Arg Val Val
35 loo l05 llo
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<210> 6
<211> 146
<212> PRT
<213> Homo sapiens
<400> 6
Met Leu Ala Gly Ala Gly Arg Pro Gly Leu Pro Gln Gly Arg His Leu
1 5 10 15
Cys Trp Leu Leu Cys Ala Phe Thr Leu Lys Leu Cys Gln Ala Glu Ala
25 30
Pro Val Gln Glu Glu Lys Leu Ser Ala Ser Thr Ser Asn Leu Pro Cys
35 40 45
Trp Leu Val Glu Glu Phe Val Val Ala Glu Glu Cys Ser Pro Cys Ser
15 50 55 60
Asn Phe Arg Ala Lys Thr Thr Pro Glu Cys Gly Pro Thr Gly Tyr Val
65 70 75 8p
Glu Lys Ile Thr Cys Ser Ser Ser Lys Arg Asn Glu Phe Lys Ser Cys
85 90 95
20 Arg Ser Ala Leu Met Glu Gln Arg Leu Phe Trp Lys Phe Glu Gly Ala
100 105 110
Val Val Cys Val Ala Leu Ile Phe Ala Cys Leu Val Ile Ile Arg Gln
115 120 125
Arg Gln Leu Asp Arg Lys Ala Leu Glu Lys Val Arg Lys Gln Ile Glu
130 135 140
Ser Ile
145
<210> 7
<211> 344
<212> PRT
<213> Homo Sapiens
<400> 7
Met Asp Phe Leu Val Leu Phe Leu Phe Tyr Leu Ala Ser Val Leu Met
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1 5 10 15
Gly Leu Val Leu Ile Cys Val Cys Ser Lys Thr His Ser Leu Lys Gly
20 25 30
Leu Ala Arg Gly Gly Ala Gln Ile Phe Ser Cys Ile Ile Pro Glu Cys
35 40 45
Leu Gln Arg Ala Val His Gly Leu Leu His Tyr Leu Phe His Thr Arg
50 55 60
Asn His Thr Phe Ile Val Leu His Leu Val Leu Gln Gly Met Vai Tyr
65 70 75 80
Thr Glu Tyr Thr Trp Glu Val Phe Gly Tyr Cys Gln~Glu Leu Glu Leu
85 90 95
Ser Leu His Tyr Leu Leu Leu Pro Tyr Leu Leu Leu Gly Val Asn Leu
100 105 110
Phe Phe Phe Thr Leu Thr Cys Gly Thr Asn Pro Gly Ile Ile Thr Lys
115 120 125
Ala Asn Glu Leu Leu Phe Leu His Val Tyr Glu Phe Asp Glu Val Met
130 135 140
Phe Pro Lys Asn Val Arg Cys Ser Thr Cys Asp Leu Arg Lys Pro Als
145 150 155 160
Arg Ser Lys His Cys Ser Val Cys Asn Trp Cys Val His Arg Phe Asp
165 170 175
His His Cys Val Trp Val Asn Asn Cys Ile Gly Ala Trp Asn Ile Arg
1B0 185 190
Tyr Phe Leu Ile Tyr Val Leu Thr Leu Thr Ala Ser Ala Ala Thr Val
2~ 195 200 205
Ala Ile Val Ser Thr Thr Phe Leu Val His Leu Val Val Met Ser Asp
210 2I5 220
Leu Tyr Gln Glu Thr Tyr Ile Asp Asp Leu Gly His Leu His Val Met
225 230 235 240
Asp Thr Val Phe Leu Ile Gln Tyr Leu Phe Leu Thr Phe Pro Arg Ile
245 250 255
Val Phe Met Leu Gly Phe Val Val Val Leu Ser Phe Leu Leu Gly Gly
260 265 270
Tyr Leu Leu Phe Val Leu Tyr Leu Ala Ala Thr Asn Gln Thr Thr Asn
275 280 285
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Glu Trp Tyr Arg Gly Asp Trp Ala Trp Cys Gln Arg Cys Pro Leu Val
290 295 300
Ala Trp Pro Pro Ser Ala Glu Pro Gln Val His Arg Asn Ile His Ser
305 310 315 320
His Gly Leu Arg Ser Asn Leu Gln Glu Ile Phe Leu Pro Ala Phe Pro
325 330 335
Cys His Glu Arg Lys Lys Gln Glu
340
<210> 8
<211> 97
<212> PRT
<2I3> Homo sapiens
<400> a
Met Thr Lys Lys Lys Arg Glu Asn Leu Gly Val Ala Leu Glu Ile Asp
1 5 10 15
Gly Leu Glu Glu Lys Leu Ser Gln Cys Arg Arg Asp Leu Glu Ala Val
25 30
20 Asn Ser Arg Leu His Ser Arg Glu Leu Ser Pro Glu Ala Arg Arg Ser
35 40 45
Leu Glu Lys Glu Lys Asn Ser Leu Met Asn Lys Ala Ser Asn Tyr Glu
50 55 60
Lys Glu Leu Lys Phe Leu Arg Gln Glu Asn Arg Lys Asn Met Leu Leu
65 70 75 g0
Ser Val Ala Ile Phe Ile Leu Leu Thr Leu Val Tyr Ala Tyr Trp Thr
85 90 95
Met
<210> 9
<211> 124
<212> PRT
<213> Homo sapiens
<400> 9
Tyr Leu Leu Phe Val Leu Tyr Leu Ala
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Met Ala Thr Ser Ser Met Ser Lys Gly Cys Phe Val Phe Lys Pro Asn
1 5 10 15
Ser Lys Lys Arg Lys Ile Ser Leu Pro Ile Glu Asp Tyr Phe Asn Lys
20 25 30
Gly Lys Asn Glu Pro Glu Asp Ser Lys Leu Arg Phe Glu Thr Tyr Gln
35 40 45
Leu Ile Trp Gln Gln Met Lys Ser Glu Asn Glu Arg Leu Gln Glu Glu
50 55 60
Leu Asn Lys Asn Leu Phe Asp Asn Leu Ile Glu Phe Leu Gln Lys Ser
65 70 75 80
His Ser Gly Phe Gln Lys Asn Ser Arg Asp Leu Gly Gly Gln Ile Lys
85 90 95
Leu Arg Glu Ile Pro Thr Ala Ala Leu Val Leu Gly Ile Tyr Ala Tyr
100 105 110
Val Cys Ser Cys Met His Leu Cys Val Phe Arg Phe
115 120
<210> 10
<211> 327
<212> PRT
<213> Homo sapiens
<400> 10
Met Ala Glu Leu Pro Gly Pro Phe Leu Cys Gly Ala Leu Leu Gly Phe
1 5 10 15
Leu Cys Leu Ser Gly Leu Ala Val Glu Val Lys Val Pro Thr Glu Pro
20 25 30
Leu Ser Thr Pro Leu Gly Lys Thr Ala Glu Leu Thr Cys Thr Tyr Ser
40 45
30 Thr Ser Val Gly Asp Ser Phe Ala Leu Glu Trp Ser Phe Val Gln Pro
50 55 60
Gly Lys Pro Ile Ser Glu Ser His Pro Ile Leu Tyr Phe Thr Asn Gly
65 70 75 80
His Leu Tyr Pro Thr Gly Ser Lys Ser Lys Arg Val Ser Leu Leu Gln
35 85 90 95
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Asn Pro Pro Thr Val Gly Val Ala Thr Leu Lys Leu Thr Asp Val His
100 105 110
Pro Ser Asp Thr Gly Thr Tyr Leu Cys Gln Val Asn Asn Pro Pro Asp
115 120 125
Phe Tyr Thr Asn Gly Leu Gly Leu Ile Asn Leu Thr Val Leu Val Pro
130 135 140
Pro Ser Asn Pro Leu Cys Ser Gln Ser Gly Gln Thr Ser Val Gly Gly
145 150 155 160
Ser Thr Ala Leu Arg Cys Ser Ser Ser Glu Gly Ala Pro Lys Pro Val
165 170 175
Tyr Asn Trp Val Arg Leu Gly Thr Phe Pro Thr Pro Ser Pro Gly Ser
180 185 190
Met Val Gln Asp Glu Val Ser Gly Gln Leu Ile Leu Thr Asn Leu Ser
195 200 205
Leu Thr Ser Ser Gly Thr Tyr Arg Cys Val Ala Thr Asn Gln Met Gly
210 215 220
Ser Ala Ser Cys Glu Leu Thr Leu Ser Val Thr Glu Pro Ser Gln Gly
225 230 235 240
Arg Val Ala Gly Ala Leu Ile Gly Val Leu Leu Gly Val Leu Leu Leu
245 250 255
Ser Val Alc Ala Phe Cys Leu Val Arg Phe Gln Lys Glu Arg Gly Lys
260 265 270
Lys Pro Lys Glu Thr Tyr Gly Gly Ser Asp Leu Arg Glu Asp Ala Ile
275 280 285
Ala Pro Gly Ile Ser Glu His Thr Cys Met Arg Ala Asp Ser Ser Lys
290 295 300
Gly Phe Leu Glu Arg Pro Ser Ser Ala Ser Thr Val Thr Thr Thr Lys
305 310 315 320
Ser Lys Leu Pro Met Val Val
325
<210> 11
<211> 375
<212> DNA
<213> Homo sapiens
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<400> 11
atggccaagt acctggcccagatcattgtgatgggcgtgcaggtggtgggcagggccttt60
gcacgggcct tgcggcaggagtttgcagccagccgggccgcagctgatgcccgaggacgc120
gctggacacc ggtctgcagccgcttccaacctctccggcctcagcctccaggaggcacag180
.
cagattctca acgtgtccaagctgagccctgaggaggtccagaagaactatgaacactta240
tttaaggtga atgataaatccgtgggtggctccttctacctgcagtcaaaggtggtccgc300
gcaaaggage gcctggatgaggaactcaaaatccaggcccaggaggacagagaaaaaggg360
cagatgcccc atacg 375
<210> 12
<211> 393
<212> DNA
<213> Homo sapiens
<400> 12
atggcaggca tcaaagctttgattagtttgtcctttggaggagcaatcggactgatgttt60
ttgatgcttg gatgtgcccttccaatatacaacaaetactggcccctctttgttctattt120
ttttacatcc tttcacctattccatactgcatagcaagaagattagtggatgatacagat180
gctatgagta acgcttgtaaggaacttgccatctttcttacaacgggcattgtcgtgtca240
gcttttggac tccctattgtatttgccagagcacatctgattgagtggggagcttgtgca300
cttgttctca caggaaacacagtcatctttgcaactatactaggctttttcttggtcttt360
ggaagcaatg acgacttcagctggcagcagtgg 393
<210> 13
<211> 726
<212> DNA
<213> Homo sapiens
<400> 13
atggcgeagc acgagcagatcctggtcctcgatccgcccacagacctcaaattcaaaggc60
cccttcacag atgtagtcactacaaatcttaaattgcgaaatccatcggatagaaaagtg120
tgtttcaaag tgaagactacagcacctcgccggtactgtgtgaggcccaacagtggaatt180
attgacccag ggtcaactgtgactgtttcagtaetgctacagccctttgactatgatccg240
aatgaaaaga gtaaacacaagtttatggtacagacaatttttgctccaccaaacacttca300
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
12/177
gatatggaag ctgtgtggaaagaggcaaaacctgatgaattaatggattccaaattgaga360
tgcgtatttg aaatgcccaatgaaaatgatasattgaatgatatggaacctagcaaagct420
gttccactga atgcatctsagcaagatggacctatgccaaaaccacacagtgtttcactt480
aatgataccg aaacaaggaaactaatggaagagtgtaaaagacttcagggagaaatgatg540
aagctatcag aagasaatcggcacctgagagatgaaggtttaaggctcagaaaggtagca600
cattcggata aacctggatcaacctcaactgcatccttcagagataatgtcaccagtcct660
cttccttcac ttcttgttgtaattgcagccattttcattggattctttctagggaaattc720
atcttg 726
<210> 14
<211> 792
<212> DNA
<213> Homo sapiens
<400> I4
atgttcgttc cctgcggggagtcggcccccgaccttgccggcttcaccctcctaatgcca60
gcagtatctg ttggaastgttggccagcttgcaatggatctgattatttctacactgaat120
atgtctaaga ttggttacttctataccgattgtcttgtgccaatggttggaaacaatcca180
tatgcgacca cagaaggasattcaacagaacttagcataaatgctgaagtgtattcattg240
ccttcasgaa agctggtggctctacagttaagatccatttttattaagtataaatcaaag300
ccattetgtg aaaaactgctttcctgggtgaaaagcagtggctgtgccagagtcattgtt360
ctttcgagca gtcattcatatcagcgtaatgatctgcagcttcgtagtactcccttccgg420
tacctactta caccttccatgcaaaaaagtgttcaaaataaaataaagagccttasctgg480
gaagasatgg aaasaagccggtgcattcctgaaatagatgattccgagttttgtatccgc540
attccgggag gaggtatcacaaaaacactctatgatgaaagctgttctaaagaaatccaa600
atggcagttc tgctgaaatttgtttcagaaggggacaacatcccagatgcattaggtctt660
gttgagtatc ttaatgagtggcttcagataetcaaaccacttagcgatgaccccacagta720
tctgcctcac ggtggaaaataccaagttcttggagattactctttggcagtggtcttccc780
cctgcacttt tc 792
<210> 15
<211> 336
<212> DNA
<213> Homo Sapiens
CA 02336225 2001-O1-24
WO 00/05367 PC'T/JP99/03929
13/177
<400> 15
atggggtctc ggttgtcccagccttttgagtcctatatcactgcgcctcccggtaccgcc60
gccgcgcccg ccaaacctgcgcccccagctacacccggagcgccgacctccccagcagaa120
caccgcctgt tgaagacctgctggagctgtcgcgtgctttctgggttggggctgatgggg180
gcgggcgggt acgtgtactgggtggcacggaagcccatgaagatgggataccccccgagt240
ccatggacca ttacgcagatggtcatcggcctcagcattgccacctggggtatcgttgtc300
atggcagacc ccaaagggaaggcctaccgcgttgtt 336
<210> 16
<211> 438
<212> DNA
<213> Homo Sapiens
<400> 16
atgcttgcgg gtgccgggaggcctggcctcccccagggccgccacctctgctggttgctc60
tgtgctttca ccttaaagctctgccaagcagaggctcccgtgcaggaagagaagctgtca120
gcaagcacct caaatttgccatgctggctggtggaagagtttgtggtagcageagagtgc180
tctccatgct ctaatttccgggctaaaactacccctgagtgtggtcccacaggatatgta240
gagsaaatca catgcagctcatctaagagaaatgagttcaaaagctgccgctcagctttg300
atggaacasc gcttattttggaagttcgaaggggctgtcgtgtgtgtggccctgatcttc360
gcttgtcttg tcatcattcgtcagcgacaattggacagaaaggctctggaaaaggtccgg420
aagcaaatcg agtccata 438
<210> 17
<211> 1032
<212> DNA
<213> Homo Sapiens
<400> 17
atggactttc tggtcctcttcttgttctacctggcttcggtgctgatgggtcttgttctt60
atctgcgtct gctcgaaaacccatagcttgaaaggcctggccaggggaggagcacagata120
ttttcctgta taattccagaatgtcttcagagagccgtgcatggattgcttcattacctt180
ttccatacga gacaccacaccttcattgtcctgcacctggtcttgcaagggatggtttat240
actgagtaca cctgggaagtatttggctactgtcaggagctggagttgtccttgcattac300
cttcttctgc cctatctgctgctaggtgtaaacctgttttttttcaccctgacttgtgga360
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
14/177
accaatcctg gcattateacaaaagcaaetgaattattatttcttcatgtttatgaattt420
gatgaagtga tgtttccaaagaacgtgaggtgctctacttgtgatttaaggaaaccagct480
cgatccaagc actgcagtgtgtgtaactggtgtgtgcaccgtttcgaccatcactgtgtt540
tgggtgaaca actgcatcggggcctggaacatcaggtacttcctcatctacgtcttgacc600
ttgacggcct cggctgccaccgtcgccattgtgagcaccacttttctggtccacttggtg660
gtgatgtcag atttataccaggagacttacatcgatgaccttggacacctccatgttatg720
gacacggtct ttcttattcagtacctgttcctgacttttccacggattgtcttcatgctg780
ggctttgtcg tggttctgagcttcctcctgggtggctacctgttgtttgtcctgtatctg840
gcggccacca accagactactaacgagtggtacagaggtgactgggcctggtgccagcgt900
tgtccccttg tggcctggcctccgtcagcagagccccaagtccaccggaacattcactcc960
catgggcttc ggagcaaccttcaagagatctttctacctgcctttccatgtcatgagagg1020
aagaaacaag as 1032
<210> 18
<211> 291
<212> DNA
<213> Homo sapiens
<400> 18
atgactaaaa agaagcgggagaatctgggcgtcgctctagagatcgatgggctagaggag60
aagctgtccc agtgtcggagagacctggaggccgtgaactccagactccacagccgggag120
ctgagcccag aggccaggaggtccctggagaaggagaaaaacagcctaatgaacaaagcc180
tccaactacg agaaggaactgaagtttcttcggcaagagaaccggaagaacatgctgctc240
tctgtggcca tctttatcctcctgacgctcgtctatgcctactggaccatg 291
<210> 19
<211> 372
<212> DNA
<213> Homo sapiens
<400> 19
atggctacgt cctcgatgtc taagggttgc tttgttttta agccaaactc caaaaagaga 60
aagatctctc tgccaataga ggactatttt aacaaaggga aaaatgagcc tgaggacagt 120
sagcttcgat tcgaaactta tcagttgata tggcagcaga tgaaatctga aaatgagcga 180
ctaca8gagg sattaaataa aaacttgttt gacaatctga ttgaatttct gcaaaastca 240
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
15/177
cattctggat tccagaagaa ttcaagagac ttgggcggtc aaataaaact cagagaaatt 300
ccaactgctg ctcttgttct tggtatatat gcgtatgttt gttcatgcat gcatctctgt 360
gtatttcgtt tt 372
<210> 20
<211> 981
<212> DNA
<213> Homo Sapiens
<400> 20
atggccgagc tcccggggcc ctttctctgc ggggccctgc taggcttcct gtgcctgagt 60
gggctggccg tggaggtgaa ggtacccaca gagccgctga gcacgcccct ggggaagaca 120
gccgagctga cctgcaccta cagcacgtcg gtgggagaca gcttcgccct ggagtggagc 180
tttgtgcagc ctgggaaacc catctctgag tcccatccaa tcctgtactt caccaatggc 240
catctgtatc caactggttctaagtcaaagcgggtcagcctgcttcagaacceccccaca300
gtgggggtgg ccacactgaaactgactgacgtccacccctcagatactggaacetacctc360
tgccaagtca acaacccaccagatttctacaccaatgggttggggctaatcaaccttact420
gtgctggttc cccccagtaatcccttatgcagtcagagtggacaaecctctgtgggaggc480
tctactgcac tgagatgcagctcttccgagggggctcctaagccagtgtacaactgggtg540
cgtcttggaa cttttcctacaccttctcctggcagcatggttcaagatgaggtgtctggc600
cagctcattc tcaccaacctctccctgacctcctcgggcacctaccgctgtgtggccacc660
aaccagatgg gcagtgcatcctgtgagctgaccctctctgtgaccgaaccctcccaaggc720
cgagtggccg gagctctgattggggtgctcctgggcgtgctgttgctgtcagttgctgcg780
ttctgcctgg tcaggttccagaasgagagggggaagaagcccaaggagacatatgggggt840
agtgaccttc gggaggatgccatcgctcctgggatctctgagcacacttgtatgagggct900
gattctagca aggggttcctggaaagaccctcgtctgccagcaccgtgacgaccaccaag960
tccaagctcc ctatggtcgtg 981
<210> 21
<211> 510
<212> DNA
<213> Homo Sapiens
<220>
<221> CDS
<222> (66)...(443)
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
16/177
<400> 21
acgcttgatc cccggccgcg gggccaggaa gtcggagttt ggcagagcgg60
gagccccgga
ctgcc atg gcc aag tac ctg gcc cag atc att gtg 110
atg ggc gtg cag gtg
Met Ala Lys Tyr Leu Ala Gln Ile Ile Val Met
Gly Val Gln Val
I 5 10 15
gtg ggc agg gcc ttt gca cgg gcc ttg cgg cag gcc agc 158
gag ttt gca
Val Gly Arg Ala Phe Ala Arg Ala Leu Arg Gln Ala Ser
Glu Phe Ala
20 25 30
cgg gcc gca get gat gcc cga gga cgc get gga gca gcc 206
cac cgg tct
Arg Ala Ala Ala Asp Ala Arg Gly Arg Ala Gly Ala Ala
His Arg Ser
35 40 45
get tcc aac ctc tcc ggc ctc agc ctc cag gag att ctc 254
gca cag cag
Ala Ser Asn Leu Ser Gly Leu Ser Leu Gln Glu Ile Leu
Ala Gln Gln
50 55 60
eac gtg tcc aag ctg agc cct gag gag gtc cag gaa cac 302
aag aac tat
Asn Val Ser Lys Leu Ser Pro Glu Glu Val Gln Glu His
Lys Asn Tyr
65 70 75
tta ttt asg gtg sat gat aaa tcc gtg ggt ggc ctg cag 350
tcc ttc tac
Leu Phe Lys Val Asn Asp Lys Ser Val Gly Gly Leu Gln
Ser Phe Tyr
80 85 90 g5
tca aag gtg gtc cgc gca aag gag cgc ctg gat aaa atc 398
gag gsa ctc
Ser Lys Val Val Arg Ala Lys Glu Arg Leu Asp Lys Ile
Glu Glu Leu
I00 105 110
cag gcc cag gag gac aga gaa asa ggg cag atg tgactgctc450
. ccc cat acg
Gln Ala GIn Glu Asp Arg Glu Lys Gly Gln Met
Pro His Thr
115 120 125
gctccccccg cccaccccgc cgcctctaat ttatagcttg 510
gtaataaatt tcttttctgc
<210> 22
<211> 697
<212> DNA
<213> Homo sapiens
<220>
<221> cDs
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
17/177
<222> (104)...(499)
<400> 22
acttccgggt gttgtctggc ccgctgctgc 60
cgccgtagcg
cgtcttgggt
ctcccggctg
cgc cgccgcctcgggtcgtg gcc atggcaggcatc 115
gagccaggag
cgacgtcacc
MetAlaGlyIle
1
eaa get ttgattagtttgtccttt ggaggagcaatc ggactgatgttt 163
Lys Ala LeuIleSerLeuSerPhe GlyGlyAlaIle GlyLeuMetPhe
5 10 15 20
ttg atg cttggatgtgcccttcca atatacaacaaa tactggcecctc 211
Leu Met LeuGlyCysAlaLeuPro IleT AsnL T T P
r s r
y y y rp ro Leu
25 30 35
ttt gtt ctatttttttacatcctt tcacctattcca tactgcatagca 259
Phe Val LeuPhePheTyrIleLeu SerProIlePro T C Il
r
y ys e Ala
40 45 50
aga aga ttagtggatgatacagat getatgagtaac gettgtaaggaa 307
Arg Arg LeuValAspAspThrAsp AlaMetSerAsn AlaCysLysGlu
55 60 65
ctt gcc atctttcttacaacgggc attgtcgtgtca gettttggactc 355
Leu Ala IlePheLeuThrThrGly IleValValSer AlaPheGlyLeu
70 75 80
cct att gta ttt gcc aga gca cat ctg att gag tgg gga get tgt gca 403
Pro Ile Val Phe Ala Arg Ala His Leu Ile Glu Trp Gly Ala Cys Ala
85 90 95 100
ctt gtt ctc aca gga aec aca gtc atc ttt gca act ata cta ggc ttt 45I
Leu Val Leu Thr Gly Asn Thr Val Ile Phe Ala Thr Ile Leu Gly Phe
105 110 115
ttc ttg gtc ttt gga agc aat gac gac ttc agc tgg cag cag tgg tgaa 500
Phe Leu Val Phe Gly Ser Asn Asp Asp Phe Ser Trp Gln Gln Ttp
120 125 130
aagaaattac tgaactattg tcaaatggac ttcctgtcat ttgttggcca ttcacgcaca 560
caggagatgg ggcagttaat gctgaatggt atagcaagcc tcttgggggt attttaggtg 620
ctcccttctc acttttattg taagcatact attttcacag agacttgctg aaggattaaa 680
aggattttct cttttgg 697
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
18/177
<210> 23
<211> 1619
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (287)...(10/5)
<400> 23
gcagaggccg tcacgtgggtcgccgaggctcgcaagtgcgcgtggccgtggcggctggtg60
tggggttgag tcagttgtgggacccggagctgctgacccagcgggtggcccaccgaaccg120
gtgacacagc ggcaggcgttagggctcgggagccgcgagcctggcctcgtcctagagctc180
ggccgagccg tcgccgccgtcgtcccccgcccccagtcagcaaaccgccgccgcgggcgc240
gcccccgctc tgcgctgtctctccgatggcgtccgcctcaggggcc gcg aag 295
atg
Met Ala Lys
1
cac gag cag atc ctg gtc ctc gat ccg ccc aca gac ctc aaa ttc aaa 343
His Glu Gln Ile Leu Val Leu Asp Pro Pro Thr Asp Leu Lys Phe Lys
5 l0 15
ggc ccc ttc aca gat gta gtc act aca aat ctt aaa ttg cga aat cca 391
Gly Pro Phe Thr Asp Val Val Thr Thr Asn Leu Lys Leu Arg Asn Pro
20 25 30 35
tcg gat aga asa gtg tgt ttc aaa gtg aag act aca gca cct cgc cgg 439
Ser Asp Arg Lys Val Cys Phe Lys Val Lys Thr Thr Ala Pro Arg Arg
40 45 50
tac tgt gtg agg ccc aac agt gga att att gac cca ggg tca act gtg 487
Tyr Cys Val Arg Pro Asn Ser Gly Ile Ile Asp Pro Gly Ser Thr Val
55 60 65
act gtt tca gta atg cta cag ccc ttt gac tat gat ccg aat gaa aag 535
Thr Val Ser Val Met Leu Gln Pro Phe Asp Tyr Asp Pro Asn Glu Lys
70 75 80
agt aaa cac aag ttt atg gta cag aca att ttt get cca cca aac act 583
Ser Lys His Lys Phe Met Val Gln Thr Ile Phe Ala Pro Pro Asn Thr
85 90 95
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
19/I77
tca gat atg gaa get gtg tgg aaa gag gca aaa cct gat gaa tta atg 631
Ser Asp Met Glu Ala Val Trp Lys Glu Ala Lys Pro Asp Glu Leu Met
100 105 110 115
gat tcc saa ttg aga tgc gta ttt gaa atg ccc aat gsa aat gat aaa 679
Asp Ser Lys Leu Arg Cys Val Phe Glu Met Pro Asn Glu Asn Asp Lys
120 125 130
ttg aat gat atg gaa cct agc aaa get gtt cca ctg aat gca tct aag 727
Leu Asn Asp Met Glu Pro Ser Lys Ala Val Pro Leu Asn Ala Ser Lys
135 140 145
caa gat gga cct atg cca aaa cca cac agt gtt tca ctt aat gat acc 775
Gln Asp Gly Pro Met Pro Lys Pro His Ser Val Ser Leu Asn Asp Thr
150 155 160
gaa aca agg saa cta atg gaa gag tgt saa aga ctt cag gga gaa atg 823
Glu Thr Arg Lys Leu Met Glu Glu Cys Lys Arg Leu Gln Gly Glu Met
165 170 I75
atg aag cta tca gaa gaa sat cgg cac ctg aga gat gaa ggt tta agg 87I
Met Lys Leu Ser Glu Glu Asn Arg His Leu Arg Asp Glu Gly Leu Arg
180 185 190 195
ctc aga aag gta gca cat tcg gat saa ect gga tca acc tca act gca 919
Leu Arg Lys Val Ala His Ser Asp Lys Pro Gly Ser Thr Ser Thr Ale
200 205 210
tcc ttc aga gat aat gtc acc agt cct ctt cct tca ctt ett gtt gta 967
Ser Phe Arg Asp Asn Val Thr Ser Pro Leu Pro Ser Leu Leu Val Val
215 220 225
att gca ttt cta aea ttc 1012
gcc att ttc ggg atc ttg
att gga ttc
Ile Ala Ala le Gly Phe Leu Lys Phe
Ile Phe I Phe Gly Ile Leu
230 235 240
tagagtgaag catgcagagtgctgtttcttttttttttttttctcttgaccagaaaaa 1070
gatttgttta cctaccatttcattggtagtatggcccacggtgaccatttttttgtgtgt1130
acagcgtcat ataggctttgcctttaatgatctcttacggttagaaaacacaataaaeac1190
aaactgttcg gctactggacaggttgtatattaccagatcatcactagcagatgtcagtt1250
gcacattgag tcctttatgaaattcataaataaagaattgttctttctttgtggttttaa1310
taagagttca agasttgttcagagtcttgtaaatgttattttaataatccctttaaattt1370
tatctgttgc tgttacctcttgasatatgatttatttagattgctaatcccactcattca1430
ggaaatgcca agaggtattccttggggaaatggtgcctcttacagtgtaaatttttcctc1490
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
2aii77
ctttaccttt gctaatatca tggcagaatt tttcttatcc cttgtgaggc agttgttgac 1550
tgagtttttc atccttacaa tcctgtccca tggtatttaa cataaaaaaa aataaaactg 1610
ttaacagat 1619
<210> 24
<211> 1066
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (65)...(859)
<400> 24
cttcttgctg ccctcgttct tgccggggcc gcggttagtc cctgctggcc accccactgc 60
gacc atg ttc gtt ccc tgc ggg gag tcg gcc ccc gac ctt gcc ggc ttc 109
Met Phe Val Pro Cys Gly Glu Ser Ala Pro Asp Leu Ala Gly Phe
1 5 10 15
acc ctc cta atg cca gca gta tct gtt gga aat gtt ggc cag ctt gca 157
Thr Leu Leu Met Pro Ala Val Ser Val Gly Asn Val Gly Gln Leu Ala
20 25 30
atg gat ctg att att tct aca ctg aat atg tct aag att ggt tac ttc 205
Met Asp Leu Ile Ile Ser Thr Leu Asn Met Ser Lys Ile Gly Tyr Phe
35 40 45
tat acc gat tgt ctt gtg cca atg gtt gga aac eat cca tat gcg acc 253
Tyr Thr Asp Cys Leu Val Pro Met Val Gly Asn Asn Pro Tyr Ala Thr
50 55 60
aca gaa gga aat tca aca gaa ctt agc ata aat get gaa gtg tat tca 301
Thr Glu Gly Asn Ser Thr Glu Leu Ser Ile Asn Ala Glu Val Tyr Ser
65 ~n
ttg cct tca aga aag ctg gtg get cta cag tta aga tcc att ttt att 349
Leu Pro Ser Arg Lys Leu Val Ala Leu Gln Leu Arg Ser Ile Phe Ile
80 85 90 95
aag tat aaa tca aag cca ttc tgt gaa aaa ctg ctt tcc tgg gtg aaa 397
Lys Tyr Lys Ser Lys Pro Phe Cys Glu Lys Leu Leu Ser Trp Val Lys
loo 105 llo
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
21/1?7
agc agt ggc tgt gcc aga gtc att gtt ctt tcg agc agt cat tca tat 445
Ser Ser Gly Cys Ala Arg Val Ile Val Leu Ser Ser Ser His Ser Tyr
115 120 125
cag cgt aat gat ctg cag ctt cgt agt act ccc ttc cgg tac cta ctt 493
Gln Arg Asn Asp Leu Gln Leu Arg Ser Thr Pro Phe Arg Tyr Leu Leu
130 135 140
aca cct tcc atg caa aaa agt gtt caa aat aaa ata aag agc ctt aac 541
Thr Pro Ser Met Gln Lys Ser Val Gln Asn Lys Ile Lys Ser Leu Asn
145 I50 155
tgg gaa gaa atg gaa aaa agc cgg tgc att cct gaa ata gat gat tcc 589
Trp Glu Glu Met Glu Lys Ser Arg Cys Ile Pro Glu Ile Asp Asp Ser
160 165 170 175
gag ttt tgt atc cgc att ccg gga gga ggt atc aca aaa aca ctc tat 637
Glu Phe Cys Ile Arg Ile Pro Gly Gly Gly Ile Thr Lys Thr Leu Tyr
180 185 190
gat gaa agc tgt tct aaa gaa atc caa atg gca gtt ctg ctg aaa ttt 685
Asp Glu Ser Cys Ser Lys Glu Ile Gln Met Ala Val Leu Leu Lys Phe
195 200 205
gtt tca gaa ggg gac aac atc cca gat gca tta ggt ctt gtt gag tat 733
Val Ser Glu Gly Asp Asn Ile Pro Asp Ala Leu Gly Leu Val Glu Tyr
210 215 220
ctt aat gag tgg ctt cag ata ctc aaa cca ctt agc gat gac ccc aca 781
Leu Asn Glu Trp Leu Gln Ile Leu Lys Pro Leu Ser Asp Asp Pro Thr
225 230 235
gta tct gcc tca cgg tgg aaa ata cca agt tct tgg aga tta-ctc ttt 829
Val Ser Ala Ser Arg Trp Lys Ile Pro Ser Ser Trp Arg Leu Leu Phe
240 245 250 255
ggc agt ggt ctt ccc cct gca ctt ttc tgatctaatt tctgttttat acct 880
Gly Ser Gly Leu Pro Pro Ala Leu Phe
260
tatacccaaa acacttacta ccaacacagc tgttaascat tctatacaaa aaaattgtat 940
gatctggtat taggaaatta ctttcacagt aaatatcaaa gaaaaaagat taagggtctc 1000
tttgccatgc ttttcatcat atgcaccaaa tgtaaatttt gtacaataaa attttatttc 1060
ctaagt 1066
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
22n~7
<210> 25
<211> 618
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (54)...(392)
<400> 25
gtttacgcca gtttgaacca aagacgccca aggttgaggc cgagttccag56
agc atg
Met
1
ggg tct cgg ttg tcc cag cct ttt gag tcc tat atc act 104
gcg cct ccc
Gly Ser Arg Leu 5er Gln Pro Phe Glu Ser Tyr Ile Thr
Ala Pro Pro
5 to 15
ggt acc gcc gcc gcg ccc gcc aaa cct gcg cec cca get 152
aca ccc gga
Gly Thr Ala Ala Ala Pro Ala Lys Pro Ala Pro Pro Ala
Thr Pro Gly
25 30
gcg ccg acc tcc cca gca gaa cac cgc ctg ttg aag acc 200
tgc tgg agc
20 Ala Pro Thr Ser Pro Ala Glu His Arg Leu Leu Lys Thr
Cys Trp Ser
35 40 45
tgt cgc gtg ctt tct ggg ttg ggg ctg atg ggg gcg ggc 248
ggg tac gtg
Cys Arg Val Leu Ser Gly Leu Gly Leu Met Gly Ala Gly
Gly Tyr Val
50 55 60 65
tac tgg gtg gca cgg aag ccc atg aag atg gga tac ccc 296
ccg agt cca
Tyr Trp Val Ala Arg Lys Pro Met Lys Met Gly Tyr Pro
Pro Ser Pro
70 75 80
tgg acc att acg cag atg gtc atc ggc ctc agc att gcc 344
acc tgg ggt
Trp Thr Ile Thr Gln Met Val Ile Gly Leu Ser Ile Ala
Thr Trp Gly
85 90 95
atc gtt gtc atg gca gac ccc aaa ggg aag gcc tac cgc 390
gtt gtt t
Ile Val Val Met Ala Asp Pro Lys Gly Lys Ala Tyr Arg
Val Val
100 105 110
gaeagtacca ccagtgaatc tgtcttctgt ctctgtccct ttccccgtga450
cacacacagc
aggcatggaa tttaatgggt gttctggaca gacacttgta catggacaga510
catcactact
CA 02336225 2001-O1-24
WO 00/05367 PCTIJP99/03929
23/177
gtggatacta caagactgag aagaaaatcg tatgttgtca ttctctggct atggagtgtt 570
tgtggccttc acagatttca caggaaccaa taaatccctc agagaagt 618
<210> 26
<211> 1021
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (413)...(853)
<400> 26
aagactataa gccccagcgg gcgacgaccg aacgcccccg ggaacaccgg gccccgagct 60
cggtcccgcg cccgaggatc ctccacgggg ctagatggct gcgtcggggg cgggagcgga 120
ggtgagcggg cgctagggccgcgagcccccgccggccettcctccagcgccctgcggacc180
ccgcagaagg cgctcgcctccctagcccgcaaaaacatatcgatttttctcgctgtggca240
acggggacgt cctgatagatcctctgctccaataggcaactccggccttccctgccctga300
cctggaacct ctgggagggctgcagagtaagtgccgcctctgcgctccgacggaggcacg360
aggcctgtgg agtaggtccctctgttccgacaggtgcgacacttggcgctcc atg 418
ctt
Met Leu
1
gcg ggt gcc ggg agg cct ggc ctc ccc cag ggc cgc cac ctc tgc tgg 466
Ala Gly Ala Gly Arg Pro Gly Leu Pro Gln Gly Arg His Leu Cys Trp
5 10 15
ttg ete tgt get tte ace tta aag cte tgc caa gca gag get ece gtg 514
Leu Leu Cys Ala Phe Thr Leu Lys Leu Cys Gln Ala Glu Ala Pro Val
20 25 30
cag gaa gag aag ctg tca gca agc acc tca aat ttg cca tgc tgg ctg 562
Gln Glu Glu Lys Leu Ser Ala Ser Thr Ser Asn Leu Pro Cys Trp Leu
35 40 45 5n
gtg gaa gag ttt gtg gta gca gaa gag tgc tct cca tgc tct aat ttc 610
Val Glu Glu Phe Val Val Ala Glu Glu Cys Ser Pro Cys Ser Asn Phe
55 60 65
cgg get aaa act acc cct gag tgt ggt ccc aca gga tat gta gag eaa 658
Arg Ala Lys Thr Thr Pro Glu Cys Gly Pro Thr Gly Tyr Val Glu Lys
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
24/177
70 75 80
atc aca tgc agc tca tct aag aga aat gag ttc aaa agc tgc cgc tca 706
Ile Thr Cys Ser Ser Ser Lys Arg Asn Giu Phe Lys Ser Cys Arg Ser
85 90 95
get ttg atg gaa csa cgc tta ttt tgg aag ttc gaa ggg get gtc gtg 754
Ala Leu Met Glu Gln Arg Leu Phe Trp Lys Phe Glu Gly Ala Val Val
100 105 110
tgt gtg gcc ctg atc ttc get tgt ctt gtc atc att cgt cag cga cea 802
Cys Val Ala Leu Ile Phe Ala Cys Leu Val Ile Ile Arg Gln Arg Gln
115 120 125 130
ttg gac aga aag get ctg gaa aag gtc cgg aag caa atc gag tcc ata 850
Leu Asp Arg Lys Ala Leu Glu Lys Val Arg Lys Gln Ile Glu Ser Ile
135 140 145
tagctacatt ccacccttgt atcctgggtc ttagagaccc tatctcagac agtgaaagtg 910
asatggactg atttgcactc ttggttcttt ggagccttgt ggtggaatcc ccttttcccc 970
atcttcttct ttcagatcat taatgagcag aataaaaaga gtaaaatggt t 1021
<210> 27
<211> 1432
<2I2> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (331)...(1365)
<400> 27
atcgcgcccg ggaggcgccggagcccagcggctggcgggccgccgtcccacccccacctc60
gcccgagtcc ggggcggccccggtgtcccctccgagcctgctgcactccacgtcccccta120
ccagggctcc agcccccagggaaatctccgaccaggcccgcccaggagccagatccaggc180
tcctggaaga accatgtccggcagctactggtcatgccaggcacacactgctgcccaaga240
ggagctgctg tttgaattatctgtgaatgttgggaagaggaatgccagagctgccggctg300
saaattaccc aaccaagagaaatctgcaggatg gac ctg gtc 354
ttt ctc
ttc
ttg
Met Asp Leu Val
Phe Leu
Phe
Leu
1 5
ttc tac ctg get tcg gtg ctg atg ggt ctt gtt ctt atc tgc gtc tgc 402
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
25/177
Phe Tyr Leu Ala Ser Val Leu Met Gly Leu Val Leu Ile Cys Val Cys
15 20
tcg aaa acc cat agc ttg aaa ggc ctg gcc agg gga gga gca cag ata 450
Ser Lys Thr His Ser Leu Lys Gly Leu Ala Arg Gly Gly Ala Gln Ile
5 25 30 35 40
ttt tcc tgt ata att cca gaa tgt ctt cag aga gcc gtg cat gga ttg 498
Phe Ser Cys Ile Ile Pro Glu Cys Leu Gln Arg Ala Val His Gly Leu
45 50 55
ctt cat tac ctt ttc cat acg aga nac cac acc ttc att gtc ctg cac 546
10 Leu His Tyr Leu Phe His Thr Arg Asn His Thr Phe Ile Val Leu His
60 65 70
ctg gtc ttg caa ggg atg gtt tat act gag tac acc tgg gaa gta ttt 594
Leu Val Leu Gln Gly Met Val Tyr Thr Glu Tyr Thr Trp Glu Val Phe
75 80 85
ggc tac tgt cag gag ctg gag ttg tcc ttg cat tac ctt ctt ctg ccc 642
Gly Tyr Cys Gln Glu Leu Glu Leu Ser Leu His Tyr Leu Leu Leu Pro
90 95 100
tat ctg ctg cta ggt gta aac ctg ttt ttt ttc acc ctg act tgt gga 690
Tyr Leu Leu Leu Gly Val Asn Leu Phe Phe Phe Thr Leu Thr Cys Gly
105 110 115 120
acc aat cct ggc att ata aca aaa gca aat gaa tta tta ttt ctt cat 738
Thr Asn Pro Gly Ile Ile Thr Lys Ala Asn Glu Leu Leu Phe Leu His
125 130 135
gtt tat gas ttt gat gae gtg atg ttt cca aag aac gtg agg tgc tct 786
Val Tyr Glu Phe Asp Glu Val Met Phe Pro Lys Asn Val Arg Cys Ser
140 145 150
act tgt gat tta agg asa cca get cga tcc aag cac tgc agt gtg tgt 834
Thr Cys Asp Leu Arg Lys Pro Ala Arg Ser Lys His Cys Ser Val Cys
155 160 165
aac tgg tgt gtg cac cgt ttc gac cat cac tgt gtt tgg gtg aac aac 882
Asn Trp Cys Val His Arg Phe Asp His His Cys Val Trp Val Asn Asn
170 175 180
tgc atc ggg gcc tgg aac atc agg tac ttc ctc atc tac gtc ttg acc 930
Cys Ile Gly Ala Trp Asn Ile Arg Tyr Phe Leu Ile Tyr Val Leu Thr
185 190 195 200
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
26/177
ttg acg gcc tcg get gcc acc gtc gcc att gtg agc acc act ttt ctg 978
Leu Thr Ala Ser Ala Ala Thr Val Ala Ile Val Ser Thr Thr Phe Leu
205 210 215
gtc cac ttg gtg gtg atg tca gat tta tac cag gag act tac atc gat 1026
Val His Leu Val Val Met Ser Asp Leu Tyr Gln Glu Thr Tyr Ile Aap
220 225 230
gac ctt gga cac ctc cat gtt atg gac acg gtc ttt ctt att cag tac 1074
Asp Leu Gly His Leu His Val Met Asp Thr Val Phe Leu Ile Gln Tyr
235 240 245
ctg ttc ctg act ttt cca cgg att gtc ttc atg ctg ggc ttt gtc gtg 1122
Leu Phe Leu Thr Phe Pro Arg Ile Val Phe Met Leu Gly Phe Val Val
250 255 260
GTT CTG AGC TTC CTC CTG GGT GGC TAC CTG TTG TTT GTC CTG TAT CTG 1170
Val Leu Ser Phe Leu Leu Gly Gly Tyr Leu Leu Phe Val Leu Tyr Leu
265 270 275 2g0
gcg gcc acc aac cag act act aac gag tgg tac aga ggt gac tgg gcc 1218
Ala Ala Thr Asn Gln Thr Thr Asn Glu Trp Tyr Arg Gly Asp Trp Ala
285 290 295
tgg tgc cag cgt tgt ccc ctt gtg gcc tgg cct ccg tca gca gag ccc 1266
Trp Cys Gln Arg Cys Pro Leu Val Ala Trp Pro Pro Ser Ala Glu Pro
300 305 310
caa gtc cac cgg aac att cac tcc cat ggg ctt cgg agc sac ett caa 1314
Gln Val His Arg Asn Ile His Ser His Gly Leu Arg Ser Asn Leu Gln
315 320 325
gag atc ttt cta cct gcc ttt cca tgt cat gag agg aag aea caa gaa 1362
Glu Ile Phe Leu Pro Ala Phe Pro Cys His Glu Arg Lys Lys Gln Glu
330 335 340
tgacaegtgt atgactgcct ttgagctgta gttcccgttt atttacacat gtggatcc 1420
tcgttttcca ag 1432
<210> 28
<211> 601
<212> DNA
<213> Homo sapiens
<220>
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
27/177
<221> CDS
<222> (62)...(355)
<400>
28
atgcgcacat agcgacttgg tgggggatcc cggcaagtaa60
tgggcgcgtc
cagtgatgac
c aa 109
atg aag
act eag
a cgg
gag
aat
ctg
ggc
gtc
get
cta
gag
atc
gat
Met lu Ile
Thr Asp
Lys
Lys
Lys
Arg
Glu
Asn
Leu
Gly
Val
Ala
Leu
G
1 - 5 10 15
ggg cta gag aag ctg cag tgt cgg gacctg gcc gtg 157
gag tcc aga gag
Gly Leu Glu Lys Leu Gln Cys Arg AspLeu Ala Val
Glu Ser Arg Glu
20 25 30
aac tcc ctc cac agc gag ctg agc gaggcc agg tcc 205
aga cgg cca agg
Asn Ser Leu His Ser Glu Leu Ser GluAla Arg Ser
Arg Arg Pro Arg
35 40 45
ctg gag gag eaa sac cta atg aac gcctcc tac gag 253
aag agc aaa aac
Leu Glu Glu Lys Asn Leu Met Asn AlaSer Tyr Glu
Lys Ser Lys Asn
50 55 60
aag gaa aag ttt ctt caa gag aac aagaac ctg ctc 301
ctg cgg cgg atg
Lys Glu Lys Phe Leu Gln Glu Asn LysAsn Leu Leu
Leu Arg Arg Met
65 70 75 80
tct gtg atc ttt atc ctg acg ctc tatgcc tgg acc 349
gcc ctc gtc tac
Ser Val Ile Phe Ile Leu Thr Leu TyrAla Trp Thr
Ala Leu Val Tyr
85 90 95
atg tgagcctggc acttggcccct 400
acttccccac
eaccagcaca
ggcttcc
Met
tgatcaggat caagcaggca cttcaagcct caataggacc aaggtgctgg ggtgttcccc 460
tcccaaccta gtgttcaagc atggcttcct ggcggcccag gccttgcctc cctggcctgc 520
tggggggttc cgggtctcca gaaggacatg gtgctggtcc ctcccttagc ccaagggaga 580
ggcaataaag acacaaagct g 601
<210> 29
<211> 585
<212> DNA
<213> Homo sapiens
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
28/177
<220>
<221> CDS
<222> (78)...(452)
<400>
29
actaacctct gccctgcagc cccgagtgca 60
cgcgagggcg tctggaatac
cgcgggaaat
gcagagtcag taagacc atggetacg tctnagggt 110
tcc tgc
tcg ttt
atg
Met Ser Ser
Ala Ser Lys
Thr Met Gly
Cys
Phe
1 5 10
gtt tttaagccaasc tccaaaaagaga aagatctctctgcca ata gag 158
Val PheLysProAsn SerLysLysArg LysIleSerLeuPro Ile Glu
15 20 25
gac tattttsacaaa gggaaaaatgag cctgaggacagtaag ctt cga 206
Asp TyrPheAsnLys GlyLysAsnGlu ProGluAspSerLys Leu Arg
30 35 40
ttc gaaacttatcag ttgatatggcag cagatgaaatctgaa aat gag 254
Phe GluThrTyrGln LeuIleTrpGln GlnMetLysSerGlu Asn Glu
45 50 55
cga ctacaagaggaa ttaaataaaaac ttgtttgacaatctg att gaa 302
Arg LeuGlnGluGlu LeuAsnLysAsn LeuPheAspAsnLeu Ile Glu
60 65 70 75
ttt ctgcaaaaatca cattctggattc cagaagaattcaaga gac ttg 350
Phe LeuGlnLysSer HisSerGlyPhe GlnLysAsnSerArg Asp Leu
80 85 90
ggc ggtcaaataaaa ctcagagaaatt ccaactgetgetctt gtt ctt 398
Gly GlyGlnIleLys LeuArgGluIle ProThrAlaAlaLeu Val Leu
95 100 105
ggt atatatgcgtat gtttgttcatgc atgcatctctgtgta ttt cgt 446
Gly IleTyrAlaTyr ValCysSerCys MetHisLeuCysVal Phe Arg
ll0 115 120
ttt taaatttttt tttgatgagc 500
tttattgttg c
agaatagtgg
aaggacctgt
Phe
tattttgtct ctcttatttg tacaattaaa ccaactatag tttatattac atattttcaa 560
aaaccaataa aaattcctta tcttt 585
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
29/177
<210> 30
<211> 1100
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (57)...(1040)
<400> 30
agaccgacct tgaccgccca cctggcagga gcaggacagg acggccggac gcggcc atg 59
Met
1
gcc gag ctcccggggccc tttctctgcggggccctg ctaggcttcctg 107
Ala Glu LeuProGlyPro PheLeuCysGlyAlaLeu LeuGlyPheLeu
5 10 15
tgc ctg agtgggctggcc gtggaggtgaaggtaccc acagagccgctg 155
Cys Leu SerGlyLeuAla ValGluValLysValPro ThrGluProLeu
20 25 30
agc acg cccctggggaag acagccgagctgacctgc acctacagcacg 203
Ser Thr ProLeuGlyLys ThrAlaGluLeuThrCys ThrTyrSerThr
35 90 45
tcg gtg ggagacagcttc gccctggagtggagcttt gtgcagcctggg 251
Ser Val GlyAspSerPhe AlaLeuGluTrpSerPhe ValGlnProGly
50 55 60 65
aaa ccc atctctgagtcc catccaatcctgtacttc accaatggccat 299
Lys Pro IleSerGluSer HisProIleLeuTyrPhe ThrAsnGlyHis
70 75 80
ctg tat ccaactggttct aagtcasagcgggtcagc ctgcttcagaac 347
Leu Tyr ProThrGlySer LysSerLysArgValSer LeuLeuGlnAsn
85 90 95
ccc ccc acagtgggggtg gccacactgaaactgact gacgtccacccc 395
Pro Pro ThrValGlyVal AlaThrLeuLysLeuThr AspValHisPro
100 105 110
tca gat actggaacctac ctctgccaagtcaacaac ccaccagatttc 443
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
301177
Ser Asp Thr Gly Thr Tyr Leu Cys Gln Val Asn Asn Pro Pro Asp Phe
115 120 125
tac acc aat ggg ttg ggg cta atc aac ctt act gtg ctg gtt 491
ccc ccc
Tyr Thr Asn Gly Leu Gly Leu Ile Asn Leu Thr Val Leu Val
Pro Pro
130 135 140 145
agt ast ccc tta tgc agt cag agt gga caa acc tct gtg gga 539
ggc tct
Ser Asn Pro Leu Cys Ser Gln Ser Gly Gln Thr Ser Val Gly
Gly Ser
150 155 160
act gca ctg aga tgc agc tct tcc gag ggg get cct aag cca 587
gtg tac
Thr Ala Leu Arg Cys Ser Ser Ser Glu Gly Ala Pro Lys Pro
Val Tyr
165 170 175
aac tgg gtg cgt ctt gga act ttt cct aca cct tct cct ggc 635
agc atg
Asn Trp Val Arg Leu Gly Thr Phe Pro Thr Pro Ser Pro Gly
Ser Met
180 185 190
gtt caa gat gag gtg tct ggc cag ctc att ctc acc sac ctc 683
tcc ctg
VaI Gln Asp Glu Val Ser Gly Gln Leu Ile Leu Thr Asn Leu
Ser Leu
195 200 205
acc tcc tcg ggc acc tac cgc tgt gtg gcc acc sac cag atg 731
ggc agt
Thr Ser Ser Gly Thr Tyr Arg Cys Val Ala Thr Asn Gln Met
Gly Ser
210 215 220 225
gca tcc tgt gag ctg acc ctc tct gtg acc gsa ecc tcc cas ggc cga 779
Ala Ser Cys Glu Leu Thr Leu Ser Val Thr Glu Pro Ser Gln Gly Arg
230 235 240
gtg gcc gga get ctg att gtg ctc ctg ggc gtg ctg ttg 827
ggg ctg tca
Val Ala Gly Ala Leu Ile Val Leu Leu Gly Val Leu Leu
Gly Leu Ser
245 250 255
gtt get gcg ttc tgc ctg agg ttc cag aaa gag agg ggg 875
gtc aag eag
Val Ala Ala Phe Cys Leu Arg Phe Gln Lys Glu Arg Gly
Val Lys Lys
260 265 270
ccc aag gag aca tat ggg agt gac ctt cgg gag gat gcc 923
ggt atc get
Pro Lys Glu Thr Tyr Gly Ser Asp Leu Arg Glu Asp Ala
Gly Ile Ala
275 280 285
cct ggg atc tct gag cac tgt atg agg get gat tct agc 971
act aag ggq
Pro Gly Ile Ser Glu His Cys Met Arg Ala Asp Ser Ser
Thr Lys Gly
290 295 300 305
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
31/I77
ttc ctg gaa aga ccc tcg tct gcc agc acc gtg acg acc acc aag tcc 1019
Phe Leu Glu Arg Pro Ser Ser Ala Ser Thr Val Thr Thr Thr Lys Ser
310 315 320
asg ctc cct atg gtc gtg tgacttctcc cgatccctga gggcggtgag ggg 1070
Lys Leu Pro Met Val Val
325
gaatatcast aattaaagtc tgtgggtacc 1100
<210> 31
<211> 313
<212> PRT
<213> Homo sapiens
<400> 31
Met Asn Gln Leu Ser Phe Leu Leu Phe Leu Ile Ala Thr Thr Arg Gly
1 5 10 15
Trp Ser Thr Asp Glu Ala Asn Thr Tyr Phe Lys Glu Trp Thr Cys Ser
25 30
Ser Ser Pro Ser Leu Pro Arg Ser Cys Lys Glu Ile Lys Asp Glu Cys
20 35 40 45
Pro Ser Ala Phe Asp Gly Leu Tyr Phe Leu Arg Thr Glu Asn Gly Val
50 55 60
Ile Tyr Gln Thr Phe Cys Asp Met Thr Ser Gly Gly Gly Gly Trp Thr
65 70 75 80
Leu Val Ala Ser Val His Glu Asn Asp Met Arg Gly Lys Cys Thr Val
85 90 95
Gly Asp Arg Trp Ser Ser Gln Gln Gly Ser Lys Als Asp Tyr Pro Glu
100 105 110
Gly Asp Gly Asn Trp Ala Asn Tyr Asn Thr Phe Gly Ser Ala Glu Ala
115 120 125
Ala Thr Ser Asp Asp Tyr Lys Asn Pro Gly Tyr Tyr Asp Ile Gln Ala
130 135 140
Lys Asp Leu Gly Ile Trp His Val Pro Asn Lys Ser Pro Met Gln His
145 150 155 160
Trp Arg Asn Ser Ser Leu Leu Arg Tyr Arg Thr Asp Thr Gly Phe Leu
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
32/177
165 170 175
Gln Thr Leu Gly His Asn Leu Phe Gly Ile Tyr Gln Lys Tyr Pro Val
180 185 190
Lys Tyr Gly Glu Gly Lys Cys Trp Thr Asp Asn Gly Pro Val Ile Pro
195 200 205
Val Val Tyr Asp Phe Gly Asp Ala Gln Lys Thr Ala Ser Tyr Tyr Ser
210 215 220
Pro Tyr Gly Gln Arg Glu Phe Thr Ala Gly Phe Val Gln Phe Arg Val
225 230 235 240
Phe Asn Asri Glu Arg Ala Ala Asn Ala Leu Cys Als Gly Met Arg Val
245 250 255
Thr Gly Cys Asn Thr Glu His His Cys Ile Gly Gly Gly Gly Tyr Phe
260 265 270
Pro Glu Ala Ser Pro Gln Gln Cys Gly Asp Phe Ser Gly Phe Asp Trp
275 280 285
Ser Gly Tyr Gly Thr His Val Gly Tyr Ser Ser Ser Arg Glu Ile Thr
290 295 300
Glu Ala Ala Val Leu Leu Phe Tyr Arg
305 310
<210>32
<211>229
<212>PRT
<213>Homo sapiens
<400> 32
Met Gly Asp Lys Ile Trp Leu Pro Phe Pro Val Leu Leu Leu Ala Ala
1 5 10 15
Leu Pro Pro Val Leu Leu Pro Gly Ala Ala Gly Phe Thr Pro Ser Leu
20 25 30
Asp Ser Asp Phe Thr Phe Thr Leu Pro Ala Gly Gln Lys Glu Cys Phe
40 45
Tyr Gln Pro Met Pro Leu Lys Ala Ser Leu Glu Ile Glu Tyr Gln Val
50 55 60
35 Leu Asp Gly Ala Gly Leu Asp Ile Asp Phe His Leu Ala Ser Pro Glu
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
33/17?
65 70 75 80
Gly Lys Thr Leu Val Phe Glu Gln Arg Lys Ser Asp Gly Val His Thr
B5 90 95
Val Glu Thr Glu Val Gly Asp Tyr Met Phe Cys Phe Asp Asn Thr Phe
100 105 110
Ser Thr Ile Ser Glu Lys Val Ile Phe Phe Glu Leu Ile Leu Asp Asn
115 120 125
Met Gly Glu Gln Ala Gln Glu Gln Glu Asp Trp Lys Lys Tyr Ile Thr
130 13s 140
Gly Thr Asp Ile Leu Asp Met Lys Leu Glu Asp Ile Leu Glu Ser Ile
145 150 155 160
Asn Ser Ile Lys Ser Arg Leu Ser Lys Ser Gly His Ile Gln Ile Leu
165 170 175
Leu Arg Ala Phe Glu Ala Arg Asp Arg Asn Ile Gln Glu Ser Asn Phe
180 185 190
Asp Arg Val Asn Phe Trp Ser Met Val Asn Leu Val Val Met Val Val
195 200 205
Val Ser Ala Ile Gln Val Tyr Met Leu Lys Ser Leu Phe Glu Asp Lys
210 215 220
Arg Lys Ser Arg Thr
225
<210> 33
<211> 467
<212> PRT
<213> Homo Sapiens
<400> 33
Met Arg Pro Gln Glu Leu Pro Arg Leu Ala Phe Pro Leu Leu Leu Leu
1 5 10 15
Leu Leu Leu Leu Leu Pro Pro Pro Pro Cys Pro Ala His Ser Ala Thr
20 25 30
Arg Phe Asp Pro Thr Trp Glu Ser Leu Asp Ala Arg Gln Leu Pro Ala
40 45
35 Trp Phe Asp Gln Ala Lys Phe Gly Ile Phe Ile His Trp Gly Val Phe
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
34/177
50 55 60
Ser Val Pro Ser Phe Gly Ser Glu Trp Phe Trp Trp Tyr Trp Gln Lys
65 70 75 80
Glu Lys Ile Pro Lys Tyr Val Glu Phe Met Lys Asp Asn Tyr Pro Pro
85 90 95
Ser Phe Lys Tyr Glu Asp Phe Gly Pro Leu Phe Thr Ala Lys Phe Phe
100 105 110
Asn Ala Asn Gln Trp Ala Asp Ile Phe Gln Ala Ser Gly Ala Lys Tyr
115 120 125
Ile Val Leu Thr Ser Lys His His Glu Gly Phe Thr Leu~Trp Gly Ser
130 135 140
Glu Tyr Ser Trp Asn Trp Asn Ala Ile Asp Glu Gly Pro Lys Arg Asp
145 150 155 160
Ile Val Lys Glu Leu Glu Val Ala Ile Arg Asn Arg Thr Asp Leu Arg
1~ 165 170 175
Phe Gly Leu Tyr Tyr Ser Leu Phe Glu Trp Phe His Pro Leu Phe Leu
180 185 190
Glu Asp Glu Ser Ser Ser Phe His Lys Arg Gln Phe Pro VaI Ser Lys
I95 200 205
Thr Leu Pro Glu Leu Tyr Glu Leu Val Asn Asn Tyr Gln Pro Glu Val
210 215 220
Leu Trp Ser Asp Gly Asp Gly Gly Ala Pro Asp Gln Tyr Trp Asn Ser
225 230 235 240
Thr Gly Phe Leu Ala Trp Leu Tyr Asn Glu Ser Pro Val Arg Gly Thr
245 250 255
Val Val Thr Asn Asp Arg Trp Gly Ala Gly Ser Ile Cys Lys His Gly
260 265 270
Gly Phe Tyr Thr Cys Ser Asp Arg Tyr Asn Pro Gly His Leu Leu Pro
275 280 285
His Lys Trp Glu Asn Cys Met Thr Ile Asp Lys Leu Ser Trp Gly Tyr
290 295 300
Arg Arg Glu Ala Gly Ile Ser Asp Tyr Leu Thr Ile Glu Glu Leu Val
305 310 315 320
Lys Gln Leu Val Glu Thr Val Ser Cys Gly Gly Asn Leu Leu Met Asn
325 330 335
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
35/177
Ile Gly Pro Thr Leu Asp Gly Thr Ile Ser Val Val Phe Glu Glu Arg
340 345 350
Leu Arg Gln Met Gly Ser Trp Leu Lys Val Asn Gly Glu Ala Ile Tyr
355 360 365
Glu Thr His Thr Trp Arg Ser Gln Asn Asp Thr Val Thr Pro Asp Val
370 375 380
Trp Tyr Thr ser Lys Pro Lys Glu Lys Leu Val Tyr Ala Ile Phe Leu
385 390 395 400
Lys Trp Pro Thr Ser Gly Gln Leu Phe Leu Gly His Pro Lys Ala Ile
405 410 ' 415
Leu Gly Ala Thr Glu Val Lys Leu Leu Gly His Gly Gln Pro Leu Asn
420 425 430
Trp Ile Ser Leu Glu Gln Asn Gly Ile Met Val Glu Leu Pro Gln Leu
435 440 495
Thr Ile His Gln Met Pro Cys Lys Trp Gly Trp Ala Leu Ala Leu Thr
450 455 460
Asn Val Ile
465
<210> 34
<211> 99
<212> PRT
<2I3> Homo sapiens
<400> 34
Met Asp Asn Val Gln Pro Lys Ile Lys His Arg Pro Phe Cys Phe Ser
1 5 10 15
Val Lys Gly His Val Lys Met Leu Arg Leu Asp Ile Ile Asn Ser Leu
20 25 30
Val Thr Thr Val Phe Met Leu Ile Val Ser Val Leu Ala Leu Ile Pro
40 45
Glu Thr Thr Thr Leu Thr Val Gly Gly Gly Val Phe Ala Leu Val Thr
50 55 60
Ala Val Cys Cys Leu Ala Asp Gly Ala Leu Ile Tyr Arg Lys Leu Leu
35 65 70 75 80
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
36/177
Phe Asn Pro Ser Gly Pro Tyr Gln Gln Lys Pro Val His Glu Lys Lys
85 90 95
Glu Val Leu
<210> 35
<211> 189
<212> PRT
<213> Homo sapiens
<400> 35
Met Glu Glu Gly Gly Asn Leu Gly Gly Leu Ile Lys Met Val His Leu
1 5 10 15
Leu Val Leu Ser Gly Ala Trp Gly Met Gln Met Trp Val Thr Phe Val
25 30
15 Ser Gly Phe Leu Leu Phe Arg Ser Leu Pro Arg His Thr Phe Gly Leu
35 40 45
Val Gln Ser Lys Leu Phe Pro Phe Tyr Phe His Ile Ser Met Gly Cys
50 55 60
Ala Phe Ile Asn Leu Cys Ile Leu Ala Ser Gln His Ala Trp Ala Gln
20 65 70 75 80
Leu Thr Phe Trp Glu Ala Ser Gln Leu Tyr Leu Leu Phe Leu Ser Leu
85 90 95
Thr Leu Ala Thr Val Asn Ala Arg Trp Leu Glu Pro Arg Thr Thr Ala
100 105 lI0
Ala Met Trp Ala Leu Gln Thr Val Glu Lys Glu Arg Gly Leu Gly Gly
115 lzo 125
Glu Val Pro Gly Ser His Gln Gly Pro Asp Pro Tyr Arg Gln Leu Arg
130 135 140
Glu Lys Asp Pro Lys Tyr Ser Ala Leu Arg Gln Asn Phe Phe Arg Tyr
145 150 155 260
His Gly Leu Ser Ser Leu Cys Asn Leu Gly Cys Val Leu Ser Asn Gly
165 170 175
Leu Cys Leu Ala Gly Leu Ala Leu Glu Ile Arg Ser Leu
180 185
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
37/177
<210> 36
<211> 363
<212> PRT
<213> Homo Sapiens
<400> 36
Met Val Asp Ser Leu Leu Ala Val Thr Leu Ala Gly Asn Leu Gly Leu
1 5 10 15
Thr Phe Leu Arg Gly Ser Gln Thr Gln Ser His Pro Asp Leu Gly Thr
IO 20 25 30
Glu Gly Cys Trp Asp Gln Leu Ser Ale Pro Arg Thr Phe Thr Leu Leu
35 40 45
Asp Pro Lys Ala Ser Leu Leu Thr Lys Ala Phe Leu Asn Gly Ala Leu
50 55 60
Asp Gly Val Ile Leu Gly Asp Tyr Leu Ser Arg Thr Pro Glu Pro Arg
65 70 75 80
Pro Ser Leu Ser His Leu Leu Ser Gln Tyr Tyr Gly Ala Gly Val Ala
85 90 95
Arg Asp Pro Gly Phe Arg Ser Asn Phe Arg Arg Gln Asn Gly Ala Ala
100 l05 110
Leu Thr Ser Ala Ser Ile Leu Ala Gln Gln Val Trp Gly Thr Leu Val
115 120 125
Leu Leu Gln Arg Leu Glu Pro Val His Leu Gln Leu Gln Cys Met Ser
130 135 140
Gln Glu Gln Leu Ala Gln Val Ala Ala Asn Ale Thr Lys Glu Phe Thr
145 150 155 160
Glu Ala Phe Leu Gly Cys Pro Ala Ile His Pro Arg Cys Arg Trp Gly
165 170 175
Ala Als Pro Tyr Arg Gly Arg Pro Lys Leu Leu Gln Leu Pro Leu Gly
180 185 190
Phe Leu Tyr Val His His Thr Tyr Val Pro Ala Pro Pro Cys Thr Asp
195 200 205
Phe Thr Arg Cys Ala Ala Asn Met Arg Ser Met Gln Arg Tyr His Gln
210 215 220
Asp Thr Gln Gly Trp Gly Asp Ile Gly Tyr Ser Phe Val Val Gly Ser
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
38/177
225 230 235 240
Asp Gly Tyr Val Tyr Glu Gly Arg Gly Trp His Trp Val Gly Ala His
245 250 255
Thr Leu Gly His Asn Ser Arg Gly Phe Gly Val Ala Ile Val Gly Asn
260 265 270
Tyr Thr Ala Ala Leu Pro Thr Glu Ala Ala Leu Arg Thr Val Arg Asp
275 280 285
Thr Leu Pro Ser Cys Ala val Arg Ala Gly Leu Leu Arg Pro Asp Tyr
290 295 300
Ala Leu Leu Gly His Arg Gln Leu Val Arg Thr Asp Cys Pro Gly Asp
305 310 315 320
Ala Leu Phe Asp Leu Leu Arg Thr Trp Pro His Phe Thr Ala Thr Val
325 330 335
Lys Pro Arg Pro Ala Arg Ser Val Ser Lys Arg Ser Arg Arg Glu Pro
340 345 350
Pro Pro Arg Thr Leu Pro Ala Thr Asp Leu Gln
355 360
<210> 37
<211> 249
<212> PRT
<213> Homo Sapiens
<400> 37
Met Gly Gly Pro Arg Gly Ala Gly Trp Val Ala Ala Gly Leu Leu Leu
1 5 10 15
Gly Ala Gly Ala Cys Tyr Cys Ile Tyr Arg Leu Thr Arg Gly Arg Arg
20 25 30
Arg Gly Asp Arg Glu Leu Gly Ile Arg Ser Ser Lys Ser Ala Glu Asp
35 40 45
Leu Thr Asp Gly Ser Tyr Asp Asp Val Leu Asn Ala Glu Gln Leu Gln
50 55 60
Lys Leu Leu Tyr Leu Leu Glu Ser Thr Glu Asp Pro Val Ile Ile Glu
65 70 75 80
Arg Ala Leu Ile Thr Leu Gly Asn Asn Ala Ala Phe Ser Val Asn Gln
CA 02336225 2001-O1-24
WO 00/05367 PCf/JP99/03929
39/177
85 90 95
Ala Ile Ile Arg Glu Leu Gly Gly Ile Pro Ile Val Ala Asn Lys Ile
100 105 110
Asn His Ser Asn Gln Ser Ile Lys Glu Lys Ala Leu Asn Ala Leu Asn
115 120 125
Asn Leu Ser Val Asn Val Glu Asn Gln Ile Lys Ile Lys Val Gln Val
130 135 140
Leu Lys Leu Leu Leu Asn Leu Ser Glu Asn Pro Ala Met Thr Glu Gly
145 150 155 160
Leu Leu Arg Ala Gln Val Asp Ser Ser Phe Leu Ser Leu Tyr Asp Ser
165 170 175
His VaI Ala Lys Glu Ile Leu Leu Arg Val Leu Thr Leu Phe Gln Asn
180 185 190
Ile Lys Asn Cys Leu Lys Ile Glu Gly His Leu Ala Val GIn Pro Thr
195 200 205
Phe Thr Glu Gly Ser Leu Phe Phe Leu Leu His Gly Glu Glu Cys Ala
210 215 220
Gln Lys Ile Arg Ala Leu Val Asp His His Asp Ala Glu Val Lys Glu
225 230 235 240
Lys Val Val Thr Ile Ile Pro Lys Ile
245
<210> 38
<211> 98
<212> PRT
<213> Homo sapiens
<400> 38
Met Ala Ser Leu Leu Cys Cys Gly Pro Lys Leu Ala Ala Cys Gly Ile
1 s l0 15
Val Leu Ser Ala Trp Gly Val Ile Met Leu Ile Met Leu Gly Ile Phe
20 25 30
Phe Asn Val His Ser Ala Val Leu Ile Glu Asp Val Pro Phe Thr Glu
40 45
35 Lys Asp Phe Glu Asn Gly Pro Gln Asn Ile Tyr Asn Leu Tyr Glu Gln
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
40/177
50 55 60
Val Ser Tyr Asn Cys Phe Ile Ala Ala Gly Leu Tyr Leu Leu Leu Gly
65 70 75 80
Gly Phe Ser Phe Cys Gln Val Arg Leu Asn Lys Arg Lys Glu Tyr Met
85 90 g5
Val Arg
<210> 39
<211> 172
<212> PRT
<213> Homo sapiens
<400> 39
Met Val Gly Pro Ala Pro Arg Arg Arg Leu Arg Pro Leu Ala Ala Leu
1 5 10 15
Ala Leu Val Leu Ala Leu Ala Pro Gly Leu Pro Thr Ala Arg Ala Gly
25 30
Gln Thr Pro Arg Pro Ala Glu Arg Gly Pro Pro Val Arg Leu Phe Thr
35 40 45
20 Glu Glu Glu Leu Ala Arg Tyr Gly Gly Glu Glu Glu Asp Gln Pro Ile
50 55 60
Tyr Leu Ala Val Lys Gly Val Val Phe Asp Val Thr Ser Gly Lys Glu
65 70 75 80
Phe Tyr Gly Arg Gly Ala Pro Tyr Asn Ala Leu Thr Gly Lys Asp Ser
85 90 95
Thr Arg Gly Val Ala Lys Met Ser Leu Asp Pro Ala Asp Leu Thr His
100 105 110
Asp Thr Thr Gly Leu Thr Ala Lys Glu Leu Glu Ala Leu Asp Glu Val
115 120 125
Phe Thr Lys Val Tyr Lys Ala Lys Tyr Pro Ile Val Gly Tyr Thr Ala
130 135 140
Arg Arg Ile Leu Asn Glu Asp Gly Ser Pro Asn Leu Asp Phe Lys Pro
145 150 155 160
Glu Asp Gln Pro His Phe Asp Ile Lys Asp Glu Phe
lss 170
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
41/177
<210> 40
<211> 120
<212> PRT
<213> Homo sapiens
<400> 40
Met Met Pro Ser Arg Thr Asn Leu Ala Thr Gly Ile Pro Ser Ser Lys
1 5 10 15
Val Lys Tyr Ser Arg Leu Ser Ser Thr Asp Asp Gly Tyr Ile Asp Leu
25 30
Gln Phe Lys Lys Thr Pro Pro Lys Ile Pro Tyr Lys Ala Ile Ala Leu
35 40 45
Ala Thr Val Leu Phe Leu Ile Gly Ala Phe Leu Ile Ile Ile Gly Ser
I5 50 55 60
Leu Leu Leu Ser Gly Tyr Ile Ser Lys Gly Gly Ala Asp Arg Ala Val
65 70 75 80
Pro Val Leu Ile Ile Gly Ile Leu Val Phe Leu Pro Gly Phe Tyr His
85 90 95
20 Leu Arg Ile Ala Tyr Tyr Ala Ser Lys Gly Tyr Arg Gly Tyr Ser Tyr
100 105 110
Asp Asp Ile Pro Asp Phe Asp Asp
115 120
<210> 41
<211> 939
<212> DNA
<213> Homo Sapiens
<400> 41
atgaaccaac tcagcttcctgctgtttctcatagcgaccaccagaggatggagtacagat60
gaggctaata cttacttcaaggaatggacctgttcttcgtctccatctctgcccagaagc120
tgcaaggaaa tcaaagacgaatgtcctagtgcatttgatggcctgtattttctccgcact180
gagaatggtg ttatctaccagaccttctgtgacatgacctctgggggtggcggctggacc240
ctggtggccagcgtgcatgagaatgacatgcgtgggaagtgcacggtgggcgatcgctgg300
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
42/177
tccagtcagc agggcagcaaagcagactacccagagggggacggcaactgggccaactac360
aacacctttg gatctgcagaggcggccacg~agcgatgactacaagaaccctggctactac420
gacatccagg ccaaggacctgggcatctggcacgtgcccaataagtcccccatgcagcac480
tggagaaaca gctccctgctgaggtaccgcacggacactggcttcctccagacactggga540
cataatctgt ttggcatctaccagaaatatccagtgaaatatggagaaggaaegtgttgg600
actgacaacg gcccggtgatccctgtggtctatgattttggcgacgcccagaaaacagca660
tcttattact caccctatggccagcgggaattcactgcgggatttgttcagttcagggta720
tttaataacg agagagcagccaacgccttgtgtgctggaatgagggtcaccggatgtaac780
actgagcacc actgcattggtggaggaggatactttccagaggccagtccccagcagtgt840
ggagattttt ctggttttgattggagtggatatggaactcatgttggttacagcagcagc900
cgtgagataa ctgaggcagctgtgcttctattctatcgt gag
<210> 42
<211> 687
<212> DNA
<213> Homo sapiens
<400> 42
atgggcgaca agatctggct gcccttcccc gtgctccttc tggccgctct gcctccggtg 60
ctgctgcctg gggcggccggcttcacaccttccctcgatagcgacttcacctttaccctt120
cccgccggcc agaaggagtgcttctaccagcccatgcccctgaaggcctcgctggagatc180
gagtaccaag ttttagatggagcaggattagatattgatttccatcttgcctctccagaa240
ggcaaaacct tagtttttgaacaaagaaaatcagatggagttcacactgtagagactgaa300
gttggtgatt acatgttctgctttgacastacattcagcaccatttctgagaaggtgatt360
ttctttgaat taatcctggataatatgggagaacaggcacaagaacaagaagattggaag420
aaatatatta ctggcacagatatattggatatgaasctggaagacatcctggaatccatc480
aacagcatca agtccagactaagcaaaagtgggcacatacaaattctgcttagagcattt540
gaagctcgtg atcgaaacatacaagaaagcaactttgatagagtcaatttctggtctatg600
gttaatttag tggtcatggtggtggtgtcagccattcaagtttatatgctgaagagtctg660
tttgaagata agaggaaaagtagaact 687
<210> 43
<211> 1401
<212> DNA
<213> Homo sapiens
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
43/177
<400> 43
atgcggccccaggagctccccaggctcgcgttcccgttgctgctgttgctgttgctgetg60
ctgccgccgccgccgtgccctgcccacagcgccacgcgcttcgaccccacctgggagtcc120
ctggacgcccgccagctgcccgcgtggtttgaccaggccaagttcggcatcttcatccac180
tggggagtgttttccgtgcccagcttcggtagcgagtggttctggtggtattggcaaeag240
gaaaagataccgaagtatgtggaatttatgaaagataattaccctcctagtttcaaatat300
gaagattttggaccactatttacagcaeaattttttaatgccaaccagtgggcagatatt360
tttcaggcctctggtgccaaatacattgtcttaacttccaascatcatgaaggctttacc420
ttgtgggggtcagaatattcgtggaactggaatgccatagatgaggggcccaagaggga~480
attgtcaaggaacttgaggtagccattaggaacagaactgacctgcgttttggactgtac540
tattccctttttgaatggtttcatccgctcttccttgaggatgaatccagttcattccat600
asgcggcaatttccagtttctaagacattgccagagctctatgagttagtgaacaactat660
cagcctgaggttctgtggtcggatggtgacggaggagcaccggatceatactggaacagc720
acaggcttcttggcctggttatataatgaaagcccagttcggggcacagtagtcaccaat780
gatcgttggggagctggtagcatctgtaagcatggtggcttctatacctgcagtgatcgt840
tataacccaggacatcttttgccacataastgggaaaactgcatgacaatagacaaactg900
tcctggggctataggagggaagctggaatctctgactatcttacaattgaageattggtg960
aagcaacttgtagagacagtttcatgtggaggaaatcttttgatgaatattgggcccaca1020
ctagatggcaccatttctgtagtttttgaggagcgactgaggcaaatggggtcctggcta1080
aaagtcaatggagaagctatttatgaaacccatacctggcgatcccagaatgacactgtc1140
accccagatgtgtggtacacatccaagcctaaagaaaaattagtctatgccatttttctt1200
aaatggcccacatcaggacagctgttccttggccatcccaaagctattctgggggcaaca1260
gaggtgaaactactgggccatggacagccacttaactggatttctttggagcasaatggc1320
attatggtagasctgccacagctaaccattcatcagatgccgtgtaaatggggctgggct1380
ctagccctga ctaatgtgat c 1401
<210> 44
<211> 297
<212> nrr.~
<213> Homo sapiens
<400> 44
atggataacg tgcagccgaa aataaaacat cgccccttct gcttcagtgt gaaaggccac 60
gtgaagatgc tgcggctgga tattatcaac tcactggtaa caacagtatt catgctcatc 120
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
44/177
gtatctgtgt tggcactgat accagaaacc acaacattga cagttggtgg aggggtgttt 180
gcacttgtga cagcagtatg ctgtcttgcc gacggggccc ttatttaccg gaagcttctg 240
ttcaatccca gcggtcctta ccagcaaaag cctgtgcatg aaaaaaaaga agttttg 297
<210> 45
<211> 567
<212> DNA
<213> Homo sapiens
<400> 45
atggaggaag gcgggaacctaggaggcctgattaagatggtccatctactggtcttgtca60
ggtgcctggg gcatgcaaatgtgggtgaccttcgtctcaggcttcctgcttttccgaagc120
cttccccgac ataccttcggactagtgcagagcaaactcttecccttctacttccacatc180
tccatgggct gtgccttcatcaacctctgcatcttggcttcacagcatgcttgggctcag240
ctcacattctgggaggccagccagctttacctgctgttcctgagccttacgctggccact300
gtcaacgccc gctggctggaaccccgcaccacagctgccatgtgggccctgcaaaccgtg360
gagaaggagc gaggcctgggtggggaggtaccaggcagccaccagggtcccgatccctac420
cgccagctgc gagagasggaccccaagtacagtgctctccgccagaatttcttccgctac480
catgggctgt cctctctttgcaatctgggctgcgtcctgagcaatgggctctgtctcgct540
ggccttgccctggaaataaggagcctc 567
<210> 46
<211> 1089
<212> DNA
<2I3> Homo sapiens
<400> 46
atggtggaca gcctcctggc agtcaccctg gctggaaacc tgggcctgac cttcctccga 60
ggttcccaga cccagagcca tccagacctg ggaactgagg gctgctggga ccagctctct 120
gcccctcggacctttacgcttttggaccccaaggcatctctgttsaccaaggccttcctc180
aatggcgccc tggatggggtcatccttggagactacctgagccggactcctgagccccgg240
ccatccctca gccacttgctgagccagtactatggggctggggtggccagagacccaggg300
ttccgcagca acttccgacggcagaacggtgctgctctgacttcagcctccatcctggcc360
cagcaggtgt ggggaacccttgtccttctacagaggctggagccagtacacctccagctt420
cagtgcatgagccaagaacagctggcccaggtggctgccaatgctaccaaggaattcact480
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
45/177
gaggccttcc tgggatgcccggccatccacccccgctgccgctggggagcggcgccttat540
cggggccgcc cgaagctgctgcagctgccgctgggattcttgtacgtgcatcacacctac600
gtgcctgcac caccctgcacggacttcacgcgctgcgcagccaacatgcgctccatgcag660
cgctaccacc aggacacgcaaggctggggagacatcggctacagtttcgtggtgggctcg720
gacggctacg tgtacgagggacgcggctggcactgggtgggcgcccacacgctcggccac780
eactcccggg gcttcggcgtggccatagtgggcaactacaccgcggcgctgcccaccgag840
gccgctctgc gcacggtgcgcgacacgctcccgagttgtgcggtgcgcgccggcctcctg900
cggccagact acgcgctgctgggccaccgccagctggtgcgcaccgactgccccggcgac960
gcgctcttcg acctgctgcgcacctggccgcacttcaccgcgactgttaagccaagacct1020
gccaggagtg tctctaagagatccaggagggagccacccccaaggaccctgccagccaca1080
gacctccaa 1089
<210> 47
<211> 747
<212> DNA
<213> Homo sapiens
<400> 47
atgggtggcc cccggggcgc gggctgggtg gcggcgggcc tgctgctcgg cgcgggcgcc 60
tgctactgca tttacaggctgacccggggtcggcggcggggcgaccgcgagctcgggata 120
cgctcttcga agtccgcagaagacttaactgatggttcatatgatgatgttctaaatgct 180
gaacaacttc agaaactcctttacctgctggagtcaacggaggatcctgtaattattgaa 240
agagctttga ttactttgggtascaatgcagccttttcagttaacceagctattattcgt 300
gaattgggtg gtattccaattgttgcaaacaaaatcaaccattccaaccagagtattaaa 360
gagaeagctt taaatgcactaaataacctgagtgtgaatgttgaaaatcasatcaagata 420
aaggtgcaag ttttgaaactgcttttgaatttgtctgaaaatccagccatgacagaagga 480
cttctccgtg cccaagtggattcatcattcctttccctttatgacagccacgtagcaaag 540
gagattcttc ttcgagtacttacgctatttcagaatataaagaactgcctcaaaatagaa 600
ggccatttag ctgtgcagcctactttcactgaaggttcattgtttttcctgttacatgga 660
gaagaatgtg cccagaaaatsagagctttagttgatcaccatgatgcagaggtgaaggaa 720
aaggttgtaa caataatacccaaeatc 747
<210> 48
<211> 294
<212> DNA
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
46/177
<213> Homo sapiens
<400> 48
atggcgtcgc tcctgtgctg tgggccgaag ctggccgcct gcggcatcgt cctcagcgcc 60
tggggagtga tcatgttgat aatgctcgga atatttttca atgtccattc cgctgtgttg 120
attgaggacg ttcccttcac ggagaaagat tttgagaatg gcccccagaa catatacaac 180
ctttacgagc aagtcagcta caactgtttc atcgctgcag gcctttacct cctcctcgga 240
ggcttctctt tctgccaagt tcggctcaat aagcgcaagg aatacatggt gcgc 2g4
<210> 49
<211> 516
<212> DNA
<213> Homo sapiens
<400> 49
atggtgggcc ccgcgccgcggcggcggctgcggccgctggcagcgctggccctggtcctg60
gcgctggccc cggggctgcccacagcccgggccgggcagacaccgcgccctgccgagcgg120
gggcccccag tgcggcttttcaccgaggaggagctggcccgctatggcggggaggaggaa180
gatcagccca tctacttggcagtgaagggagtggtgtttgatgtcacctccggaaaggag240
ttttatggac gaggagccccctacaatgccttgacggggaaggactccactagaggggta300
gccasgatgt ccttggatcctgcagacctcacccatgacactacgggtctcacggccasg360
gaactggagg ccctggatgaggtcttcaccaaagtgtacaaagccaaataccccatcgtc420
ggctacactg cccggagaattctcaatgaggatggcagccctaacctggacttcaagcct480
gaagaccagc cccattttgacatcaaggatgagttc 516
<210> 50
<211> 360
<212> DNA
<213> Homo sapiens
<400> 50
atgatgccgt cccgtaccaa cctggctact ggaatcccca gtagtaaagt gaaatattca 60
aggctctcca gcacagacga tggctacatt gaccttcagt ttaagaaaac ccctcctaag 120
atcccttata aggccatcgc acttgccact gtgctgtttt tgattggcgc ctttctcatt 180
attataggct ccctcctgct gtcaggctac atcagcaaag ggggggcaga ccgggccgtt 240
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
47/177
ccagtgctga tcattggcat tctggtgttc ctacccggat tttaccacct gcgcatcgct 300
tactatgcat ccaaaggcta ccgtggttac tcctatgatg acattccaga ctttgatgac 360
<210> 51
<211> 1065
<212> DNA
<213> Homo Sapiens
<220>
<221> CDS
<222> (2)...(943)
<400> 51
a atg aac caa ctc agc ttc ctg ctg ttt ctc ata gcg acc acc aga gga 49
Met Asn Gln Leu Ser Phe Leu Leu Phe Leu Ile Ala Thr Thr Arg Gly
1 5 10 15
tgg agt aca gat gag get sat act tac ttc aag gaa tgg acc tgt tct 97
Trp Ser Thr Asp Glu Ala Asn Thr Tyr Phe Lys Glu Trp Thr Cys Ser
25 30
tcg tct cca tct ctg ccc aga agc tgc aag gaa atc aaa gac gaa tgt 145
20 Ser Ser Pro Ser Leu Pro Arg Ser Cys Lys Glu Ile Lys Asp Glu Cys
35 40 45
cct agt gca ttt gat ggc ctg tat ttt ctc cgc act gag aat ggt gtt 193
Pro Ser Ala Phe Asp Gly Leu Tyr Phe Leu Arg Thr Glu Asn Gly Val
50 55 60
atc tac cag acc ttc tgt gac atg acc tct ggg ggt ggc ggc tgg acc 241
Ile Tyr Gln Thr Phe Cys Asp Met Thr Ser Gly Gly Gly Gly Trp Thr
65 70 75 80
ctg gtg gcc agc gtg cat gag sat gac atg cgt ggg aag tgc acg gtg 289
Leu Val Ala Ser Val His Glu Asn Asp Met Arg Gly Lys Cys Thr Val
85 90 95
ggc gat cgc tgg tcc agt cag cag ggc agc aaa gca gac tac cca gag 337
Gly Asp Arg Trp Ser Ser Gln Gln Gly Ser Lys Ala Asp Tyr Pro Glu
100 105 110
ggg gac ggc aac tgg gcc aac tac aac acc ttt gga tct gca gag gcg 385
Gly Asp Gly Asn Trp Ala Asn Tyr Asn Thr Phe Gly Ser Ala Glu Ala
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
48/177
115 120 125
gcc acgagcgatgactac eagaaccctggctactacgac atccaggcc 433
Ala ThrSerAspAspTyr LysAsnProGlyTyrTyrAsp IleGlnAla
130 135 140
aag gacctgggcatctgg cacgtgcccaataagtccccc atgcagcac 481
Lys AspLeuGlyIleTrp HisValProAsnLysSerPro MetGlnHis
145 150 155 160
tgg agaaacagctccctg ctgaggtaccgcacggacact ggcttcetc 529
Trp ArgAsnSerSerLeu LeuArgTyrArgThrAspThr GlyPheLeu
165 170 175
cag acactgggacataat ctgtttggcatctaccagaaa tatccagtg 577
Gln ThrLeuGlyHisAsn LeuPheGlyIleTyrGlnLys TyrProVal
180 185 190
aaa tatggagaaggaaag tgttggactgacaacggcccg gtgatccct 625
Lys TyrGlyGluGlyLys CysTrpThrAspAsnGlyPro ValIlePro
195 200 205
gtg gtctatgattttggc gacgcccagaaaacagcatct tattactca 673
Val ValTyrAspPheGly AspAlaGlnLysThrAlaSer TyrTyrSer
210 215 220
ccc tatggccagcgggaa ttcactgcgggatttgttcag ttcagggta 721
Pro TyrGlyGlnArgGlu PheThrAlaGlyPheValGln PheArgVal
225 230 235 240
ttt aataacgagagagca gccaacgccttgtgtgetgga atgagggtc 769
Phe AsnAsnGluArgAla AlaAsnAlaLeuCysAlaGly MetArgVal
245 250 255
acc gga tgt eac act gag cac cac tgc att ggt gga gga gga tac ttt 817
Thr Gly Cys Asn Thr Glu His His Cys Ile Gly Gly Gly Gly Tyr Phe
260 265 270
cca gag gcc agt ccc cag cag tgt gga gat ttt tct ggt ttt gat tgg 865
Pro Glu Ala Ser Pro Gln Gln Cys Gly Asp Phe Ser Gly Phe Asp Trp
275 280 285
agt gga tat gga act cat gtt ggt tac agc agc agc cgt gag ata act 913
Ser Gly Tyr Gly Thr His Val Gly Tyr Ser Ser Ser Arg Glu Ile Thr
290 295 300
gag gca get gtg ctt cta ttc tat cgt tgagagtttt gtgggaggga 960
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
49/177
Glu Ala Ala Val Leu Leu Phe Tyr Arg
305 310
acccagacct etcctcccaa ccatgagatc ccaaggatgg agaacaactt acccagtagc 1020
tagaatgtta atggcagaag agaaaacaat aaatcatatt gactc 1065
<210> 52
<211> 937
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (177)...(866)
<400> 52
cttttggaga actgcgcttc ccgccgccgc ggccgccacc 60
tctttcggag
ggagtgttcg
tggagtttct tcagactcca ggagtccaga gaggasacgc 120
gatttccctg
tcaaccacga
ggagcggaga caacagtacc gatcgcccca gcaggg 176
tgacgcctct
ttcagcccgg
atg ggc aag atctggctgccc ttccccgtgctccttctggcc get 224
gac
Met Gly Lys IleTrpLeuPro PheProValLeuLeuLeuAla Ala
Asp
1 5 io 15
ctg cct gtg ctgctgcctggg gcggccggcttcacaccttcc ctc 272
ccg
Leu Pro Val LeuLeuProGly AlaAlaGlyPheThrProSer Leu
Pro
20 25 30
gat agc ttc acctttaccctt cccgccggccagaaggagtgc ttc 320
gac
Asp Ser Phe ThrPheThrLeu ProAlsGlyGlnLysGluCys Phe
Asp
40 45
tac cag atg cccctgaaggcc tcgctggagatcgagtaccaa gtt 368
ccc
Tyr Gln Met ProLeuLysAla SerLeuGluIleGluTyrGln Val
Pro
50 55 60
30 tta gat gca ggattagatatt gatttccatcttgcctctcca gaa 416
gga
Leu Asp Ala GlyLeuAspIle AspPheHisLeuAlaSerPro Glu
Gly
65 70 75 80
ggc aaa tta gtttttgaacaa agaaaatcagatggagttcac act 464
acc
Gly Lys Leu ValPheGluGln ArgLysSerAspGlyValHis Thr
Thr
35 85 90 95
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
50/177
gta gag gaa gtt gattac atg aat aca 512
act ggt ttc ttc
tgc
ttt
gac
Val GluThrGlu ValGlyAspTyr Met Asn ThrPhe
Phe
Cys
Phe
Asp
100 105 110
agc accatttct gagasggtgatt ttctttgaa atcctg gataat 560
tta
Ser ThrIleSer GluLysValIle PhePheGlu IleLeu AspAsn
Leu
115 120 125
atg ggagaacag gcacaagaacan gaagattgg aaatat attact 608
aag
Met GlyGluGln AlaGInGluGln GluAspTrp LysTyr IleThr
Lys
130 135 140
ggc acagatata ttggatatgaaa ctggaagac ctggaa tccatc 656
atc
Gly ThrAspIle LeuAspMetLys LeuGluAsp LeuGlu SerIle
Ile
145 150 155 160
aac agcatcaag tccagaetaagc saaagtggg atacaa attctg 704
cac
Asn SerIleLys SerArgLeuSer LysSerGly IleGln IleLeu
His
165 170 175
ctt agagcattt gaagetcgtgat cgaaacata gaaagc aacttt 752
csa
Leu ArgAlaPhe GluAlaArgAsp ArgAsnIle GluSer AsnPhe
Gln
180 185 190
gat agagtcaat ttctggtctatg gttaattta gtcatg gtggtg 800
gtg
Asp ArgValAsn PheTrpSerMet ValAsnLeu ValMet ValVal
Val
195 200 205
gtg tcagccatt caagtttatatg ctgaagagt tttgan gataag 848
ctg
Val SerAlaIle ValTyr LysSer PheGlu
Gln Met Leu As
Leu L
p
ys
210 215 220
agg saaagtaga taaaactcca gagtn attganaaatg gOp
act aacta cgtaac
Arg Ser
Lys Arg
Thr
225
aggcataaaa atgcaataaa ctgttacagt caagacc g37
<210> 53
<211> 1678
<212> DNA
<213> Homo sapiens
<220>
<221> cns
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
51/177
<222> (56)...(1459)
<400> 53
agcgctcccg aggccgcggg agcctgcaga gaggacagcc ggcctgcgcc gggac 55
atg cgg ccc cag gag ctc ccc agg ctc gcg ttc ccg ttg ctg ctg ttg 103
Met Arg Pro Gln Glu Leu Pro Arg Leu Ala Phe Pro Leu Leu Leu Leu
1 5 10 15
ctg ttg ctg ctg ctg ccg ccg ccg ccg tgc cct gcc cac agc gcc acg 151
Leu Leu Leu Leu Leu Pro Pro Pro Pro Cys Pro Ala His Ser Ala Thr
20 25 30
cgc ttc gac ccc acc tgg gag tcc ctg gac gcc cgc cag ctg ccc gcg 199
Arg Phe Asp Pro Thr Trp Glu Ser Leu Asp Ala Arg Gln Leu Pro Ala
35 40 45
tgg tttgaccaggcc aagttcggcatcttc atccactggggagtg ttt 247
Trp PheAspGlnAla LysPheGlyIlePhe IleHisTrpGlyVal Phe
50 55 60
tcc gtgcccagcttc ggtagcgagtggttc tggtggtattggcaa aeg 295
Ser ValProSerPhe GlySerGluTrpPhe TrpTrpTyrTrpGln Lys
65 70 75 80
gaa aagataccgaag tatgtggaatttatg aaagataattaccct cct 343
Glu LysIleProLys TyrValGluPheMet LysAspAsnTyrPro Pro
85 90 95
agt ttcaaatatgaa gattttggaccacta tttacagcaaaattt ttt 391
Ser PheLysTyrGlu AspPheGlyProLeu PheThrAlaLysPhe Phe
loo los 110
aat gcc aac cag tgg gca gat att ttt cag gcc tct ggt gcc aaa tac 439
Asn Ala Asn Gln Trp Ala Asp Ile Phe Gln Ala Ser Gly Ala Lys Tyr
115 120 125
att gtc tta act tcc saa cat cat gaa ggc ttt acc ttg tgg ggg tca 487
Ile Val Leu Thr Ser Lys His His Glu Gly Phe Thr Leu Trp Gly Ser
130 135 140
gaa tat tcg tgg aac tgg aat gcc ata gat gag ggg ccc sag agg gac 535
Glu Tyr Ser Trp Asn Trp Asn Ala Ile Asp Glu Gly Pro Lys Arg Asp
145 150 155 160
att gtc aag gaa ett gag gta gcc att agg aac aga act gac ctg cgt 583
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
52/177
Ile Val Lys Glu Leu Glu Val Ala Ile Arg Asn Arg Thr Asp Leu Arg
165 170 175
ttt gga ctg tac tat tcc ctt ttt gaa tgg ttt cat ccg ctc ttc ctt 631
Phe Gly Leu Tyr Tyr Ser Leu Phe Glu Trp Phe His Pro Leu Phe Leu
180 185 . 190
gag gat gaa tcc agt tca ttc cat aag cgg caa ttt cca gtt tct aag 679
Glu Asp Glu Ser Ser Ser Phe His Lys Arg Gln Phe Pro Val Ser Lys
195 200 205
aca ttg cca gag ctc tat gag tta gtg aac aac tat cag cct gag gtt 727
Thr Leu Pro Glu Leu Tyr Glu Leu Val Asn Asn Tyr Gln Pro Glu Val
210 215 220
ctg tgg tcg gat ggt gac gga gga gca ccg gat cas tac tgg aac agc 775
Leu Trp Ser Asp Gly Asp Gly Gly Ala Pro Asp Gln Tyr Trp Asn Ser
225 230 235 240
aca ggc ttc ttg gcc tgg tta tat aat gaa agc cca gtt cgg ggc aca 823
Thr Gly Phe Leu Ala Trp Leu Tyr Asn Glu Ser Pro Val Arg Gly Thr
245 250 255
gta gtc acc aat gat cgt tgg gga get ggt agc atc tgt aag cat ggt 871
Val Val Thr Asn Asp Arg Trp Gly Ala Gly Ser Ile Cys Lys His Gly
260 265 270
ggc ttc tat acc tgc agt gat cgt tat aac cca gga cat ctt ttg cca 919
Gly Phe Tyr Thr Cys Ser Asp Arg Tyr Asn Pro Gly His Leu Leu Pro
275 280 285
cat aaa tgg gaa aac tgc atg aca ata gac aaa ctg tcc tgg ggc tat 967
His Lys Trp Glu Asn Cys Met Thr Ile Asp Lys Leu Ser Trp Gly Tyr
290 295 300
agg agg gaa get gga atc tct gac tat ctt aca att gaa gas ttg gtg -1015
Arg Arg Glu Ala Gly Ile Ser Asp Tyr Leu Thr Ile Glu Glu Leu Val
305 310 315 320
aag caa ctt gta gag aca gtt tca tgt gga gga aat ctt ttg atg aat 1063
Lys Gln Leu Val Glu Thr Val Ser Cys Gly Gly Asn Leu Leu Met Asn
325 330 335
att ggg ccc aca cta gat ggc acc att tct gta gtt ttt gag gag cga 1111
Ile Gly Pro Thr Leu Asp Gly Thr Ile Ser Val Val Phe Glu Glu Arg
340 345 350
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
53/I77
ctg agg caa atg ggg tcc tgg cta aaa gtc aat gga gaa get att tat 1159
Leu Arg Gln Met Gly Ser Trp Leu Lys Val Asn Gly Glu Ala Ile Tyr
355 360 365
gaa acc cat acc tgg cga tcc cag aat gac act gtc acc cca gat gtg 1207
Glu Thr His Thr Trp Arg Ser Gln Asn Asp Thr Val Thr Pro Asp Val
370 375 380
tgg tacacatccaagcctaaa gaaaaattagtc tatgccatttttctt 1255
Trp TyrThrSerLysProLys GluLysLeuVal TyrAlaIlePheLeu
385 390 395 400
aaa tggcccacatcaggacag ctgttccttggc catcccaaagetatt 1303
Lys TrpProThrSerGlyGln LeuPheLeuGly HisProLysAlaIle
405 410 415
ctg ggggcaacagaggtgaaa ctactgggccat ggacagccacttaac 1351
Leu GlyAlaThrGluValLys LeuLeuGlyHis GlyGlnProLeuAsn
420 425 930
tgg atttctttggagcaaaat ggcattatggta gaactgccaca eta 1399
g
Trp IleSerLeuGluGlnAsn GlyIleMetVal GluLeuProGl L
n eu
435 440 445
acc attcatcagatgccgtgt aaatggggctgg getctagccctgact 1447
Thr IleHisGlnMetProCys LysTrpGlyTrp AlaLeuAlaLeuThr
450 455 460
eat gtg atc taaagtgcag cagagtggct gatgctgcaa gttatgtcta aggc 1500
Asn Val Ile
465
taggaactat caggtgtcta taattgtagc acatggagaa agcasatgta saactggata 1560
agaaaattat tttggcagtt cagccctttc cctttttccc actaaatttt ttcttaeatt 1620
acccatgtaa ccattttaac tctccagtgc actttgccat tsaagtctct tcacattg 1678
<210> 54
<2I1> 467
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (114)...(413)
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
54/1??
<400>
54
aggggagggc ggtgctcc gc gcggtggc g gttgctatcg cgcagaa cctactcagg
60
c ctt
cagccagctg agaagagttg gggaaagtg ctgctgctgg tgcagac gcgatg
116
a gtc
~t
1
gat aacgtg cagccgaaaataaaa cat cccttctgcttc agtgtg 164
cgc
Asp AsnVal GlnProLysIleLys His ProPheCysPhe SerVal
Arg
5 10 15
aaa ggccac gtgaagatgctgcgg ctg attatcaactca ctggta 212
gat
Lys GlyHis ValLysMetLeuArg Leu IleIleAsnSer LeuVal
Asp
20 25 30
aca acagta ttcatgctcatcgta tct ttggcactgata ccagaa 260
gtg
Thr ThrVal PheMetLeuIleVal Ser LeuAlaLeuIle ProGlu
Val
35 40 45
acc acaaca ttgacagttggtgga ggg tttgcacttgtg acagca 308
gtg
Thr ThrThr LeuThrValGlyGly Gly PheAlaLeuVal ThrAla
Val
50 55 60 65
gta tgctgt cttgccgacggggcc ctt taccggaagctt ctgttc 356
att
Val CysCys LeuAlaAspGlyAla Leu TyrArgLysLeu LeuPhe
Ile
70 75 80
aat cccagc ggtccttaccagcaa aag gtgcatgaaaaa aaagaa 404
cct
Asn ProSer GlyProTyrGlnGln Lys ValHisGluLys LysGlu
Pro
85 90 95
gtt ttgtaattttata tacttttt a ttgatactaagtatt aaa 450
t gt
Val Leu
catatttctg tattctt ~ 467
<210> 55
<211> 875
<212> DNA
<213> Homo sapiens
<220>
<221> cns
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
55/177
<222> (272)...(841)
<400> 55
attggttggg ggaaacccac gaggggacgc ggccgaggag ggtcgctgtc cacccggggg 60
cgtgggagtg aggtaccaga ttcagcccat ttggccccga cgcctctgtt ctcggaatcc 120
gggtgctgcg gattgaggtc ccggttccta acgaatctct gctggattgg ccgtaaccct 180
gtccccgagc gggctcacag ggtctgaagg ccacgcatga ggcaaaggta aagttctgag 240
ccacccggtg cctccttccc aggactgcaa g atg gag gaa ggc ggg aac cta 292
Met Glu Glu Gly Gly Asn Leu
1 5
gga ggc ctg att aag atg gtc cat cta ctg gtc ttg tca ggt gcc tgg 340
Gly Gly Leu Ile Lys Met Val His Leu Leu Val Leu Ser Gly Ala Trp
10 15 20
ggc atg caa atg tgg gtg acc ttc gtc tca ggc ttc ctg ctt ttc cga 388
Gly Met Gln Met Trp Val Thr Phe Val Ser Gly Phe Leu Leu Phe Arg
30 35
agc ctt ccc cga cat acc ttc gga cta gtg cag agc aaa etc ttc ccc 436
Ser Leu Pro Arg His Thr Phe Gly Leu Val Gln Ser Lys Leu Phe Pro
40 45 50 55
20 ttc tac ttc cac atc tcc atg ggc tgt gcc ttc atc aac ctc tgc atc 484
Phe Tyr Phe His Ile Ser Met Gly Cys Ala Phe Ile Asn Leu Cys Ile
60 65 70
ttg get tca cag cat get tgg get cag ctc aca ttc tgg gag gcc agc 532
Leu Ala Ser Gln His Ala Trp Ala Gln Leu Thr Phe Trp Glu Ala Ser
25 75 80 85
cag ctt tac ctg ctg ttc ctg agc ctt acg ctg gcc act gtc aac gcc 580
Gln Leu Tyr Leu Leu Phe Leu Ser Leu Thr Leu Ala Thr Val Asn Ala
90 95 100
cgc tgg ctg gaa cec cgc acc aca get gcc atg tgg gcc ctg caa acc 628
Arg Trp Leu Glu Pro Arg Thr Thr Ala Ala Met Trp Ala Leu Gln Thr
105 110 115
gtg gag aag gag cga ggc ctg ggt ggg gag gta cca ggc agc cac cag 676
Val Glu Lys Glu Arg Gly Leu Gly Gly Glu Val Pro Gly Ser His Gln
120 125 130 I35
ggt ccc gat ccc tac cgc cag ctg cga gag aag gac ccc aag tac agt 724
CA 02336225 2001-O1-24
WO OO/OS367 PCT/JP99/03929
56/I77
Gly Pro Asp Pro Tyr Arg Gln Leu Arg Glu Lys Asp Pro Lys Tyr Ser
140 145 150
get ctc cgc cag aat ttc ttc cgc tac cat ggg ctg tcc tct ctt tgc 772
Ala Leu Arg Gln Asn Phe Phe Arg Tyr His Gly Leu Ser Ser Leu Cys
155 160 165
ast ctg ggc tgc gtc ctg agc aat ggg ctc tgt ctc get ggc ctt gcc 820
Asn Leu Gly Cys Val Leu Ser Asn Gly Leu Cys Leu Ala Gly Leu Ala
170 175 180
ctg gaa ata egg agc ctc tagcatgggc cctgcatgct aataaatgct tcttcag 875
Leu Glu Ile Arg Ser Leu
185
<210> 56
<211> 1256
<212> rn~A
<213> Homo Sapiens
<220>
<221> CDS
<222> (150)...(1241)
<400> 56
atgtaagagc cacctcctcc ccaggactca gggatggctc tccagatgtc accactgcag 60
atattggagc caacactcca gatgctacaa aaggctgtcc agatgtccaa gcttccttgc I20
cagatgccaa agccaagtcc ccaccgacc atg gtg gac agc ctc ctg gca gtc 173
Met Val Asp Ser Leu Leu Ala Val
1 5
acc ctq get gga aac ctg ggc ctg acc ttc ctc cga ggt tcc cag acc 221
Thr Leu Ala Gly Asn Leu Gly Leu Thr Phe Leu Arg Gly Ser Gln Thr
10 15 20
cag agc cat cca gac ctg gga act gag ggc tgc tgg gac cag ctc tct 269
Gln Ser His Pro Asp Leu Gly Thr Glu Gly Cys Trp Asp Gln Leu Ser
25 30 35 40
gcc cct cgg acc ttt acg ctt ttg gac ccc aag gca tct ctg tta acc 31?
Ala Pro Arg Thr Phe Thr Leu Leu Asp Pro Lys Ala Ser Leu Leu Thr
45 50 55
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
57/177
aag gcc ttc ctc aat ggc gcc ctg gat ggg gtc atc ctt gga gac tac 365
Lys Ala Phe Leu Asn Gly Ala Leu Asp Gly Val Ile Leu Gly Asp Tyr
60 65 70
ctg agc cgg act cct gag ccc cgg cca tcc ctc agc cac ttg ctg agc 413
Leu Ser Arg Thr Pro Glu Pro Arg Pro Ser Leu Ser His Leu Leu Ser
75 80 85
cag tac tat ggg get ggg gtg gcc aga gac cca ggg ttc cgc agc aac 461
Gln Tyr Tyr Gly Ala Gly Val Ala Arg Asp Pro Gly Phe Arg Ser Asn
90 95 100
ttc cga cgg cag aac ggt get get ctg act tca gcc tcc atc ctg gcc 509
Phe Arg Arg Gln Asn Gly Ala Ala Leu Thr Ser Ala Ser Ile Leu Ala
105 110 115 120
cag cag gtg tgg gga acc ctt gtc ctt cta cag agg ctg gag cca gta 557
Gln Gln Val Trp Gly Thr Leu Val Leu Leu Gln Arg Leu Glu Pro Val
125 130 135
cac ctc cag ctt cag tgc atg agc caa gaa cag ctg gcc cag gtg get 605
His Leu Gln Leu Gln Cys Met Ser Gln Glu Gln Leu Ala Gln Val Ala
140 145 150
gcc aat get acc aag gaa ttc act gag gcc ttc ctg gga tgc ccg gcc 653
Ala Asn Ala Thr Lys Glu Phe Thr Glu Ala Phe Leu Gly Cys Pro Ala
155 160 165
atc cac ccc cgc tgc cgc tgg gga gcg gcg cct tat cgg ggc cgc ccg 701
Ile His Pro Arg Cys Arg Trp Gly Ala Ala Pro Tyr Arg Gly Arg Pro
170 175 180
aag ctg ctg cag ctg ccg ctg gga ttc ttg tac gtg cat cac acc tac 749
Lys Leu Leu Gln Leu Pro Leu Gly Phe Leu Tyr Val His His Thr Tyr
185 190 195 200
gtg cct gca cca ccc tgc acg gac ttc acg cgc tgc gca gcc asc atg 797
Val Pro Ala Pro Pro Cys Thr Asp Phe Thr Arg Cys Ala Ala Asn Met
205 210 215
cgc tcc atg cag cgc tac cac cag gac acg caa ggc tgg gga gac atc 845
Arg Ser Met Gln Arg Tyr His Gln Asp Thr Gln Gly Trp Gly Asp Ile
220 225 230
ggc tac agt ttc gtg gtg ggc tcg gac ggc tac gtg tac gag gga cgc 893
Gly Tyr Ser Phe Val Val Gly Ser Asp Gly Tyr Val Tyr Glu Gly Arg
CA 02336225 2001-O1-24
WO OOI05367 PCT/JP99/03929
581177
235 240 245
ggc tgg cac tgg gtg ggc gcc cac acg ctc ggc cac aac 941
tcc cgg ggc
Gly Trp His Trp Val Gly Ala His Thr Leu Gly His Asn
Ser Arg Gly
250 255 260
ttc ggc gtg gcc ata gtg ggc aac tac acc gcg gcg ctg 989
ccc acc gag
Phe Gly Val Ala Ile Val Gly Asn Tyr Thr Ala Ala Leu
Pro Thr Glu
265 270 275 280
gcc get ctg cgc acg gtg cgc gac acg ctc ccg agt tgt 1037
gcg gtg.cgc.
Ala Ala Leu Arg Thr Val Arg Asp Thr Leu Pro Ser Cys
Ala Val Arg
285 290 295
gcc ggc ctc ctg cgg cca gac tac gcg ctg ctg ggc cac 1085
cgc cag ctg
Ala Gly Leu Leu Arg Pro Asp Tyr Ala Leu Leu Gly His
Arg Gln Leu
300 305 310
gtg cgc acc gac tgc ccc ggc gac gcg ctc ttc gac ctg 1133
ctg cgc acc
Val Arg Thr Asp Cys Pro Gly Asp Ala Leu Phe Asp Leu
Leu Arg Thr
315 320 325
tgg ccg cac ttc acc gcg act gtt aag cca aga cct gcc 1181
agg agt gtc
Trp Pro His Phe Thr Ala Thr Val Lys Pro Arg Pro Ala
Arg Ser Val
330 335 340
tct aag aga tcc agg agg gag cca ccc cca agg acc ctg 1229
cca gcc aca
Ser Lys Arg Ser Arg Arg Glu Pro Pro Pro Arg Thr Leu
Pro Ala Thr
345 350 355 360
gac ctc caa tasagacagc atggaaac 1256
Asp Leu Gln
<210> 57
<211> 884
<212> DNA
<213> Homo Sapiens
<220>
<221> CDS
<222> (135)...(884)
<400> 57
catttccttt ctccacatcc aggtcaggtg gcgtttgctg tggcggctag gcccgcgtgc 60
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
59/177
gctggagacc tccgcgctgg cccccgcgag cctcctgccc tggcccggcg ctgcggctct 120
gccgcggcgg cagc atg ggt ggc ccc cgg ggc gcg ggc tgg gtg gcg gcg 170
Met Giy Gly Pro Arg Gly Ala Gly Trp Val Ala Ala
1 5 10
ggc ctg ctg ctc ggc gcg ggc gcc tgc tac tgc att tac agg ctg acc 218
Gly Leu Leu Leu Gly Ala Gly Ala Cys Tyr Cys Ile Tyr Arg Leu Thr
20 25
cgg ggt cgg cgg cgg ggc gac cgc gag ctc ggg ata cgc tct tcg aag 266
Arg Gly Arg Arg Arg Gly Asp Arg Glu Leu Gly Ile Arg Ser Ser Lys
10 30 35 40
tcc gca gaa gac tta act gat ggt tca tat gat gat gtt cta aat get 314
Ser Ala Glu Asp Leu Thr Asp Gly Ser Tyr Asp Asp VaI Leu Asn Ala
45 50 55 60
gaa caa ctt cag aaa ctc ctt tac ctg ctg gag tca acg gag gat cct 362
15 Glu Gin Leu Gln Lys Leu Leu Tyr Leu Leu Glu Ser Thr Glu Asp Pro
65 70 75
gta att att gaa aga get ttg att act ttg ggt aac ast gca gcc ttt 410
Val Ile Ile Glu Arg Ala Leu Ile Thr Leu Gly Asn Asn Ala Ala Phe
80 B5 90
tca gtt asc caa get att att cgt gaa ttg ggt ggt att cca att gtt 458
Ser Val Asn Gln Ala Ile Ile Arg Glu Leu Gly Gly Ile Pro Ile Val
95 100 105
gca aac aaa atc aac cat tcc aac cag agt att aaa gag aaa get tta 506
Ala Asn Lys Ile Asn His Ser Asn Gln Ser Ile Lys Glu Lys Ala Leu
110 115 120
aat gca cta aat aac ctg agt gtg aat gtt gaa ant can atc aag ata 554
Asn Ala Leu Asn Asn Leu Ser Val Asn Val Glu Asn Gln Ile Lys Ile
125 130 135 140
aag gtg caa gtt ttg aaa ctg ctt ttg aat ttg tct gaa aat cca gcc 602
Lys Val Gln Val Leu Lys Leu Leu Leu Asn Leu Ser Glu Asn Pro Ala
145 150 155
atg aca gaa gga ctt ctc cgt gcc caa gtg gat tcn tca ttc ctt tcc 650
Met Thr Glu Gly Leu Leu Arg Ala Gln Val Asp Ser Ser Phe Leu Ser
160 165 170
ctt tat gac agc cac gta gca aag gag att ctt ctt cga gta ctt acg 698
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
60!177
Leu TyrAspSerHis ValAlaLysGlu Ile Leu Val LeuThr
Leu Arg
175 180 185
cta tttcagaatata aagaactgcctc aaaatagaaggccat ttaget 746
Leu PheGlnAsnIle LysAsnCysLeu LysIleGluGIyHis LeuAla
190 195 200
gtg cagectactttc actgaaggttca ttgtttttcctgtta catgga 794
Val GlnProThrPhe ThrGluGlySer LeuPhePheLeuLeu HisGly
205 210 215 220
gaa gaatgtgcccag aaaataagaget ttagttgatcaccat gatgca 842
Glu GluCysAlaGln LysIleArgAla LeuValAspHisHis AspAla
225 230 235
gag gtgaaggaaaag gttgtaacaata atacccsaaatctga 884
Glu ValLysGluLys ValValThrIle IleProLysIle
240 245
<210> 58
<211> 589
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (48). ..(344)
<400> 58
gctttccgag cccgcttgca cttcttt atggcg tcg 56
cctcggcgat
ccccgactcc
MetAla Ser
1
ctc ctg tgc tgt ccgaagctggccgcc tgcggcatcgtcctc agc 104
ggg
Leu Leu Cys Cys ProLysLeuAlaAla CysGlyIleValLeu Ser
Gly
5 10 15
gcc tgg gga gtg atgttgataatgctc ggaatatttttcaat gtc 152
atc
Ala Trp Gly Val MetLeuIleMetLeu GlyIlePhePheAsn Val
Ile
20 25 30 35
cat tcc get gtg attgaggacgttccc ttcacggagasagat ttt 200
ttg
His Ser Ala Val Leu Ile Glu Asp Val Pro Phe Thr Glu Lys Asp Phe
CA 02336225 2001-O1-24
.
WO 00/05367 PCT/JP99/0392~
s lim7
40 45 50
gag aat ggc ccc aac ata aac ctt gag caa gtc agc 248
cag tac tac tac
Glu Asn Gly Pro Asn Ile Asn Leu Glu Gln Val Ser
Gln Tyr Tyr Tyr
55 60 65
sac tgt ttc atc gca ggc tac ctc ctc gga ggc ttc 296
get ctt ctc tct
Asn Cys Phe Ile Ala Gly Tyr Leu Leu Gly Gly Phe
Ala Leu Leu Ser
70 75 80
ttc tgc caa gtt ctc aat cgc aag tac atg gtg cgc 341
cgg aag gaa
Phe Cys Gln Val Leu Asn Arg Lys Tyr Met Val Arg
Arg Lys Glu
B5 90 95
tagggcccc ggcgcgtttccccgctccagcccctcctct 400
atttaaagac
tccctgcacc
gtgtcaccca ggtcgcgtcc cacccttgccggcgccctctgtgggactgg gtttcccggg460
cgagagactg aatcccttct cccatctctggcatccggcccccgtggaga gggctgaggc520
tggggggctg ttccgtctct ctgtgtcccgtatctcaata aagagaatct580
ccacccttcg
gctctcttc 589
<210> 59
<211> 673
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (25)...(543)
<900> 59
cttgccttgc gctgcgcgct cacc atg gtg ggc ccc gcg ccg cgg cgg cgg 51
Met Val Gly Pro Ala Pro Arg Arg Arg
1 5
ctg cgg ccg ctg gca gcg ctg gcc ctg gtc ctg gcg ctg gcc ccg ggg gg
Leu Arg pro Leu Ala Ala Leu Ala Leu Val Leu Ala Leu Ala Pro Gly
10 15 20 25
ctg ccc aca gcc cgg gcc ggg cag aca ccg cgc cct gcc gag cgg ggg 147
Leu Pro Thr Ala Arg Ala Gly Gln Thr Pro Arg Pro Ala Glu Arg Gly
30 35 40
cec cca gtg cgg ctt ttc acc gag gag gag ctg gcc cgc tat ggc ggg 195
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
62/177
Pro Pro Val Arg Leu Phe Thr Glu Glu Glu Leu Ala Arg Tyr Gly Gly
45 50 55
gag gag gsa gat cag ccc atc tac ttg gca gtg aag gga gtg gtg ttt 243
Glu Glu Glu Asp Gln Pro Ile Tyr Leu Ala Val Lys Gly Val Val Phe
60 65 70
gat gtc acc tcc gga aag gag ttt tat gga cga gga gcc ccc tac aat 291
Asp Val Thr Ser Gly Lys Glu Phe Tyr Gly Arg Gly Ala Pro Tyr Asn
75 80 85
gcc ttg acg ggg aag gac tcc act aga ggg gta gcc aag atg tcc ttg 339
Ala Leu Thr Gly Lys Asp Ser Thr Arg Gly Val Ala Lys Met Ser Leu
90 95 100 105
gat cct gca gac ctc acc cat gac act acg ggt ctc acg gcc aag gaa 387
Asp Pro Ala Asp Leu Thr His Asp Thr Thr Gly Leu Thr Ala Lys Glu
110 115 120
ctg gag gcc ctg gat gag gtc ttc acc aaa gtg tac aaa gcc aaa tac 435
Leu Glu Ala Leu Asp Glu Val Phe Thr Lys Val Tyr Lys Ala Lys Tyr
125 130 135
ccc atc gtc ggc tac act gcc cgg aga att ctc aat gag gat ggc agc 483
Pro Ile Val Gly Tyr Thr Ala Arg Arg Ile Leu Asn Glu Asp Gly Ser
140 145 150
cct aac ctg gac ttc aag cct gaa gac cag ccc cat ttt gac atc aag 531
Pro Asn Leu Asp Phe Lys Pro Glu Asp Gln Pro His Phe Asp Ile Lys
155 160 165
gat gag ttc tgatgttccc cctgcaggag caggttcttg ggagcgtgag 580
Asp Glu Phe
170
gcaggaagac actaggtgct gaatctcctg caaaactggc tgcctggagg ccctgagcca 640
cccagatctg aataaaacag atgcttaccc tgg 673
<210> 60
<211> 1425
<212> DNA
<213> Homo Sapiens
<220>
<221> cDs
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
63/177
<222> (127)...(489)
<400> 60
tcccgcctgg ggccggctga gccatgcaac cttgggcgct
60
gtggcactta
agcgggccat
gcc aaccgtg ggcgagctct gcggcgctcc gctgtgtcag
120
gggtgtgcgg
gcggcctggc
cgt gttatg atgccgtcccgtacc aacctggetactgga atccccagt 168
Met MetProSer Thr LeuAlaThrGly ZleProSer
Arg Asn
1 5 10
agt eaagtg aaatattcaaggctc tccagcacagacgat ggctacatt 216
Ser Lysval LysTyrSerArgLeu SerSerThrAspAsp GlyTyrIle
20 25 30
gac cttcag tttsagaaaacccct cctaagatcccttat caggccatc 264
Asp LeuGln PheLysLysThrPro ProLysIleProTyr LysAlaIle
35 40 45
15 gca cttgcc actgtgctgtttttg attggcgcctttctc attattata 312
Ala LeuAla ThrValLeuPheLeu IleGlyAlaPheLeu IleIleIle
50 55 60
ggc tccctc ctgctgtcaggctac atcagcaaagggggg gcagaccgg 360
Gly SerLeu LeuLeuSerGlyTyr IleSerLysGlyGly AlaAspArg
65 70 75
gcc gttcca gtgctgatcattggc attctggtgttccta cccggattt 408
Ala ValPro ValLeuIleIleGly IleLeuValPheLeu ProGlyPhe
80 85 90
tac cacctg cgcatcgettactat gcatccaaaggctac cgtggttac 456
Tyr HisLeu ArgIleAlaTyrTyr AlaSexLysGlyTyr ArgGlyTyr
95 100 105 110
tcc tat gat gac att cca gac ttt gat gac tagcacccac ccca 500
Ser Tyr Asp Asp Ile Pro Asp Phe Asp Asp
115 120
tagctgagga ggagtcacagtggaactgtcccagctttaagatatctagcagaaactata560
gctgaggact aaggaattctgcagcttgcagatgtttaagaaaataatggccagattttt620
tgggtccttc ccaasgatgttaagtgaacctacagttagctaattaggacsagctctatt680
tttcatccct gggccctgacaagtttttccacaggaatatgtatcatggaagaatagagg740
ttattctgta atggaasagtgttgcctgccaccaccctctgtagagctgagcatttcttt800
taaatagtct tcattgccaatttgttcttgtagcaaatggaacaatgtggtatggctaat860
CA 02336225 2001-O1-24
WO 00/05367 PC1'/JP991039Z9
64/177
ttcttattat taagtagtttattttaaaaatatctgagtatattatcctgtacacttatc920
cctaccttca tgttccagtggaagaccttagtaaaatcaaagatcagtgagttcatctgt980
aatatttttt ttacttgctttcttactgacagcaaccaggaatttttttatcctgcagag1040
caagttttca aaatgtaaatacttcctctgtttaacagtccttggaccattctgatccag1100
ttcaccagta ggttggacagcatataatttgcatcattttgtcccttgtaaatcaagatg1160
ttctgcagat tattcctttaacggccggacttttggctgtttcctaatgaeacatgtagt1220
ggttattatt tagagtttatagccgtattgctagcaccttgtagtatgtcatcattctgc1280
tcatgattcc aaggatcagcctggatgcctagaggactagatcaccttagtttgattcta1340
ttttttagct tgcaaaaagtgacttatattccaaagaaattaaaatgttgaaatccaaat1400
cctagaaata aaatgagttaacttc 1425
<210> 61
<211> 307
<212> PRT
<213> Homo sapiens
<400> 61
Met Ser Met Ile Leu Ser Ala Ser Val Ile Arg Val Arg Asp Gly Leu
1 5 10 15
Pro Leu Ser Ala Ser Thr Asp Tyr Glu Gln Ser Thr Gly Met Gln Glu
20 25 30
Cys Arg Lys Tyr Phe Lys Met Leu Ser Arg Lys Leu Ala Gln Leu Pro
35 40 45
Asp Arg Cys Thr Leu Lys Thr Gly His Tyr Asn Ile Asn Phe Ile Ser
50 55 60
Ser Leu Gly Val Ser Tyr Met Met Leu Cys Thr Glu Asn Tyr Pro Asn
65 70 75 80
Val Leu Ala Phe Ser Phe Leu Asp Glu Leu Gln Lys Glu Phe Ile Thr
B5 90 95
Thr Tyr Asn Met Met Lys Thr Asn Thr Ala Val Arg Pro Tyr Cys Phe
100 105 110
Ile Glu Phe Asp Asn Phe Ile Gln Arg Thr Lys Gln Arg Tyr Asn Asn
115 120 125
Pro Arg Ser Leu Ser Thr Lys Ile Asn Leu Ser Asp Met Gln Thr Glu
130 135 140
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
65/177
Ile Lys Leu Arg Pro Pro Tyr Gln Ile Ser Met Cys Glu Leu Gly Ser
145 150 155 160
Ala Asn Gly Val Thr Ser Ala Phe Ser Val Asp Cys Lys Gly Ale Gly
165 170 175
Lys Ile Ser Ser Ala His Gln Arg Leu Glu Pro Ala Thr Leu Ser Gly
180 185 190
Ile Val Gly Phe Ile Leu Ser Leu Leu Cys Gly Ala Leu Asn Leu Ile
195 200 205
Arg Gly Phe His Ala Ile Glu Ser Leu Leu Gln Ser Asp Gly Asp Asp
210 215 220
Phe Asn Tyr Ile Ile Ala Phe Phe Leu Gly Thr Ala Ala Cys Leu Tyr
225 230 235 240
Gln Cys Tyr Leu Leu Val Tyr Tyr Thr Gly Trp Arg Asn Val Lys Ser
245 250 255
Phe Leu Thr Phe Gly Leu Ile Cys Leu Cys Asn Met Tyr Leu Tyr Glu
260 265 270
Leu Arg Asn Leu Trp Gln Leu Phe Phe His Val Thr Val Gly Ala Phe
275 280 285
Val Thr Leu Gln Ile Trp Leu Arg Gln Ala Gln Gly Lys Ala Pro Asp
290 295 300
Tyr Asp Val
305
<210> 62
<211> 183
<212> PRT
<213> Homo sapiens
<400> 62
Met Thr Ala Gln Gly Gly Leu Val Ale Asn Arg Gly Arg Arg Phe Lys
1 5 10 15
Trp Ala Ile Glu Leu Ser Gly Pro Gly Gly Gly Ser Arg Gly Arg Ser
20 25 30
Asp Arg Gly ser Gly Gln Gly Asp Ser Leu Tyr Pro Val Gly Tyr Leu
35 40 45
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/0392~
66/177
Asp Lys Gln Val Pro Asp Thr Ser Val Gln Glu Thr Asp Arg Ile Leu
50 55 60
Val Glu Lys Arg Cys Trp Asp Ile Ala Leu Gly Pro Leu Lys Gln Ile
65 70 75 BO
Pro Met Asn Leu Phe Ile Met Tyr Met Ala Gly Asn Thr Ile Ser Ile
85 90 95
Phe Pro Thr Met Met Val Cys Met Met Ala Trp Arg Pro Ile Gln Ala
100 105 110
Leu Met Ala Ile Ser Ala Thr Phe Lys Met Leu Glu Ser Ser Ser Gln
115 120 125
Lys Phe Leu Gln Gly Leu Val Tyr Leu Ile Gly Asn Leu Met Gly Leu
130 135 140
Als Leu Ala Val Tyr Lys Cys Gln Ser Met Gly Leu Leu Pro Thr His
145 150 155 160
Ala Ser Asp Trp Leu Ala Phe Ile Glu Pro Pro Glu Arg Met Glu Phe
165 170 175
Ser Gly Gly Gly Leu Leu Leu
180
<210> 63
<211> 327
<212> PRT
<213> Homo sapiens
<400> 63
Met Arg Ala Leu Pro Gly Leu Leu Glu Ala Arg Ala Arg Thr Pro Arg
1 5 10 15
Leu Leu Leu Leu Gln Cys Leu Leu Ala Ala Ala Arg Pro Ser Ser Ale
20 25 30
Asp Gly Ser Ala Pro Asp Ser Pro Phe Thr Ser Pro Pro Leu Arg Glu
an v5
Glu Ile Met Ala Asn Asn Phe Ser Leu Glu Ser His Asn Ile Ser Leu
50 55 60
Thr Glu His Ser Ser Met Pro Val Glu Lys Asn Ile Thr Leu Glu Arg
35 65 70 75 80
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
67/177
Pro Ser Asn Val Asn Leu Thr Cys Gln Phe Thr Thr Ser Gly Asp Leu
85 90 95
Asn Ala Val Asn Val Thr Trp Lys Lys Asp Gly Glu Gln Leu Glu Asn
100 105 110
Asn Tyr Leu Val Ser Ala Thr Gly Ser Thr Leu Tyr Thr Gln Tyr Arg
115 120 125
Phe Thr Ile Ile Asn Ser Lys Gln Met Gly Ser Tyr Ser Cys Phe Phe
130 135 140
Arg Glu Glu Lys Glu Gln Arg Gly Thr Phe Asn Phe Lys Val Pro Glu
145 150 155 160
Leu His Gly Lys Asn Lys Pro Leu Ile Ser Tyr Val Gly Asp Ser Thr
165 170 175
Val Leu Thr Cys Lys Cys Gln Asn Cys Phe Pro Leu Asn Trp Thr Trp
180 185 190
Tyr Ser Ser Asn Gly Ser Val Lys Val Pro Val Gly Val Gln Met Asn
195 200 205
Lys Tyr Val Ile Asn Gly Thr Tyr Ala Asn Glu Thr Lys Leu Lys Ile
210 215 220
Thr Gln Leu Leu Glu Glu Asp Gly Glu Ser Tyr Trp Cys Arg Ala Leu
225 230 235 240
Phe Gln Leu Gly Glu Ser Glu Glu His Ile Glu Leu Val Val Leu Ser
245 250 255
Tyr Leu Val Pro Leu Lys Pro Phe Leu Val Ile Val Ala Glu Val Ile
260 265 270
Leu Leu Val Ala Thr Ile Leu Leu Cys Glu Lys Tyr Thr Gln Lys Lys
275 280 285
Lys Lys His Ser Asp Glu Gly Lys Glu Phe Glu Gln Ile Glu Gln Leu
290 295 300
Lys Ser Asp Asp Ser Asn Gly Ile Glu Asn Asn Val Pro Arg His Arg
305 310 315 320
Lys Asn Glu Ser Leu Gly Gln
325
<210> 64
<211> 223
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/039Z9
68/177
<212> PRT
<213> Homo sapiens
<400> 64
Met Lys Phe Val Pro Cys Leu Leu Leu Val Thr Leu Ser Cys Leu Gly
1 5 10 15
Thr Leu Gly Gln Ala Pro Arg Gln Lys Gln Gly Ser Thr Gly Glu Glu
20 25 30
Phe His Phe Gln Thr Gly Gly Arg Asp Ser Cys Thr Met Arg Pro Ser
35 40 45 '
Ser Leu Gly Gln Gly Ala Gly Glu Val Trp Leu Arg Val Asp Cys Arg
50 55 60
Asn Thr Asp Gln Thr Tyr Trp Cys Glu Tyr Arg Gly Gln Pro Ser Met
65 70 75 80
Cys Gln Ala Phe Ala Ala Asp Pro Lys Ser Tyr Trp Asn Gln Ala Leu
85 90 g5
Gln Glu Leu Arg Arg Leu His His Ala Cys Gln Gly Ala Pro Val Leu
loo los llo
Arg Pro Ser Val Cys Arg Glu Ala Gly Pro Gln Ala His Met Gln Gln
115 120 125
Val Thr Ser Ser Leu Lys Gly Ser Pro Glu Pro Asn Gln Gln Pro Glu
130 135 140
Ala Gly Thr Pro Ser Leu Arg Pro Lys Ala Thr Val Lys Leu Thr Glu
145 150 155 160
Ala Thr Gln Leu Gly Lys Asp Ser Met Glu Glu Leu Gly Lys Als Lys
165 170 175
Pro Thr Thr Arg pro Thr Ala Lys Pro Thr Gln Pro Gly Pro Arg Pro
180 185 190
Gly Gly Asn Glu Glu Ala Lys Lys Lys Ala Trp Glu His Cys Trp Lys
195 200 205
Pro Phe Gln Ala Leu Cys Ala Phe Leu Ile Ser Phe Phe Arg Gly
210 215 220
<210> 65
<2I1> 4B
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
69/177
<212> PRT
<213> Homo Sapiens
<400> 65
Met Arg Leu Leu Leu Leu Leu Leu Val Ala Ala Ser Ala Met Val Arg
1 5 10 15
Ser Glu Ala Ser Ala Asn Leu Gly Gly Val Pro Ser Lys Arg Leu Lys
20 25 30
Met Gln Tyr Ala Thr Gly Pro Leu Leu Lys Phe Gln Ile Cys Val Ser
35 40 45
<210> 66
<211> 371
<212> PRT
<213> Homo Sapiens
<400> 66
Met Ala Trp Thr Lys Tyr Gln Leu Phe Leu Ala Gly Leu Met Leu Val
1 5 10 15
Thr Gly Ser Ile Asn Thr Leu Ser Ala Lys Trp Ala Asp Asn Phe Met
20 25 30
Ala Glu Gly Cys Gly Gly Ser Lys Glu His Ser Phe Gln His Pro Phe
35 40 45
Leu Gln Ala Val Gly Met Phe Leu Gly Glu Phe Ser Cys Leu Ala Ala
5o s~
Phe Tyr Leu Leu Arg Cys Arg Ala Ala Gly Gln Ser Asp Ser Ser Val
65 70 75 g0
Asp Pro Gln Gln Pro Phe Asn Pro Leu Leu Phe Leu Pro Pro Ala Leu
85 90 95
Cys Asp Met Thr Gly Thr Ser Leu Met Tyr Val Ala Leu Asn Met Thr
100 105 110
Ser Ala Ser Ser Phe Gln Met Leu Arg Gly Ala Val Ile Ile Phe Thr
115 120 125
Gly Leu Phe Ser Val Ala Phe Leu Gly Arg Arg Leu Val Leu Ser Gln
130 135 140
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
70/177
Trp Leu Gly Ile Leu Ala Thr Ile Ala Gly Leu Val Val Val Gly Leu
145 150 155 160
Ala Asp Leu Leu Ser Lys His Asp Ser Gln His Lys Leu Ser Glu Val
165 170 175
Ile Thr Gly Asp Leu Leu Ile Ile Met Ala Gln Ile Ile Val Ala Ile
180 185 190
Gln Met Val Leu Glu Glu Lys Phe Val Tyr Lys His Asn Val His Pro
195 200 205
Leu Arg Ala Val Gly Thr Glu Gly Leu Phe Gly Phe Val Ile Leu Ser
210 215 220
Leu Leu Leu Val Pro Met Tyr Tyr Ile Pro Ala Gly Ser Phe Ser Gly
225 230 235 240
Asn Pro Arg Gly Thr Leu Glu Asp Ala Leu Asp Ala Phe Cys Gln Val
245 250 255
I5 Gly Gln Gin Pro Leu Ile Ala Val Ala Leu Leu Gly Asn Ile Ser Ser
260 265 270
Ile Ala Phe Phe Asn Phe Ala Gly Ile Ser Val Thr Lys Glu Leu Ser
275 280 285
Ala Thr Thr Arg Met Val Leu Asp Ser Leu Arg Thr Val Val Ile Trp
290 295 300
Ala Leu Ser Leu Ala Leu Gly Trp Glu Ala Phe His Ala Leu Gln Ile
305 310 315 320
Leu Gly Phe Leu Ile Leu Leu Ile Gly Thr Ala Leu Tyr Asn Gly Leu
325 330 335
His Arg Pro Leu Leu Gly Arg Leu Ser Arg Gly Arg Pro Leu Ala Glu
340 345 350
Glu Ser Glu Gln Glu Arg Leu Leu Gly Gly Thr Arg Thr Pro Ile Asn
355 360 365
Asp Ala Ser
3fl 370
<210> 67
<211> 90
<212> PRT
<213> Homo sapiens
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
71/177
<400> 67
Met Phe His Gln Ile Trp Ala Ala Leu Leu Tyr Phe Tyr Gly Ile Ile
1 5 10 15
Leu Asn Ser Ile Tyr Gln Cys Pro Glu His Ser Gln Leu Thr Thr Leu
20 25 30
Gly Val Asp Gly Lys Glu Phe Pro Glu Val His Leu Gly Gln Trp Tyr
35 40 95
Phe Ile Ala Gly Ala Ala Pro Thr Lys Glu Glu Leu Ala Thr Phe Asp
50 55 60
Pro Val Asp Asn Ile Val Phe Asn Met Ala Ala Gly Ser Ala Pro Met
65 70 75 BO
Gln Leu His Leu Arg Ala Thr Ile Arg Met
85 90
<210>68
<211>499
<212>PRT
<213>Homo sapiens
<400> 68
Met Val Asp Arg Gly Pro Leu Leu Thr Ser Ala Ile Ile Phe Tyr Leu
i 5 10 15
Ala Ile Gly Ala Ala Ile Phe Glu Val Leu Glu Glu Pro His Trp Lys
20 25 30
Glu Ala Lys Lys Asn Tyr Tyr Thr Gln Lys Leu His Leu Leu Lys Glu
40 45
Phe Pro Cys Leu Gly Gln Glu Gly Leu Asp Lys Ile Leu Glu Val Val
50 55 60
30 Ser Asp Ale Ala Gly Gln Gly Val Ala Ile Thr Gly Asn Gln Thr Phe
65 70 75 80
Asn Asn Trp Asn Trp Pro Asn Ala Met Ile Phe Ala Ala Thr Val Ile
85 90 95
Thr Thr Ile Gly Tyr Gly Asn Val Ala Pro Lys Thr Pro Ala Gly Arg
35 loo 105 110
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
72/177
Leu Phe Cys Val Phe Tyr Gly Leu Phe Gly Val Pro Leu Cys Leu Thr
115 120 125
Trp Ile Ser Ala Leu Gly Lys Phe Phe Gly Gly Arg Ala Lys Arg Leu
130 135 140
Gly Gln Phe Leu Thr Lys Arg Gly Val Ser Leu Arg Lya Ala Gln Ile
145 150 155 160
Thr Cys Thr Val Ile Phe Ile Val Trp Gly Val Leu Val His Leu Val
165 170 175
Ile Pro Pro Phe Val Phe Met Val Thr Glu Gly Trp Asn Tyr Ile Glu
180 185 190
Gly Leu Tyr Tyr Ser Phe Ile Thr Ile Ser Thr Ile Gly Phe Gly Asp
195 200 205
Phe Val Ala Gly Val Asn Pro Ser Ala Asn Tyr His Ala Leu Tyr Arg
210 215 220
Tyr Phe Val Glu Leu Trp Ile Tyr Leu Gly Leu Ala Trp Leu Ser Leu
225 230 235 240
Phe Val Asn Trp Lys Val Ser Met Phe Val Glu Val His Lys Ala Ile
245 250 255
Lys Lys Arg Arg Arg Arg Arg Lys Glu Ser Phe Glu Ser Ser Pro His
260 265 270
Ser Arg Lys Ala Leu Gln Val Lys Gly Ser Thr Ala Ser Lys Asp Val
275 280 285
Asn Ile Phe Ser Phe Leu Ser Lys Lys Glu Glu Thr Tyr Asn Asp Leu
290 295 300
Ile Lys Gln Ile Gly Lys Lys Ala Met Lys Thr Ser Gly Gly Gly Glu
305 310 315 320
Thr Gly Pro Gly Pro Gly Leu Gly Pro Gln Gly Gly Gly Leu Pro Ala
325 330 335
Leu Pro Pro Ser Leu Val Pro Leu Val Val Tyr Ser Lys Asn Arg Val
340 345 350
Pro Thr Leu Glu Glu Val Ser Gln Thr Leu Arg Ser Lys Gly His Val
355 360 365
Ser Arg Ser Pro Asp Glu Glu Ala Val Ala Arg Ala Pro Glu Asp Ser
370 375 380
Ser Pro Ala Pro Glu Val Phe Met Asn Gln Leu Asp Arg Ile Ser Glu
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
73/177
385 390 395 400
Glu Cys Glu Pro Trp Asp Ala Gln Asp Tyr His Pro Leu Ile Phe Gln
405 410 415
Asp Ala Ser Ile Thr Phe Val Asn Thr Glu Ala Gly Leu Ser Asp Glu
420 425 430
Glu Thr Ser Lys Ser Ser Leu Glu Asp Asn Leu Ala Gly Glu Glu Ser
435 440 445
Pro Gln Gln Gly Ala Glu Ala Lys Ala Pro Leu Asn Met Gly Glu Phe
450 455 460
Pro Ser Ser Ser Glu Ser Thr Phe Thr Ser Thr Glu Ser Glu Leu Ser
465 470 475 480
Val Pro Tyr Glu Gln Leu Met Asn Glu Tyr Asn Lys Ale Asn Ser Pro
485 490 495
Lys Gly Thr
<210> 69
<211> 106
<212> PRT
<213> Homo sapiens
<400> 69
Met Ala Ser Ser Gly Ala Gly Asp Pro Leu Asp Ser Lys Arg Gly Glu
1 5 10 15
Ala pro Phe Ala Gln Arg Ile Asp Pro Thr Arg Glu Lys Leu Thr Pro
20 25 30
Glu Gln Leu His Ser Met Arg Gln Ala Glu Leu Als Gln Trp Gln Lys
40 45
Val Leu Pro Arg Arg Arg Thr Arg Asn Ile Val Thr Gly Leu Gly Ile
30 50 55 60
Gly Ala Leu Val Leu Ala Ile Tyr Gly Tyr Thr Phe Tyr Ser Ile Ser
65 70 75 80
Gln Glu Arg Phe Leu Asp Glu Leu Glu Asp Glu Ala Lys Ala Ala Arg
85 90 95
35 Ala Arg Ala Leu Ala Arg Ala Ser Gly Ser
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
74/177
100 105
<210> 70
<211> 152
<212> PRT
<213> Homo sapiens
<400> 70
Met Asp Tyr Val Cys Cys Ala Tyr Asn Asn Ile Thr Gly Arg Gln Asp
1 5 10 15
Glu Thr His Phe Thr Val Ile Ile Thr Ser Val Gly Leu Glu Lys Leu
25 30
Ala Gln Lys Gly Lys Ser Leu Ser Pro Leu Ala Ser Ile Thr Gly Ile
35 40 45
15 Ser Leu Phe Leu Ile Ile Ser Met Cys Leu Leu Phe Leu Tip Lys Lys
50 55 60
Tyr Gln Pro Tyr Lys Val Ile Lys Gln Lys Leu Glu Gly Arg Pro Glu
65 70 75 80
Thr Glu Tyr Arg Lys Ala Gln Thr Phe Ser Gly His Glu Asp Ala Leu
20 85 90 95
Asp Asp Phe Gly Ile Tyr Glu Phe Val Ala Phe Pro Asp Val Ser Gly
100 105 110
Val Ser Arg Ile Pro Ser Arg Ser Val Pro Ala Ser Asp Cys Val Ser
115 120 125
Gly Gln Asp Leu His Ser Thr Val Tyr Glu Val Ile Gln His Ile Pro
130 135 140
Als Gln Gln Gln Asp His Pro Glu
145 150
<210> 71
<211> 921
<212> DNA
<213> Homo sapiens
<400> 71
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
75/177
atgtctatga ttttatctgcctcagtcattcgtgtcagagatggactgccactttctgct60
tctactgatt atgaacaaagcacaggaatgcaggagtgcagaaagtattttaaaatgctt120
tcgaggaaac ttgctcaacttcctgatagatgtacactgaaaactggacattataacatt180
aettttatta gctctctgggagtgagctacatgatgttgtgcactgaaaattacccaaat240
gttctcgcct tctctttcctggatgagcttcagaaggagttcattactacttataacatg300
atgaagacaa atactgctgtcagaccatactgtttcattgeatttgataacttcattcag360
aggaccaagc agcgatataataatcccaggtctctttcaacaaegataaatctttctgac420
atgcagacgg aaatcaagctgaggcctccttatcaaatttccatgtgcgaactggggtca480
gccaetggag tcacatcagcattttctgttgactgtaaeggtgctggtaagatttcttct540
gctcaccagc gactggaaccagcaactctgtcagggattgtaggatttatccttagtctt600
ttatgtggag ctctgaatttaattcgaggctttcatgctatagaaagtctcctgcagagt660
gatggtgatg attttaattacatcattgcatttttccttggaacagcagcctgcctttac720
cagtgttatt tacttgtctactacaccggctggcggaatgtcaaatcttttttgactttt780
ggcttaatct gtctatgcaacatgtatctctatgaactgcgcaacctctggcagcttttc840
I5 tttcatgtga ctgtgggagcatttgttacactacagatctggctaaggcaagcccagggc900
aaggctcccg attatgatgt c 921
<210> 72
<211> 549
<212> DNA
<213> Homo Sapiens
<400> 72
atgacggccc aggggggcct ggtggctaac cgaggccggc gcttcaagtg ggccattgag 60
ctaagcgggc ctggaggaggcagcaggggtcgaagtgaccggggcagtggccagggagac120
tcgctctacc cagtcggttacttggacaagcaagtgcctgataccagcgtgcaagagaca180
gaccggatcc tggtggagaagcgctgctgggacatcgccttgggtcccctcaaacagatt240
cccatgaatc tcttcatcatgtacatggcaggcaatactatctccatcttccctactatg300
atggtgtgta tgatggcctggcgacccattcaggcacttatggccatttcagccactttc360
aagatgttag aaagttcaagccagaagtttcttcagggtttggtctatctcattgggaac420
ctgatgggtt tggcattggc tgtttacaag tgccagtcca tgggactgtt acctacacat 480
gcatcggatt ggttagcctt cattgagccc cctgagagaa tggagttcag tggtggagga 540
ctgcttttg 549
<210> 73
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
76/177
<211> 981
<212> DNA
<213> Homo sapi.ens
<400> 73
atgcgcgccc tccccggcctgctggaggccagggcgcgta 60
cgccccggct
gctcctectc
cagtgccttc tcgctgccgcgcgcccaagctcggcggacggcagtgcccc 120
agattcgcct
tttacaagtc cacctctcagagaagaaataatggcaaataacttttccttggagagtcat180
aacatatcac tgactgaacattctagtatgccagtagaaaaaaatatcactttagaaagg240
ccttctaatg taaatctcacatgccagttcacaacatctggggatttgaatgcagtaaat300
gtgacttgga aaaaagatggtgaacaacttgagaataattatcttgtcagtgcaacagga360
agcaccttgt atacccaatacaggttcaccatcattaatagcaaacasatgggaagttat420
tcttgtttct ttcgagaggaasaggaecaaaggggaacatttaatttcaaagtccctgaa480
cttcatggga aaaacaagccattgatctcttacgtaggggattctactgtcttgacatgt540
aastgtcaaa attgttttcctttaaattggacctggtacagtagtaatgggagtgtaaag600
gttcctgttg gtgttcaaatgaataaatatgtgatcaatggaacatatgctaacgeaaca660
aagctgaaga taacacaacttttggaggaagatggggsatcttactggtgccgtgcacta720
ttcceattag gcgagagtgaagaacacattgagcttgtggtgctgagctatttggtgccc780
ctcaaaccat ttcttgtaatagtggctgaggtgattcttttagtggccaccattctgctt840
tgtgaaaagt acacacaaaagaasaagaagcactcagatgaggggaaagaatttgagcag900
attgaacagc tgaaatcaga ggtatagaaaataatgtccccaggcataga960
tgatagcaat
aaaaatgagt 981
ctctgggcca
g
<210> 74
<211> 669
<212> DNA
<213> Homo sapiens
<400> 74
atgaagttcg tcccctgcctcctgctggtgaccttgtcctgcctggggactttgggtcag 60
gccccgaggc aaaagcaaggaagcactggggaggaattccatttccagactggagggaga 120
gattcctgca ctatgcgtcccagcagcttggggcaaggtgctggagaegtctggcttcgc 180
gtcgactgcc gcaacacagaccagacctactggtgtgagtacagggggcagcccagcatg 240
tgccaggctt tcgctgctgaccccasatcttactggaatcaagccctgcaggagctgagg 300
cgccttcacc atgcgtgccagggggccccggtgcttaggccatccgtgtgcagggaggct 360
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
77/177
ggaccccagg cccatatgcagcaggtgacttccagcctcaagggcagcccagagcccaac420
cagcagcctg aggctgggacgccatctctgaggcccaaggccacagtgaeactcacagaa480
gcaacacagc tgggaaaggactcgatggaagagctgggaaaagccaaacccaccacccga540
cccacagcca aacctacccagcctggacccaggcccggagggaatgaggaagceaagaag600
aaggcctggg aacattgttggaaacccttccaggccctgtgcgcctttctcatcagcttc660
ttccgaggg 669
<210> 75
<211> 144
<212> DNA
<213> Homo sapiens
<400> 75
atgaggcttc tgctgcttct cctagtggcg gcgtctgcga tggtccggag cgaggcctcg 60
gccaatctgg gcggcgtgcc cagcaagaga ttsaagatgc agtacgccac ggggccgctg 120
ctcaagttcc agatttgtgt ttcc 144
<210> 76
<211> 1113
<212> DNA
<213> Homo sapiens
<400> 76
atggcctgga ccaagtacca gctgttcctg gccgggctca tgcttgttac cggctccatc 60
aacacgctct cggcaaaatgggcggacaatttcatggccgagggctgtggagggagcaag120
gagcacagct tccagcatcccttcctccaggcagtgggcatgttcctgggagaattctcc180
tgcctggctg ccttctacctcctccgatgcagagctgcagggcaatcagactccagcgta240
gacccccagc agcccttcaaccctcttcttttcctgcccccagcgctctgtgacatgaca300
gggaccagcc tcatgtatgtggctctgaacatgaccagtgcctccagcttccagatgctg360
cggggtgcag tgatcatattcactggcctgttctcggtggccttcctgggccggaggctg420
,
gtgctgagcc agtggctgggcatcctagccaccatcgcggggctggtggtcgtgggcctg480
gctgacctcc tgagcaagcacgacagtcagcacaagctcagcgaagtgatcacaggggac540
ctgttgatca tcatggcccagatcatcgttgccatccagatggtgctagaggagaagttc600
gtctacaaec acaatgtgcacccactgcgggcagttggcactgagggcctctttggcttt660
gtgatcctct ccctgctgctggtgcccatgtactacatccccgccggctccttcagcgga720
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
78/x77
aaccctcgtg ggacactggaggatgcattggacgccttctgccaggtgggccagcagccg780
ctcattgccg tggcactgctgggcaacatcagcagcattgccttcttcaacttcgcaggc840
atcagcgtca ccaaggaactgagcgccaccacccgcatggtgttggacagcttgcgeacc900
gttgtcatct gggcactgagcctggcactgggctgggaggccttccatgcactgcagatc960
cttggcttcc tcatactccttataggcactgccctctacaatgggctacaccgtccgctg1020
ctgggccgcc tgtccaggggccggcccctggcagaggagsgcgagcaggagagactgctg1080
ggtggcaccc gcactcccatcaatgatgccagc 1113
<210> 77
<211> 270
<212> DNA
<213> Homo sapiens
<400> 77
atgttccaccsaatttgggcagctctgctctacttctatggtattatccttaactccatc60
taccagtgcc ctgagcacagtcaactgacaactctgggcgtggatgggaaggagttccca120
gaggtccact tgggccagtggtactttatcgcaggggcagctcccaccaaggaggagttg180
gcaacttttg accctgtggacaacattgtcttcaatatggctgctggctctgccccgatg240
cagctccacc ttcgtgctaccatccgcatg 270
<210>78
<211>1497
<212>DNA
<213>Homo sapiens
<400> 78
atggtggacc ggggccctctgctcacctcggccatcatcttctacctggccatcggggcg60
gcgatcttcg aagtgctggaggagccacactggaaggaggccaagaaaaactactacaca120
cagaagctgc atctgctcaaggagttcccgtgcctgggtcaggagggcctggacaagatc180
ctagaggtggtatctgatgctgcaggacagggtgtggccatcacagggaaccagaccttc240
aacaactgga actggcccaatgcaatgatttttgcagcgaccgtcattaccaccattgga300
tatggcaatg tggctcccaagacccccgccggtcgcctcttctgtgttttctatggtctc360
ttcggggtgc cgctctgcctgacgtggatcagtgccctgggcaagttcttcgggggacgt420
gceaagagac tagggcagttccttaccaagagaggtgtgagtctgcggaaggcgcagatc480
acgtgcacagtcatcttcatcgtgtggggcgtcctagtccacctggtgatcccacccttc540
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/0392~
79/177
gtattcatgg tgactgaggg gtggaactac atcgagggcc tctactactc cttcatcacc 600
atctccacca tcggcttcgg tgactttgtg gccggtgtga accccagcgc caactaccac 660
gccctgtacc gctacttcgt ggagctctgg atctacttgg ggctggcctg gctgtccctt 720
tttgtcaact ggaaggtgag catgtttgtg gaagtccaca aagccattaa gaagcggegg 780
cggcgacgga aggagtcctt tgagagctcc ccacactccc ggaaggccct gcaggtgaag 840
gggagcacag cctccaagga cgtcaacatc ttcagctttc tttccaagaa ggaagagacc 900
tacaaegacc tcatcaagca gatcgggaag aaggccatga agacaagcgg gggtggggag 960
acgggcccgg gcccagggct ggggcctcaa ggcggtgggc tcccagcact gcccccttcc 1020
ctggtgcccc tggtagtcta ctccaagaac cgggtgccca ccttggaaga ggtgtcacag 1080
acactgagga gcaaaggccs cgtatcaagg tccccagatg aggaggctgt ggcacgggcc 1140
cctgaagaca gctcccctgc ccccgaggtg ttcstgaacc agctggaccg catcagcgag 1200
gaatgcgagc catgggacgc ccaggactac cacccactca tcttccaggs cgccagcatc 1260
accttcgtga acacggaggc tggcctctca gacgaggaga cctccaagtc ctcgctagag 1320
gacaacttgg caggggagga gagcccccag cagggggctg aagccaaggc gcccctgaac 1380
atgggcgagt tcccctcctc ctccgagtcc accttcacca gcactgagtc tgagctctct 1440
gtgccttacg aacagctgat gaatgagtac aacaaggcta acagccccaa gggcaca 1497
<210> 79
<211> 318
<212> DNA
<213> Homo sapiens
<400> 79
atggcgtctt cgggagctgg tgaccctctg gattctaagc gtggagaggc cccgttcgct 60
cagcgtatcg acccgactcgggagaagctgacacccgagcaactgcattccatgcggcag120
gcggagcttg cccagtggcagaaggtcctsccacggcggcgaacccggaacatcgtgacc180
ggcctaggca tcggggccctggtgttggctatttatggttacaccttctactcgatttcc240
caggagcgtt tcctagatgagctagaagacgaggccaaagctgcccgagcccgagctctg300
gcaagggcgt cagggtcc 318
<210> 80
<211> 456
<212> DNA
<213> Homo Sapiens
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
80/177
<400> 80
atggactatg tgtgctgtgcttacaacaacataaccggcaggcaagatgaaactcatttc60
acagttatca tcacttccgtaggactggagaagcttgcacagaaaggaaaatcattgtca120
cctttagcaa gtataactggaatatcactatttttgattatatccatgtgtcttctcttc180
ctatggaaaa aatatcaaccctacaeagttataaaacagaaactagaaggcaggccagaa240
acagaataca ggaaagctcaaacattttcaggccatgaagatgctctggatgacttcgga300
atatatgaat ttgttgcttttccagatgtttctggtgtttccaggatcccaegcaggtct360
gttccagcct ctgattgtgtatcggggcaagatttgcacagtacagtgtatgaagttatt420
cagcacatcc ctgcccagcagcaagaccatccagag 456
<210> 81
<211> 1436
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (66)...(989)
<400> 81
gcacttcggg gcgcgtcact cggagcggcg ggtcccgtct cgacaggtct tctctgttgg 60
ttgaa atg tct atg att tta tct gcc tca gtc att cgt gtc aga gat 107
Met Ser Met Ile Leu Set Ala Ser Val Ile Arg Val Arg Asp
1 5 ~ 10
gga ctg cca ctt tet get tct act gat tat gas caa agc aca gga atg 155
Gly Leu Pro Leu Ser Ala Ser Thr Asp Tyr Glu Gln Ser Thr Gly Met
15 20 25 30
cag gag tgc aga aag tat ttt aaa atg ctt tcg agg aaa ctt get caa 203
Gln Glu Cys Arg Lys Tyr Phe Lys Met Leu Ser Arg Lys Leu Ala Gln
40 dS
30 ctt cct gat aga tgt aca ctg aaa act gga cat tat aac att aat ttt 251
Leu Pro Asp Arg Cys Thr Leu Lys Thr Gly His Tyr Asn Ile Asn Phe
50 55 ~n
att agc tct ctg gga gtg agc tac atg atg ttg tgc act gaa aat tac 299
Ile Ser Ser Leu Gly Val Ser Tyr Met Met Leu Cys Thr Glu Asn Tyr
35 65 70 75
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
81/177
cca aat gtt ctc gcc ttc tct ttc ctg gat gag ctt cag aag gag ttc 347
Pro Asn Val Leu Ala Phe Ser Phe Leu Asp Glu Leu Gln Lys Glu Phe
80 85 90
att act act tat aac atg atg.aag aca aat act get gtc aga cca tac 395
Ile Thr Thr Tyr Asn Met Met Lys Thr Asn Thr Ala Val Arg Pro Tyr
95 100 105 110
tgt ttc att gaa ttt gat aac ttc att cag agg acc aag cag cga tat 443
Cys Phe Ile Glu Phe Asp Asn Phe Ile Gln Arg Thr Lys Gln Arg Tyr
115 I20 125
~10 aat aatcccagg tctctttcaacaaagata aatctttctgac atgcag 491
Asn AsnProArg SerLeuSerThrLysIle AsnLeuSerAsp MetGln
130 135 140
acg gaaatcaag ctgaggcctccttatcaa atttccatgtgc gaactg 539
Thr GluIleLys LeuArgProProTyrGln IleSerMetCys GluLeu
145 150 155
ggg tcagccaat ggagtcacatcagcattt tctgttgactgt aaaggt 587
Gly SerAlaAsn GlyValThrSerAlaPhe SerValAspCys LysGly
160 165 170
get ggtaagatt tcttctgetcaccagcga ctggaaccagca actctg 635
Ala GlyLysIle SerSerAlaHisGlnArg LeuGluProAla ThrLeu
175 180 185 190
tca gggattgta ggatttatcettagtctt ttatgtggaget ctgaat 683
Ser GlyIleVal GlyPheIleLeuSerLeu LeuCysGlyAla LeuAsn
I95 200 205
tta attcgaggc tttcatgetatagaaagt ctcctgcagagt gatggt 731
Leu IleArgGly PheHisAlaIleGluSer LeuLeuGlnSer AspGly
210 215 220
gat gattttaat tacatcattgcatttttc cttggaacagca gcctgc 779
Asp AspPheAsn TyrIleIleAlaPhePhe LeuGlyThrAla AlaCys
225 230 235
ctt tac cag tgt tat tta ctt gtc tac tac acc ggc tgg cgg aat gtc 827
Leu Tyr Gln Cys Tyr Leu Leu Val Tyr Tyr Thr Gly Trp Arg Asn Val
240 245 250
aaa tct ttt ttg act ttt ggc tta atc tgt cta tgc aac atg tat ctc 875
Lys Ser Phe Leu Thr Phe Gly Leu Ile Cys Leu Cys Asn Met Tyr Leu
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
82/177
255 260 265 270
tat gas ctg cgc aac ctc tgg cag ctt ttc ttt cat gtg act gtg gga 923
Tyr Glu Leu Arg Asn Leu Trp Gln Leu Phe Phe His Val Thr Val Gly
275 280 285
gca ttt gtt aca cta cag atc tgg cta agg caa gcc cag ggc aeg get 971
Ala Phe Val Thr Leu Gln Ile Trp Leu Arg Gln Ala Gln Gly Lys Ala
290 295 300
ccc gat tat gat gtc tgacaccatc cttcagatct attgccttgg cttc 1020
Pro Asp Tyr Asp Val
305
agggggataa ggagggaacatatcatasctgcactgtgatgaagaagctgttccccacag1080
aggagaagct ctgctttctttctctccaactttccttttttaaaatcagcatgatgtgcc1140
tgtgagcatg gsagagtcctctcagaagaatgttggccatgagactatcattcagaggag1200
gaggggattt ctctcttcaaggccataacagtggaagaacagtcatatgccattggaagt1260
cttggccagc agtcctgaatccttcctgaagagttcagaaaatagatgtggtattgctct1320
gaggaccagg caggaggaactctacaacctgagtttgcctttgtgaggcattagtataga1380
ccaaatasaa agctgcagaaattggaaagtttatgttttaastaaatgactgtgat 1936
<210> 82
<211> 997
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (87)...(638)
<400> 82
gagacaeagc ggagaacgct ggtgggcctg ttgtggagta cgctttggac tgagaagcat 60
cgaggctata ggacgcagct gttgcc atg acg gcc cag ggg ggc ctg gtg 110
Met Thr Ala Gln Gly Gly Leu Val
1 5
get sac cga ggc cgg cgc ttc asg tgg gcc att gag cta agc ggg cct 158
Ala Asn Arg Gly Arg Arg Phe Lys Trp Ala Ile Glu Leu Ser Gly Pro
10 15 20
gga gga ggc agc agg ggt cga agt gac cgg ggc agt ggc cag gga gac 206
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
83/177
Gly Gly Gly Ser Arg Gly Arg Ser Asp Arg Gly Ser Gly Gln Gly Asp
25 30 35 40
tcg ctc tac cca gtc ggt tac ttg gac aag caa gtg cct gat acc agc 254
Ser Leu Tyr Pro Val Gly Tyr Leu Asp Lys Gln Val Pro Asp Thr Ser
45 50 55
gtg caa gag aca gac cgg atc ctg gtg gag aag cgc tgc tgg gac atc 302
Val Gln Glu Thr Asp Arg Ile Leu Val Glu Lys Arg Cys Trp Asp Ile
60 65 70
gcc ttg ggt ccc ctc aaa cag att ccc atg aat ctc ttc atc atg tac 350
Ala Leu Gly Pro Leu Lys Gln Ile Pro Met Asn Leu Phe Ile Met Tyr
75 80 85
atg gca ggc aat act atc tcc atc ttc cct act atg atg gtg tgt atg 398
Met Ala Gly Asn Thr Ile Ser Ile Phe Pro Thr Met Met Val Cys Met
90 95 I00
atg gcc tgg cga ccc att cag ctt atg att tca gcc act 446
gca gcc ttc
Met Ala Trp Arg Pro Ile Gln Leu Met Ile Ser Ala Thr
Ala Ala Phe
105 110 115 120
aag atg tta gas agt tca agc aag ttt cag ggt ttg gtc 494
cag ctt tat
Lys Met Leu Glu Ser Ser Ser Lys Phe Gln Gly Leu Val
Gln Leu Tyr
125 130 135
ctc att ggg aac ctg atg ggt gca ttg gtt tac aag tgc 542
ttg get cag
Leu Ile Gly Asn Leu Met Gly Ala Leu Val Tyr Lys Cys
Leu Ala Gln
140 145 150
tcc atg gga ctg tta cct aca gca tcg tgg tta gcc ttc 590
cat gat att
Ser Met Gly Leu Leu Pro Thr Ala Ser Trp Leu Ala Phe
His Asp Ile
155 160 165
gag ccc cct gag aga atg gag agt ggt gga ctg ctt ttg 640
ttc gga tgaac
Glu Pro Pro Glu Arg Met Glu Ser Gly Gly Leu Leu Leu
Phe Gly
170 175 180
atgagaaagc agcgcctggt ccctatgtatttgggtcttatttacatcct tctttaagcc700
cagtggctcc tcagcatact cttasactaatcacttatgttaaaaagasc caaaagactc760
ttttctccat ggtggggtga caggtcctagaaggacaatgtgcatattac gacaaacaca820
aagaaactat accataaccc aaggctgaaaataatgtagaaaactttatt tttgtttcca880
gtacagagca aaacsacaec aaaaaaacataactatgtaaacaagagaat aactgctgct940
saatcaagaa ctgttgcagc atctcctttcaataaattaaatggttgaga acaatgc997
ccaaatas
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
84/177
<210> 83
<211> 1753
<212> DNA
<213> Homo Sapiens
<220>
<221> CDS
<222> {134)...(1117)
<400> 83
tcttcagcgt cctacccgcg gcactggctg cgagcgccgg gccacctgcg agtgtgcgca 60
gggactctgg acacccgcgg cggcgagctg agggagcagt ctccacgagg acccaggcgg 120
accctctggc gcc atg cgc gcc ctc ccc ggc ctg ctg gag gcc agg gcg 169
Met Arg Ala Leu Pro Gly Leu Leu Glu Ala Arg Ala
1 5 10
cgt acg ccc cgg ctg ctc ctc ctc cag tgc ctt ctc get gcc gcg cgc 217
Arg Thr Pro Arg Leu Leu Leu Leu Gln Cys Leu Leu Ala Ala Ale Arg
15 20 25
cca agc tcg gcg gac ggc agt gcc cca gat tcg cct ttt aca agt cca 265
Pro Ser Ser Ala Asp Gly Ser Ala Pro Asp Ser Pro Phe Thr Ser Pro
35 40
cct ctc aga gaa gaa ata atg gca aat eac ttt tcc ttg gag agt cat 313
Pro Leu Arg Glu Glu Ile Met Ala Asn Asn Phe Ser Leu Glu Ser His
45 50 55 60
eac ata tca ctg act gaa cat tct agt atg cca gta gaa aaa aat atc 361
Asn Ile Ser Leu Thr Glu His Ser Ser Met Pro Val Glu Lys Asn Ile
65 70 75
act tta gaa agg cct tct aat gta aat ctc aca tgc cag ttc aca aca 409
Thr Leu Glu Arg Pro Ser Asn Val Asn Leu Thr Cys Gln Phe Thr Thr
80 85 90
tct ggg gat ttg aat gca gta sat gtg act tgg aaa aaa gat ggt gaa 457
Ser Gly Asp Leu Asn Ala Val Asn Val Thr Trp Lys Lys Asp Gly Glu
95 100 105
caa ctt gag aat aat tat ctt gtc agt gca aca gga agc acc ttg tat 505
Gln Leu Glu Asn Asn Tyr Leu Val Ser Ala Thr Gly Ser Thr Leu Tyr
CA 02336225 2001-O1-24
WO 00/05367 PCT/,1P99/0392~
85/177
110 115 I20
acc caa tac agg ttc acc atc att sat agc aaa caa atg gga agt tat 553
Thr Gln Tyr Arg Phe Thr Ile Ile Asn Ser Lys Gln Met Gly Ser Tyr
125 130 135 140
tct tgt ttc ttt cga gag gaa aag gaa caa agg gga aca ttt aat ttc 601
Ser Cys Phe Phe Arg Glu Glu Lys Glu Gln Arg Gly Thr Phe Asn Phe
145 150 155
aaa gtc cct gaa ctt cat ggg aea aac aag cca ttg atc tct tac gta 649
Lys Val Pro Glu Leu His Gly Lys Asn Lys Pro Leu Ile Ser Tyr Val
160 165 170
ggg gat tct act gtc ttg aca tgt saa tgt caa aat tgt ttt cct tta 697
Gly Asp Ser Thr Val Leu Thr Cys Lys Cys Gln Asn Cys Phe Pro Leu
175 180 185
aat tgg acc tgg tac agt agt aat ggg agt gta aag gtt cct gtt ggt 745
Asn Trp Thr Trp Tyr Ser Ser Asn Gly Ser Val Lys Val Pro Val Gly
190 195 200
gtt caa atg aat aaa tat gtg atc aat gga aca tat get aac gaa aca 793
Val Gln Met Asn Lys Tyr Val Ile Asn Gly Thr Tyr Ala Asn Glu Thr
205 210 215 220
eag ctg aag ata aca caa ctt ttg gag gaa gat ggg gaa tct tac tgg 841
Lys Leu Lys Ile Thr Gln Leu Leu Glu Glu Asp Gly Glu Ser Tyr Trp
225 230 235
tgc cgt gca cta ttc caa tta ggc gag agt gaa gaa cac att gag ctt 889
Cys Arg Ala Leu Phe Gln Leu Gly Glu Ser Glu Glu His Ile Glu Leu
240 245 250
gtg gtg ctg agc tat ttg gtg ccc ctc aaa cca ttt ctt gta ata gtg 937
Val Val Leu Ser Tyr Leu Val Pro Leu Lys Pro Phe Leu Val Ile Val
255 260 265
get gag gtg att ctt tta gtg gcc acc att ctg ctt tgt gaa aag tac 985
Ala Glu Val Ile Leu Leu Val Als Thr Ile Leu Leu Cys Glu Lys Tyr
270 275 286
acs caa sag aaa asg aag cac tca gat gag ggg aaa gaa ttt gag cag 1033
Thr Gln Lys Lys Lys Lys His Ser Asp Glu Gly Lys Glu Phe Glu Glri
285 290 295 300
att gaa cag ctg aaa tca gat gat agc eat ggt ata gaa aat aat gtc 1081
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
86/177
Ile Glu Gln Leu Lys Ser Asp Asp Ser Asn Gly Ile Glu Asn Asn Val
305 310 315
ccc agg cat aga aaa aat gag tct ctg ggc cag tgaatacaaa acatca 1130
Pro Arg His Arg Lys Asn Glu Ser Leu Gly Gln
320 325
tgtcgagaat cattggaaga tatacagagt tcgtatttca gctttattta tccttcctgt 1190
taagagcctc tgagttttta gttttaaaag gatgaaaagc ttatgcaaca tgctcagcag 1250
gagcttcatc aacgatatat gtcagatcta aaggtatatt ttcattctgt aattatgtta 1310
cataasagca atgtaaatca gaataaatat gttagaccag aataaaatta attatattct 1370
ggtcttcaaa ggacacacag aacagatatc agcagaatca cttaatactt catagaacaa 1430
aaatcactca aaacctgttt ataaccaaag aattcatgaa aaagaaagcc tttgccattt 1490
gtcttagaaa gttatttttt taaaasaaat catacttact attagtatct atggaagtat 1550
atgtaacaat ttttatgtaa aggtcatctt tctgtgatag tgaasaaata tgtctttact 1610
aagttgaaat gaatactttc tgcctttgct catgatagtt attctacaat ctccacaaga 1670
aaaatatacc ttttatccgg saatattggt ttaaggcaaa taaataaaac tgtgcttgct 1730
cteaagctct gcactacaae agc 1753
<210> 84
<211> 1117
<212> DrrA
<213> Homo sapiens
<220>
<221> CDS
<222> (62)...(733)
<400> 84
cgtcccactt gtgttctctc tcctggtgca gagttgcaag caagtttatc ggagtatcgc 60
c atg aag ttc gtc ccc tgc ctc ctg ctg gtg acc ttg tcc tgc ctg 106
Met Lys Phe Val Pro Cys Leu Leu Leu Val Thr Leu Ser Cys Leu
1 5 10 15
ggg act ttg ggt cag gcc ccg agg caa aag caa gga agc act ggg gag 154
Gly Thr Leu Gly Gln Ala Pro Arg Gln Lys Gln Gly Ser Thr Gly Glu
20 25 30
gaa ttc cat ttc cag act gga ggg aga gat tcc tgc act atg cgt ccc 202
Glu Phe His Phe Gln Thr Gly Gly Arg Asp Ser Cys Thr Met Arg pro
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
87/177
35 40 45
agc agc ttg ggg caa ggt get gga gea gtc tgg ctt cgc gtc gac tgc 250
Ser Ser Leu Gly Gln Gly Ala Gly Glu Val Trp Leu Arg Val Asp Cys
50 55 60
cgc aac aca gac cag acc tac tgg tgt gag tac agg ggg cag ccc agc 298
Arg Asn Thr Asp Gln Thr Tyr Trp Cys Glu Tyr Arg Gly Gln Pro Ser
65 70 75
atg tgc cag get ttc get get gac ccc aaa tct tac tgg aat caa gcc 346
Met Cys Gln Als Phe Ala Ala Asp Pro Lys Ser Tyr Trp Asn Gln Ala
80 B5 90 g5
ctg cag gag ctg agg cgc ctt cac cat gcg tgc cag ggg gcc ccg gtg 394
Leu Gln Glu Leu Arg Arg Leu His His Ala Cys Gln Gly Ala Pro Val
100 105 110
ctt agg cca tcc gtg tgc agg gag get gga ccc cag gcc cat atg cag 442
Leu Arg Pro Ser Val Cys Arg Glu Ala Gly Pro Gln Ala His Met Gln
115 120 125
cag gtg act tcc agc ctc aag ggc agc cca gag ccc aac cag cag cct 490
Gln Val Thr Ser Sex Leu Lys Gly Ser Pro Glu Pro Asn Gln Gln Pro
130 135 140
gag get ggg acg cca tct ctg agg cec aag gcc aca gtg aaa ctc aca 538
Glu Ala Gly Thr Pro Ser Leu Arg Pro Lys Ala Thr Val Lys Leu Thr
145 150 255
gaa gca aca cag ctg gga aag gac tcg atg gaa gag ctg gga saa gcc 586
Glu Ala Thr Gln Leu Gly Lys Asp Ser Met Glu Glu Leu Gly Lys Ala
160 165 170 175
aaa ccc acc acc cga ccc aca gcc aaa cct acc cag cct gga ccc agg 634
Lys Pro Thr Thr Arg Pro Thr Ala Lys Pro Thr Gln Pro Gly Pro Arg
180 185 190
ccc gga ggg aat gag gaa gca aag aag aag gcc tgg gaa cat tgt tgg 682
Pro GIy Gly Asn Glu Glu AIa Lys Lys Lys Ala Trp Glu His Cys Trp
195 200 205
aaa ccc ttc cag gcc ctg tgc gcc ttt ctc atc agc ttc ttc cga ggg 730
Lys Pro Phe Gln Ala Leu Cys Ala Phe Leu Ile Ser Phe Phe Arg Gly
210 215 220
tgacaggtga aagaccccta cagatctgac ctctccctga cagacaacca tctcttttta 790
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
88/177
tattatgccg ctttcaatccaacgttctcacactggaagaagagagtttctaatcagatg850
caacggccca aattcttgatctgcagcttctctgaagtttggaaaagaaaccttcctttc910
tggagtttgc agagttcagcastatgatagggaacaggtgctgatgggcccaagagtgac970
aagcatacac aactacttattatctgtagaagttttgctttgttgatctgagccttctat1030
gaaagtttaa atatgteacgcattcatgaatttccagtgttcagtaaetagcagctatgt1090
gtgtgcaaaa taaaagaatgatttcag 1117
<210> 85
<211> 1380
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (43)...(189)
<400> 85
gcagtctgtc tgagggcggc cgaagtggct ggctcattta ag atg agg ctt ctg 54
Met Arg Leu Leu
1
ctg ctt ctc cta gtg gcg gcg tct gcg atg gtc cgg agc gag gcc tcg 102
Leu Leu Leu Leu Val Ala Ala Ser Ala Met Val Arg Ser Glu Ala Ser
5 10 15 20
gcc aat ctg ggc ggc gtg ccc agc aag aga tta aag atg cag tac gcc 150
Ala Asn Leu Gly Gly Val Pro Ser Lys Arg Leu Lys Met Gln Tyr Ala
25 30 35
acg ggg ccg ctg ctc aag ttc cag att tgt gtt tcc tgag 190
Thr Gly Pro Leu Leu Lys Phe Gln Ile Cys Val Ser
40 45
gttataggcg ggtgtttgag gagtacatgc gggttattag ccagcggtac ccagacatcc 250
gcattgaagg agagaattacctccctcaaccaatatatagacacatagcatctttcctgt 310
cagtcttcaa actagtattaataggcttaataattgttggcaaggatccttttgctttct 370
ttggcatgca agctcctagcatctggcagtggggccaagaaaataaggtttatgcatgta 430
tgatggtttt cttcttgagcaacatgattgagaaccagtgtatgtcaacaggtgcatttg 490
agataacttt aaatgatgtacctgtgtggtctaagctggaatctggtcaccttccatcca 550
tgcaacaact tgttcaaattcttgacaatgaaatgaagctcaatgtgcatatggattcaa 610
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
89/177
tcccacacca tcgatcatag caccacctat cagcactgaa aactcttttg cattaaggga 670
tcattgcaag agcagcgtga ctgacattat gaaggcctgt actgaagaca gceagctgtt 730
agtacagacc agatgctttc ttggcaggct cgttgtacct cttggaaaac ctcaatgeaa 790
gatagtgttt cagtgctggc atattttgga attctgcaca ttcatggagt gcaataatac 850
tgtatagctt tccccacctc ccacaaeatc acccagttaa tgtgtgtgtg tgtttttttt 910
tttaaggtea acattactac ttgtaacttt ttttcttagt catatttgaa eaagtagaaa 970
attgagttac satttgattt tttttccaaa gatgtctgtt aaatctgttg tgcttttata 1030
tgaatatttg ttttttatag tttaaaattg atcctttggg aatccagttg aagttcccaa 1090
atactttata agagtttatc agacatctct aatttggcca tgtccagttt atacagttta 1150
caaaatatag cagatgcaag attatggggg asatcctata ttcagagtac tctataaatt 1210
tttgtgtatg tgtgtatgtg cgtgtgatta ccagagaact actaaaaaaa ccaactgctt 1270
tttaaatcct attgtgtagt taaagtgtca tgccttgacc aatctaatga attgattaat 1330
tsactgggcc tttatactta actaaatasa aaactaagca gatatgagtt 1380
<210> e6
<211> 1503
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (51)...(1166)
<400> 86
gtgacggggc ccggcgccgc taactggagc gaaccccagc gtccgccgac atg gcc 56
Met Ala
1
tgg acc aag tac cag ctg ttc ctg gcc ggg ctc atg ctt gtt acc ggc 104
Trp Thr Lys Tyr Gln Leu Phe Leu Ala Gly Leu Met Leu Val Thr Gly
5 in is
tcc atc aac acg ctc tcg gca aaa tgg gcg gac aat ttc atg gcc gag 152
Ser Ile Asn Thr Leu Ser Ala Lys Trp Ala Asp Asn Phe Met Ala Glu
20 25 30
ggc tgt gga ggg agc aag gag cac agc ttc cag cat ccc ttc ctc cag 200
Gly Cys Gly Gly Ser Lys Glu His Ser Phe Gln His Pro Phe Leu Gln
35 40 45 50
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
90/177
gca gtg ggc atg ttc ctg gga gaa ttc tcc tgc ctg get gcc ttc tac 248
Ala Val Gly Met Phe Leu Gly Glu Phe Ser Cys Leu Ala Ala Phe Tyr
55 60 65
ctc ctc cga tgc aga get gca ggg caa tca gac tcc agc gta gac ccc 296
Leu Leu Arg Cys Arg Ala Ala Gly Gln Ser Asp Ser Ser Val Asp Pro
70 75 80
cag cagcccttc aaccctcttctt ttcctgcccccagcgctc tgt gac 344
Gln GlnProPhe AsnProLeuLeu PheLeuProProAlaLeu Cys Asp
85 90 95
atg acagggacc agcctcatgtat gtggetctgcacatgacc agt gcc 392
Met ThrGlyThr SerLeuMetTyr ValAlaLeuAsnMetThr Ser Ala
100 105 110
tcc agcttccag atgctgcggggt gcagtgatcatattcact ggc ctg 440
Ser SerPheGln MetLeuArgGly AlaValIleIlePheThr Gly Leu
115 120 125. 130
ttc tcggtggcc ttcctgggccgg aggctggtgctgagccag tgg ctg 488
Phe SerValAla PheLeuGlyArg ArgLeuValLeuSerGln Trp Leu
135 140 145
ggc atc cta gcc acc atc gcg ggg ctg gtg gtc gtg ggc ctg get gac 536
Gly Ile Leu Ala Thr Ile Ala Gly Leu Val Val Val Gly Leu Ala Asp
150 155 160
ctc ctg agc aag cac gac agt cag cac aag ctc agc gaa gtg atc aca 584
Leu Leu Ser Lys His Asp Ser Gln His Lys Leu Ser Glu Val Ile Thr
165 170 175
ggg gac ctg ttg atc atc atg gcc cag atc atc gtt gcc atc cag atg 632
Gly Asp Leu Leu Ile Ile Met Ala Gln Ile Ile Val Ala Ile Gln Met
180 185 190
gtg cta gag gag aag ttc gtc tac aaa cac aat gtg cac cca ctg cgg 680
Val Leu Glu Glu Lys Phe Val Tyr Lys His Asn Val His Pro Leu Arg
195 200 205 210
gca gtt ggc act gag ggc ctc ttt ggc ttt gtg atc ctc tcc ctg ctg 728
Ala Val Gly Thr Glu Gly Leu Phe Gly Phe Val Ile Leu Ser Leu Leu
215 220 225
ctg gtg ccc atg tac tac atc ccc gcc ggc tcc ttc agc gga aac cct 776
Leu Val Pro Met Tyr Tyr Ile Pro Ala Gly Ser Phe Ser Gly Asn Pro
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
91/177
230 235 240
cgt ggg aca ctg gag gat gca ttg gac gcc ttc tgc cag gtg ggc cag 824
Arg Gly Thr Leu Glu Asp Ala Leu Asp Ala Phe Cys Gln Val Gly Gln
245 250 255
cag ccg ctc att gcc gtg gca ctg ctg ggc aac atc agc agc att gcc 872
Gln Pro Leu Ile Ala Val Ala Leu Leu Gly Asn Ile Ser Ser Ile Ala
260 265 270
ttc ttc aac ttc gca ggc atc agc gtc acc aag gaa ctg agc gcc acc 920
Phe Phe Asn Phe Ala Gly Ile Ser Val Thr Lys Glu Leu Ser Ala Thr
275 280 285 290
acc cgc atg gtg ttg gac agc ttg cgc acc gtt gtc atc tgg gca ctg 968
Thr Arg Met Val Leu Asp Ser Leu Arg Thr Val Val Ile Trp Ala Leu
295 300 305
agc ctg gca ctg ggc tgg gag gcc ttc cat gca ctg cag atc ctt ggc 1016
Ser Leu Ala Leu Gly Trp Glu Ala Phe His Ala Leu Gln Ile Leu Gly
310 315 320
ttc ctc ata ctc ctt ata ggc act gcc ctc tac aat ggg cta cac cgt 1064
Phe Leu Ile Leu Leu Ile Gly Thr Ala Leu Tyr Asn Gly Leu His Arg
325 330 335
ccg ctg ctg ggc cgc ctg tcc agg ggc cgg ccc ctg gca gag gag agc 1112
Pro Leu Leu Gly Arg Leu Ser Arg Gly Arg Pro Leu Ala Glu Glu Ser
340 345 350
gag cag gag aga ctg ctg ggt ggc acc cgc act ccc atc aat gat gcc 1160
Glu Gln Glu Arg Leu Leu Gly Gly Thr Arg Thr Pro Ile Asn Asp Ala
355 360 365 370
agc tgaggttccc tggaggcttc tactgccacc cgggtgctcc ttctccc 1210
Ser
tgagactgag gccacacagg ctggtgggcc ccgaatgccc tatccccaag gcctcaccct 1270
gtcccctccc tgcagaaccc ccagggcagc tgctgccaca gaagataaca acacccaagt 1330
cctctttttc tcactaccac ctgcagggtg gtgttaccca gcccccacaa gcctgagtgc 1390
agtggcagac ctcagctctc tggacccctc ctacagcact agagctaaat catgaagttg 1450
aattgtagga atttaccacc gtagtgtatc tgaatcataa actagattat cat 1503
<210> 87
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
92/177
<211> 733
<212> DNA
<2I3> Homo sapiens
<220>
<221> CDS
<222> (40)...(312)
<400> 87
gttaaggcac acagagcacc agctccctcc tgcctgaag atg ttc cac caa att 54
Met Phe His Gln Ile
1 5
tgg gca get ctg ctc tac ttc tat ggt att atc ctt aac tcc atc tac 102
Trp Ala Ala Leu Leu Tyr Phe Tyr Gly Ile Ile Leu Asn Ser Ile Tyr
10 15 20
I5 cag tgc cct gag cac agt caa ctg aca act ctg ggc gtg gat ggg aag 150
Gln Cys Pro Glu His Ser Gln Leu Thr Thr Leu Gly Val Asp Gly Lys
25 30 35
gag ttc cca gag gtc cac ttg ggc cag tgg tac ttt atc gca ggg gca 198
Glu Phe Pro Glu Val His Leu Gly Gln Trp Tyr Phe Ile Ala Gly Ala
90 45 50
get cec acc aag gag gag ttg gca act ttt gac cct gtg gac aac att 246
Ala Pro Thr Lys Glu Glu Leu Ala Thr Phe Asp Pro Val Asp Asn Ile
55 60 65
gtc ttc aat atg get get ggc tct gcc ccg atg cag ctc cac ctt cgt 294
Val Phe Asn Met Ala Ala Gly Ser Ala Pro Met Gln Leu His Leu Arg
70 75 80 85
get acc atc cgc atg tgagtggaaa gatgggctct gtgtgccccg g 340
Ala Thr Ile Arg Met
30 aaetggatct accacctgactgaagggagcacagatctcagaactgaaggccgccctgac400
atgaagactg agctcttttccagctcatgcccaggtggaatcatgctgaatgagacaggc460
cagggttacc agcgctttctcctctacaatcgctcaccacatcctcccgaaaagtgtgtg520
gaggaattca agtccctgacttcctgcctggactccaaagccttcttattgactcctagg580
eatcaegagg cctgtgagctgtccaataactgacctgtaacttcatctaagtccccagat640
35 gggtacaatg ggagctgagttgttggagggagaagctggagacttccagctccagctccc700
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
93/177
actcaagata ataaagataa tttttcaatc ctc 733
<210> 88
<211> 3768
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (358)...(1857)
<400> 88
gctagtggcg cgcggaggagcgacgcgtggagaegcggcccacgtgtctgcccagagtca60
agtcctgtgt tcttcccgctccttacgcatccgcggtccagggcgccctttcagccccgc120
tggtgttcgc ccaccccgggccgcgtgagtggggccccacgcagctccccgcactccgtg180
ggccaacttg gccaagcaactctgtccggggagcggtgcttgcggggggtgagtaccggg240
cactgcgcat gcggagctccaaattcaaacagctgttttcagaggctggagggcgggcgg300
actggtagca gctggggctaggagaggctttctctaggaggcggccgctcgggagcc 357
atg gtg gac cgg ggc cct ctg ctc acc tcg gcc atc atc 405
ttc tac ctg
Met Val Asp Arg Gly Pro Leu Leu Thr Ser Ala Ile Ile
Phe Tyr Leu
1 5 10 15
gcc atc ggg gcg gcg atc ttc gaa gtg ctg gag gag cca 453
cac tgg aag
Ala Ile Gly Ala Ala Ile Phe Glu Val Leu Glu Glu Pro
Hi
s Trp Lys
20 25 30
gag gcc aag aaa aac tac tac aca cag aag ctg cat ctg 501
ctc aag gag
Glu Ala Lys Lys Asn Tyr Tyr Thr Gln Lys Leu His Leu
Leu Lys Glu
40 45
ttc ccg tgc ctg ggt cag gag ggc ctg gac aag atc cta 549
gag gtg gta
30 Phe Pro Cys Leu Gly Gln Glu Gly Leu Asp Lys Ile Leu
Glu Val Val
50 55 60
tct gat get gca gga cag ggt gtg gcc atc aca ggg aac 597
cag acc ttc
Ser Asp Ala Ala Gly Gln Gly Val Ala Ile Thr Gly Asn
Gln Thr Phe
65 70 75 80
35 aac aac tgg aac tgg ccc aat gca atg att ttt gca gcg 695
acc gtc att
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
94/277
Asn Asn Trp Asn Trp Pro Asn Ala Met Ile Phe Ala Ala Thr Val Ile
85 90 95
acc acc att gga tat ggc aat gtg get ccc aag acc ccc gcc ggt cgc 693
Thr Thr Ile Gly Tyr Gly Asn Val Ala Pro Lys Thr Pro Ala Gly Arg
loo l05 llo
ctc ttc tgt gtt ttc tat ggt ctc ttc ggg gtg ccg ctc tgc ctg acg 741
Leu Phe Cys Val Phe Tyr Gly Leu Phe Gly Val Pro Leu Cys Leu Thr
115 120 125
tgg atc agt gcc ctg ggc aag ttc ttc ggg gga cgt gcc asg aga eta 789
Trp Ile Ser Ala Leu Gly Lys Phe Phe Gly Gly Arg Ala Lys Arg Leu
130 135 140
ggg cag ttc ctt acc aag aga ggt gtg agt ctg cgg aag gcg cag atc 837
Gly Gln Phe Leu Thr Lys Arg Gly Val Ser Leu Arg Lys Ala Gln Ile
145 150 155 160
acg tgc aca gtc atc ttc atc gtg tgg ggc gtc cta gtc cac ctg gtg 885
Thr Cys Thr Val Ile Phe Ile Val Trp Gly Val Leu Val His Leu Val
165 170 175
atc cca ccc ttc gta ttc atg gtg act gag ggg tgg aac tac atc gag 933
Ile Pro Pro Phe Val Phe Met Val Thr Glu Gly Trp Asn Tyr Ile Glu
180 185 190
ggc ctc tac tac tcc ttc atc acc atc tcc acc atc ggc ttc ggt gac 981
Gly Leu Tyr Tyr Ser Phe Ile Thr Ile Ser Thr Ile Gly Phe Gly Asp
195 200 205
ttt gtg gcc ggt gtg sac ccc agc gcc sac tac cac gcc ctg tac cgc 1029
Phe Val Ala Gly Val Asn Pro Ser Ala Asn Tyr His Ala Leu Tyr Arg
210 215 2~n
tac ttc gtg gag ctc tgg atc tac ttg ggg ctg gcc tgg ctg tec ett 1077
Tyr Phe Val Glu Leu Trp Ile Tyr Leu Gly Leu Ala Trp Leu Ser Leu
225 230 235 ~dn
ttt gtc aac tgg aag gtg agc atg ttt gtg gaa gtc cac aaa gcc att 1125
Phe VaI Asn Trp Lys Val Ser Met Phe Val Glu Val His Lys Ala.Ile
245 250 255
aag eag cgg cgg cgg cga cgg aag gag tcc ttt gag agc tcc cca cac 1173
Lys Lys Arg Arg Arg Arg Arg Lys Glu Ser Phe Glu Ser Ser Pro His
260 265 270
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
95/177
tcc cgg aag gcc ctg cag gtg eag ggg agc aca gcc tcc aag gac gtc 1221
Ser Arg Lys Ala Leu Gln Val Lys Gly Ser Thr Ala Ser Lys Asp Val
275 280 285
aac ttc aag aac gac 1269
atc agc aag ctc
ttt gaa
ctt gag
tcc acc
tac
Asn Phe Lys Asn Asp
Ile Ser Lys Leu
Phe Glu
Leu Glu
Ser Thr
Tyr
290 295 300
atc aag cag gcc agc ggt ggg I3I7
atc atg ggg gag
ggg aag
aag aca
aag
Ile Lys Gln Lys Ala Ser Gly Gly
Ile Met Gly Glu
Gly Lys
Lys Thr
305 310 315 320
acg ggc ccg cca ctg ggg caa ggt ctc cca 1365
ggc ggg cct ggc ggg gca
Thr Gly Pro Pro Leu Gly Gln Gly Leu Pro
Gly Gly Pro Gly Gly Ala
325 330 335
ctg ccc cct ctg ccc ctg gtc tcc aac cgg 1413
tcc gtg gta tac aag gtg
Leu Pro Pro Leu Pro Leu Val Ser Asn Arg
Ser Val Val Tyr Lys Val
340 345 350
ccc acc ttg gag tca cag ctg agc ggc cac 1461
gaa gtg aca agg aaa gta
Pro Thr Leu Glu Ser Gln Leu Ser Gly His
Glu Val Thr Arg Lys Val
355 360 365
tca agg tcc gat gag get gca gcc gaa gac 1509
cca gag gtg cgg cct agc
2a Ser Arg Ser Asp Glu Ala Ala Ala Glu Asp
Pro Glu Val Arg Pro Ser
370 375 380
tcc cct gcc gag ttc atg cag gac atc agc 1557
ccc gtg aac ctg cgc gag
Ser Pro Ala Glu Phe Gln Asp Ile Ser
Pro Val Met Leu Arg Glu
Asn
385 390 395 400
gaa tgc gag tgg gcc tac cca atc ttc 1605
cca gac cag cac ctc cag
gac
Glu Cys Trp Ala Tyr Pro Ile Phe
Glu Asp Gln His Leu Gln
Pro Asp
405 410 415
gac gcc acc gtg gag ggc 1653
agc ttc eac get ctc
atc acg tca
gac
gag
Asp Thr Glu
Ala Phe Ala
Ser Val Gly
Ile Asn Leu
Thr Ser
Asp
Glu
420 425 a3n
gag acc tcc aag tcc tcg cta gag gac aac ttg gca ggg gag gag agc 1701
Glu Thr Ser Lys Ser Ser Leu Glu Asp Asn Leu Ala Gly Glu Glu Ser
435 440 445
ccc cag cag ggg get gaa gcc sag gcg ccc ctg aac atg ggc gag ttc 1749
Pro Gln Gln Gly Ala Glu Ala Lys Ala Pro Leu Asn Met Gly Glu Phe
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
96/177
450 455 460
ccc tcc tcc tcc gag tcc acc ttc acc agc act gag tct gag ctc tct 1797
Pro Ser Ser Ser Glu Ser Thr Phe Thr Ser Thr Glu Ser Glu Leu Ser
465 470 475 480
gtg cct tac gsa cag ctg atg aat gag tac aac aag get aac agc ccc 1845
Val Pro Tyr Glu Gln Leu Met Asn Glu Tyr Asn Lys Ala Asn Ser Pro
485 490 495
aag ggc aca tgaggcaggg ccggctcccc accccacctt tgatgg 1890
Lys Gly Thr
cctcttcccc cctcacccta gggtgtcccg agatgaccgg gacgcctggc ccctggtggg 1950
ggggcagcct cggaactggg agtggggggc caggggcctt cctaaccttc catcatcccc 2010
agctagatgt atgcccggga cagggcctct gttctccagc tgaaccatac cctggctgtg 2070
ggggcatctg tcctgagctt ggctggtgta tctcacaatg caaagacatg ctggctggcg 2130
ggacaggtgg gcaggactga ccctgaggag gccttgcctg cagggtcttt gtcccaccat 2190
ttggtggagt atcacacggt tctctgaggt ccggggcctc agctgtttaa gtttaccggt 2250
attactgagc tcggcatttg gagagqgagc tctgaagtgt ctggggaggt accgctgtgc 2310
gtggggtcag gtgtttccgt accacagcag gagcagggcc cgcccgcatc ccagctgtgg 2370
gcctgccggt caggtcgggc acctactaca aaccgtagtg gggtggaggc tgctggaggt 2430
gggagtgagg agatgagggc agggtctcaa acagtcctga ctcacagggc ctggaaacaa 2490
gtcctatgtg ggcctggggc ctggggtcct catcctcctt gttggtctac tcaggcccag 2550
cccagagctg tgttccctgt ctcaggtcaa gcagtggcag acgcaaggct ttctgtgggc 2610
ccccaagtgg taggagggag agtagcagag catgggttac tggaagccgg gactgctagg 2670
gctggtggcc agggagctgc asgagtgagg ctcagctctg gctggttctg cccttacccc 2730
tcctgcccgc cggagaactg cacaccctgc ccgctggccc caggacctgc actcccaatc 2790
ctgctgtctt ctccttccct gtgccctgaa caaggacctc actgcccgcc ttcccctccc 2850
accagccccc ttgggccagg cagggtgagg ccasattgct cttggcccac aaatgggtga 2910
tggtcagata tgtgaatcaa gctcctttct ctagctagtg tttgatgtgc acgtgtgtgt 2970
gcacagtgcg tgtgtgcaca cgcacacctg tgcactcgtg tgtgtttaag aaaggaaagg 3030
atttgggctg gggagcaaaa gataatgtga aactgttggt ggactctctg gtgaggggtg 3090
ggcagaactt gctgctacta gagttcttgg gttctccatg atgttcaccc tggggctggc 3150
ccactgtgtc ctgaatgttt ttgttatttt ttgttttatt ttttaaacaa actgctgttt 3210
ttatatacct ggaatctgtt gttggcttca gagccagtgg ttaaagagca gggtcccaag 3270
gattgggaga tctagtgtct gccctcctgc cctgcaactc aattgggcct ttttcggtga 3330
cctcatccaa ggccatgatg tcaagggcca tgtccccaag cagaggtgga gaaggggaca 3390
CA 02336225 2001-O1-24
WO 00/0536? PCT/JP99/03929
97/177
ctgaggtgag caaaagcaggaaggggcatccactgcgggtgactggaggccgggcaggaa3450
gcaagtcatc agagccgctcagctccgttcactctctgccttctgccccactactgtggg3510
gcagtggggc cagagcccacctccecaacatgtgaagacagtgatgggcacgtgcccaca3570
cccccacttc tctagccgtttgcagaggccgccacccagcaggggcctgaaaaggagcag3630
cctcgtattt ttctgtgaaatgttttaatgaaccatgttgttgctggttgtcctggcatc3690
gcgcacactg tatgtacatactggcaacgatgtcsaatgtaatttattttaacattttta3750
caataaaaca tgaggtgg 3768
<210> 89
<211> 770
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
I5 <222> (24)...(344)
<400> 89
accgcgaagg gaggagtggc aac atg gcg tct tcg gga get ggt gac cct ctg 53
Met Ala Ser Ser Gly Ala Gly Asp Pro Leu
1 5 to
gat tct aag cgt gga gag gcc ccg ttc get cag cgt atc gac ccg act 101
Asp Ser Lys Arg Gly Glu Ala Pro Phe Ala Gln Arg Ile Asp Pro Thr
15 20 25
cgg gag aag ctg aca ccc gag caa ctg cat tcc atg cgg cag gcg gag 149
Arg Glu Lys Leu Thr Pro Glu Gln Leu His Ser Met Arg Gln Ala Glu
35 40
ctt gcc cag tgg cag asg gtc cta cca cgg cgg cga acc cgg aac atc 197
Leu Ala Gln Trp Gln Lys Val Leu Pro Arg Arg Arg Thr Arg Asn Ile
45 50 55
gtg acc ggc cta ggc atc ggg gcc ctg gtg ttg get att tat ggt tac 245
Val Thr Gly Leu Gly Ile Gly Ala Leu Val Leu Ala Ile Tyr Gly Tyr
60 65 70
acc ttc tac tcg att tcc cag gag cgt ttc cta gat gag cta gaa gac 293
Thr Phe Tyr Ser Ile Ser Gln Glu Arg Phe Leu Asp Glu Leu Glu Asp
75 80 85 gp
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
98/177
gag gcc aaa get gcc cga gcc cga get ctg gca agg gcg tca ggg tcc 341
Glu Ala Lys Ala Ala Arg Ala Arg Ala Leu Ala Arg Ala Ser Gly Ser
95 100 105
taatctgga tgggtattga tcatgtccaa cctgctggag ccccttcaca tggtggatga 400
tgccccatga ccctgtagaaattgaatcctgctcacaacattgttggccttcttactaac460
cttggaccgt gattgagcccaagaaaccagggacttacgcatttggccaatgtcaaaaga520
acagaacttt gcccactgcacacttgctgtgtacaatgactgagccctttcttgtagttt580
gtttccttgt ttgagaggtgtgcatgcgaccgtggcttttcccaaagtttctgactttgt640
ggtttacccc cttcaccttccagggacgcagttgttacgaggttagacgtggcagctctg700
tgcagtgttt gagcctacagtgggatacatagggtcasattgagsataataaactgagtc760
attctcctgg 770
<210> 90
<211> 1229
<2I2> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (96)...(554}
<400> 90
cctactcctg gattaggagg actgacaata ctacatatat cattaagcat gggcctcgct 60
tagaagttgc atctgagaaa gtagcccaga agaca atg gac tat gtg tgc tgt 113
Met Asp Tyr Val Cys Cys
1 5
get tac aac aac ata acc ggc agg caa gat gsa act cat ttc aca gtt 161
Ala Tyr Asn Asn Ile Thr Gly Arg Gln Asp Glu Thr His Phe Thr Val
10 15 20
atc atc act tcc gta gga ctg gag aag ctt gca cag aaa gga aaa tca 209
Ile Ile Thr Ser Val Gly Leu Glu Lys Leu Ala Gln Lys Gly Lys Ser
25 30 35
ttg tca cct tta gca agt ata act gga ata tca cta ttt ttg att ata 257
Leu Ser Pro Leu Ala Ser Ile Thr Gly Ile Ser Leu Phe Leu Ile Ile
45 50
35 tcc atg tgt ctt ctc ttc cta tgg aaa aaa tat caa ccc tac aaa gtt 305
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
99/177
Ser Met Cys Leu Leu Phe Leu Trp Lys Lys Tyr Gln Pro Tyr Lys Val
55 60 65 70
ata aaa cag aaa cta gaa ggc agg cca gaa aca gaa tac agg aaa get 353
Ile Lys Gln Lys Leu Glu Gly Arg Pro Glu Thr Glu Tyr Arg Lys Ala
75 80 85
caa aca ttt tca ggc cat gaa gat get ctg gat gac ttc gga ata tat 401
Gln Thr Phe Ser Gly His Glu Asp Ala Leu Asp Asp Phe Gly Ile Tyr
90 95 100
gaa ttt gtt get ttt cca gat gtt tct ggt gtt tcc agg atc cca agc 449
Glu Phe Val Ala Phe Pro Asp Val Ser Gly Val Ser Arg Ile Pro Ser
105 110 115
agg tct gtt cca gcc tct gat tgt gta tcg ggg caa gat ttg cac agt 497
Arg Ser Val Pro Ala Ser Asp Cys Val Ser Gly Gln Asp Leu His Ser
120 125 130
aca gtg tat gas gtt att cag cac atc cct gcc cag cag caa gac cat 545
Thr Val Tyr Glu Val Ile Gln His Ile Pro Ala Gln Gln Gln Asp His
135 140 145 150
cca gag tgaactttca tgggctaaac agtacattcg agtgaaattc tgaagaaac 600
Pro Glu
attttaagga aaaacagtggaaaagtatattaatctggaatcagtgasgaaaccaagacc660
sacacctctt actcattattcctttacatgcagaatagaggcatttatgcaaattgaact720
gcaggttttt cagcatatacacaatgtcttgtgcaacagaaaaacatgttggggaaatat780
tcctcagtgg agagtcgttctcatgctgacggggagaacgaeagtgacaggggtttcctc840
ataegttttg tatgaaatatctctacaaecctcaettagttctactctacactttcacta900
tcatcaacac tgagactatcctgtctcacctaceaatgtggaaactttacattgttcgat960
ttttcagcag actttgttttattaaatttttattagtgttaagaatgctaaagtttcaat1020
tttatttcca eatttctatcttgttatttgtacaacaaagtaataaggatggttgtcaca1080
aaaacaaaac tatgccttctcttttttttcaatcaccagtagtatttttgagaagacttg1140
tgaacactta aggaaatgactattaaagtcttatttttatttttttcaaggaaagatgga1200
ttcaaataaa ttattctgtttttgctttt 1229
<210> 91
<211> 358
<212> PRT
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
100/177
<213> Homo sapience
<400> 91
Met Ala Pro Gln Asn Leu Ser Thr Phe Cys Leu Leu Leu Leu Tyr Leu
1 5 10 15
Ile Gly Ala Val Ile Ala Gly Arg Asp Phe Tyr Lys Ile Leu Gly Val
20 25 30
Pro Arg Ser Ala Ser Ile Lys Asp Ile Lys Lys Ala Tyr Arg Lys Leu
35 40 45
Ala Leu Gln Leu His Pro Asp Arg Asn Pro Asp Asp Pro Gln Ala Gln
50 55 60
Glu Lys Phe Gln Asp Leu Gly Ala Ala Tyr Glu Val Leu Ser Asp Ser
65 70 75 80
Glu Lys Arg Lys Gln Tyr Asp Thr Tyr Gly Glu Glu Gly Leu Lys Asp
85 90 95
Gly His Gln Ser Ser His Gly Asp Ile Phe Ser His Phe Phe Gly Asp
100 105 110
Phe Gly Phe Met Phe Gly Gly Thr Pro Arg Gln Gln Asp Arg Asn Ile
115 120 125
Pro Arg Gly Ser Asp Ile Ile Val Asp Leu Glu Val Thr Leu Glu Glu
130 135 140
Val Tyr Ala Gly Asn Phe Val Glu Val Val Arg Asn Lys Pro Val Ala
145 150 155 160
Arg Gln Ala Pro Gly Lys Arg Lys Cys Asn Cys Arg Gln Glu Met Arg
165 170 17s
Thr Thr Glri Leu Gly Pro Gly Arg Phe Gln Met Thr Gln Glu Val Val
180 185 190
Cys Asp Glu Cys Pro Asn Val Lys Leu Val Asn Glu Glu Arg Thr Leu
195 200 205
Glu Val Glu Ile Glu Pro Gly Val Arg Asp Gly Met Glu Tyr Pro Phe
210 215 220
Ile Gly Glu Gly Glu Pro His Val Asp Gly Glu Pro Gly Asp Leu Arg
225 230 235 240
Phe Arg Ile Lys Val Val Lys His Pro Ile Phe Glu Arg Arg Gly Asp
245 250 255
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/0392~
101/177
Asp Leu Tyr Thr Asn Val Thr Ile Ser Leu Val Glu Ser Leu Val Gly
260 265 270
Phe Glu Met Asp Ile Thr His Leu Asp Gly His Lys Val His Ile Ser
275 280 285
Arg Asp Lys Ile Thr Arg Pro Gly Ala Lys Leu Trp Lys Lys Gly Glu
290 295 300
Gly Leu Pro Asn Phe Asp Asn Asn Asn Ile Lys Gly Ser Leu Ile Ile
305 310 315 320
Thr Phe Asp Val Asp Phe Pro Lys Glu Gln Leu Thr Glu Glu Ala Arg
325 330 335
Glu Gly Ile Lys Gln Leu Leu Lys Gln Gly Ser Val Gln Lys Val Tyr
340 345 350
Asn Gly Leu Gln Gly Tyr
355
<210> 92
<211> 226
<zl2> PRT
<213> Homo sapience
<400> 92
Met Lys Met Val Ala Pro Trp Thr Arg Phe Tyr Ser Asn Ser Cys Cys
1 5 10 15
Leu Cys Cys His Val Arg Thr Gly Thr Ile Leu Leu Gly Val Trp Tyr
20 25 30
Leu Ile Ile Asn Ala Val Val Leu Leu Ile Leu Leu Ser Ala Leu Ala
40 45
Asp Pro Asp Gln Tyr Asn Phe Ser Ser Ser Glu Leu Gly Gly Asp Phe
50 55 60
30 Glu Phe Met Asp Asp Ala Asn Met Cys Ile Ala Ile Ala Ile Ser Leu
65 70 75 80
Leu Met Ile Leu Ile Cys Ala Met Ala Thr Tyr Gly Ala Tyr Lys Gln
B5 90 95
Arg Ala Ala Trp Ile Ile Pro Phe Phe Cys Tyr Gln Ile Phe Asp Phe
35 loo l05 110
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
102/177
Ala Leu Asn Met Leu Val Ala Ile Thr Val Leu Ile Tyr Pro Asn Ser
115 120 125
Ile Gln Glu Tyr Ile Arg Gln Leu Pro Pro Asn Phe Pro Tyr Arg Asp
130 135 140
Asp Val Met Ser Val Asn Pro Thr Cys Leu Val Leu Ile Ile Leu Leu
145 150 155 I60
Phe Ile Ser Ile Ile Leu Thr Phe Lys Gly Tyr Leu Ile Ser Cys Val
165 170 175
Trp Asn Cys Tyr Arg Tyr Ile Asn Gly Arg Asn Ser Ser Asp Val Leu
180 185 190
Val Tyr Val Thr Ser Asn Asp Thr Thr Val Leu Leu Pro Pro Tyr Asp
195 200 205
Asp Ala Thr Val Asn Gly Ala Ala Lys Glu Pro Pro Pro Pro Tyr Val
210 215 220
ser Ala
225
<210> 93
<211> 195
<2I2> PRT
<213> Homo sapience
<400> 93
Met Arg Leu Leu Leu Leu Leu Leu VaI Ala Ala Ser Ala Met Val Arg
1 5 10 15
Ser Glu Ala Ser Ala Asn Leu Gly Gly Val Pro Ser Lys Arg Leu Lys
20 25 30
Met Gln Tyr Ala Thr Gly Pro Leu Leu Lys Phe Gln Ile Cys Val Ser
40 45
30 Xaa Gly Tyr Arg Arg Val Phe Glu Glu Tyr Met Arg Val Ile Ser Gln
50 55 60
Arg Tyr Pro Asp Ile Arg Ile Glu Gly Glu Asn Tyr Leu Pro Gln Pro
65 70 75 80
Ile Tyr Arg His Ile Ala Ser Phe Leu Ser Val Phe Lys Leu Val Leu
35 85 90 95
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
103/177
Ile Gly Leu Ile Ile Val Gly Lys Asp Pro Phe Ala Phe Phe Gly Met
100 105 I10
Gln Ala Pro Ser Ile Trp Gln Trp Gly Gln Glu Asn Lys Val Tyr Ala
115 120 125
Cys Met Met Val Phe Phe Leu Ser Asn Met Ile Glu Asn Gln Cys Met
130 135 140
Ser Thr Gly Ala Phe Glu Ile Thr Leu Asn Aap Val Pro Val Trp Ser
145 150 155 160
Lys Leu Glu Ser Gly His Leu Pro Ser Met Gln Gln Leu Val Gln Ile
165 170 175
Leu Asp Asn Glu Met Lys Leu Asn Val His Met Asp Ser Ile Pro His
180 185 I90
His Arg Ser
195
<210>94
<211>339
<212>PRT
<213>Homo sapience
<400> 94
Met Asn Trp Glu Leu Leu Leu Trp Leu Leu Val Leu Cys Ala Leu Leu
i 5 10 15
Leu Leu Leu Val Gln Leu Leu Arg Phe Leu Arg Ala Asp Gly Asp Leu
20 25 30
Thr Leu Leu Trp Ala Glu Trp Gln Gly Arg Arg Pro Glu Trp Glu Leu
40 45
Thr Asp Met Val Val Trp Val Thr Gly Ala Ser Ser Gly Ile Gly Glu
50 55 60
30 Glu Leu Ala Tyr Gln Leu Ser Lys Leu Gly Val Ser Leu Val Leu Ser
65 70 75 80
Ala Arg Arg Val His Glu Leu Glu Arg Val Lys Arg Arg Cys Leu Glu
85 90 95
Asn Gly Asn Leu Lys Glu Lys Asp Ile Leu Val Leu Pro Leu Asp Leu
35 loo io5 110
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
104/177
Thr Asp Thr Gly Ser His Glu Ale Ala Thr Lys Ala Val Leu Gln Glu
115 120 125
Phe Gly Arg Ile Asp Ile Leu Val Asn Asn Gly Gly Met Ser Gln Arg
130 135 140
Ser Leu Cys Mat Asp Thr Ser Leu Asp Val Tyr Arg Lys Leu Ile Glu
145 150 155 160
Leu Asn Tyr Leu Gly Thr Val Ser Leu Thr Lys Cys Val Leu Pro His
165 170 175
Met Ile Glu Arg Lys Gln Gly Lys Ile Val Thr Val Asn Ser Ile Leu
180 185 190
Gly Ile Ile Ser Val Pro Leu Ser Ile Gly Tyr Cys Ala Ser Lys His
195 200 205
Ala Leu Arg Gly Phe Phe Asn Gly Leu Arg Thr Glu Leu Ala Thr Tyr
210 215 220
Pro Gly Ile Ile Val Ser Asn Ile Cys Pro Gly Pro Val Gln Ser Asn
225 230 235 240
Ile Val Glu Asn Ser Leu Ala Gly Glu Val Thr Lys Thr Ile Gly Asn
245 250 255
Asn Gly Asp Gln Ser His Lys Met Thr Thr Ser Arg Cys Val Arg Leu
260 265 270
Met Leu Ile Ser Met Ala Asn Asp Leu Lys Glu Val Trp Ile Ser Glu
275 280 285
Gln Pro Phe Leu Leu Val Thr Tyr Leu Trp Gln Tyr Met Pro Thr Trp
290 295 300
Ala Trp Trp Ile Thr Asn Lys Met Gly Lys Lys Arg Ile Glu Asn Phe
305 310 315 320
Lys Ser Gly Val Asp Ala Asp Ser Ser Tyr Phe Lys Ile Phe Lys Thr
325 330 335
Lya His Asp
<210> 95
<211> 487
<212> PRT
<213> Homo sapience
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
105/177
<400> 95
Met Asp Gly Thr Glu Thr Arg Gln Arg Arg Leu Asp Ser Cys Gly Lys
1 5 10 15
Pro Gly Glu Leu Gly Leu Pro His Pro Leu Ser Thr Gly Gly Leu Pro
20 25 30
Val Ala Ser Glu Asp Gly Ala Leu Arg Ala Pro Glu Ser Gln Ser Val
35 40 45
Thr Pro Lys Pro Leu Glu Thr Glu Pro Ser Arg Glu Thr Ala Trp Ser
50 55 60
Ile Gly Leu Gln Val Thr Val Pro Phe Met Phe Ala Gly Leu Gly Leu
65 70 ?5 80
Ser Trp Ala Gly Met Leu Leu Asp Tyr Phe Gln His Trp Pro Val Phe
85 90 95
Val Glu Val Lys Asp Leu Leu Thr Leu Val Pro Pro Leu Val Gly Leu
loo l05 110
Lys Gly Asn Leu Glu Met Thr Leu Ala Ser Arg Leu Ser Thr Ala Ala
115 120 125
Asn Thr Gly Gln Ile Asp Asp Pro Gln Glu Gln His Arg Val Ile Ser
130 135 140
Ser Asn Leu Ala Leu Ile Gln Val Gln Ala Thr Val Val Gly Leu Leu
145 150 155 160
Ala Ala Val Ala Ala Leu Leu Leu Gly Val Val Ser Arg Glu Glu Val
165 170 175
Asp Val Als Lys Val Glu Leu Leu Cys Ala Ser Ser Val Leu Thr Ala
180 185 190
Phe Leu Ala Ala Phe Ala Leu Gly Val Leu Met Val Cys Ile Val Ile
195 200 205
Gly Ala Arg Lys Leu Gly Val Asn Pro Asp Asn Ile Ala Thr Pro Ile
210 215 220
Ala Ala Ser Leu Gly Asp Leu Ile Thr Leu Ser Ile Leu Ala Leu Val
225 230 235 240
Ser Ser Phe Phe Tyr Arg His Lys Asp Ser Arg Tyr Leu Thr Pro Leu
245 250 255
Val Cys Leu Ser Phe Ala Ala Leu Thr Pro Val Trp Val Leu Ile Ala
260 265 270
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
106/177
Lys Gln Ser Pro Pro Ile Val Lys Ile Leu Lys Phe Gly Trp Phe Pro
275 280 285
Ile Ile Leu Ala Met Val Ile Ser Ser Phe Gly Gly Leu Ile Leu Ser
290 295 300
Lys Thr Val Ser Lys Gln Gln Tyr Lys Gly Met Ala Ile Phe Thr Pro
305 310 315 320
Val Ile Cys Gly Val Gly Gly Asn Leu Val Ala Ile Gln Thr Ser Arg
325 330 335
Ile Ser Thr Tyr Leu His Met Trp Ser Ala Pro Gly Val Leu Pro Leu
340 345 350
Gln Met Lys Lys Phe Trp Pro Asn Pro Cys Ser Thr Phe Cys Thr Ser
355 360 365
Glu Ile Asn Ser Met Ser Ala Arg Val Leu Leu Leu Leu Val Val Pro
370 375 380
Gly His Leu Ile Phe Phe Tyr Ile Ile Tyr Leu Val Glu Gly Gln Ser
385 390 395 400
Val Ile Asn Ser Gln Thr Phe Val Val Leu Tyr Leu Leu Ala Gly Leu
405 410 415
Ile Gln Val Thr Ile Leu Leu Tyr Leu Ala Glu Val Met Val Arg Leu
420 425 430
Thr Trp His Gln Ala Leu Asp Pro Asp Asn His Cys Ile Pro Tyr Leu
435 440 445
Thr Gly Leu Gly Asp Leu Leu Gly Thr Gly Leu Leu Ala Leu Cys Phe
450 455 460
Phe Thr Asp Trp Leu Leu Lys Ser Lys Ala Glu Leu Gly Gly Ile Ser
465 470 475 480
Glu Leu Ala Ser Gly Pro Pro
485
<210> 96
<211> 393
<212> PRT
<2I3> Homo sapience
<400> 96
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/039Zg
107/177
Met Arg Thr Leu Phe Asn Leu Leu Trp Leu Ala Leu Ala Cys Ser Pro
1 5 10 15
Val His Thr Thr Leu Ser Lys Ser Asp Ala Lys Lys Ala Ala Ser Lys
20 25 30
Thr Leu Leu Glu Lys Ser Gln Phe Ser Asp Lys Pro Val Gln Asp Arg
35 40 45
Gly Leu Val Val Thr Asp Leu Lys Ala Glu Ser Val Val Leu Glu His
50 55 60
Arg Ser Tyr Cys Ser Ala Lys Ala Arg Asp Arg His Phe Ala Gly Asp
65 70 75 80
Val Leu Gly Tyr Val Thr Pro Trp Asn Ser His Gly Tyr Asp Val Thr
85 90 g5
Lys Val Phe Gly Ser Lys Phe Thr Gln Ile Ser Pro Val Trp Leu Gln
100 105 110
Leu Lys Arg Arg Gly Arg Glu Met Phe Glu Val Thr Gly Leu His Asp
115 120 125
Val Asp Gln Gly Trp Met Arg Ala Val Arg Lys His Ala Lys Gly Leu
130 135 140
His Ile Val Pro Arg Leu Leu Phe Glu Asp Trp Thr Tyr Asp Asp Phe
145 150 155 160
Arg Asn Val Leu Asp Ser Glu Asp Glu Ile Glu Glu Leu Ser Lys Thr
165 170 175
Val Val Gln Val Ala Lys Asn Gln His Phe Asp Gly Phe Val Val Glu
180 185 190
Val Trp Asn Gln Leu Leu Ser Gln Lys Arg Val Gly Leu Ile His Met
195 200 205
Leu Thr His Leu Ala Glu Ala Leu His Gln Ala Arg Leu Leu Ala Leu
210 215 220
Leu Val Ile Pro Pro Ala Ile Thr Pro Gly Thr Asp Gln Leu Gly Met
225 230 235 240
Phe Thr His Lys Glu Phe Glu Gln Leu Ala Pro Val Leu Asp Gly Phe
245 250 255
Ser Leu Met Thr Tyr Asp Tyr Ser Thr Ala His Gln Pro Gly Pro Asn
260 265 270
Ala Pro Leu Ser Trp Val Arg Ala Cys Val Gln Val Leu Asp Pro Lys
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
108/177
275 280 285
Ser Lys Trp Arg Ser Lys Ile Leu Leu Gly Leu Asn Phe Tyr Gly Met
290 295 300
Asp Tyr Ala Thr Ser Lys Asp Ala Arg Glu Pro Val Val Gly Ala Arg
305 310 315 320
Tyr Ile Gln Thr Leu Lys Asp His Arg Pro Arg Met Val Trp Asp Ser
325 330 335
Gln Ala Ser Glu His Phe Phe Glu Tyr Lys Lys Ser Arg Ser Gly Arg
340 345 350
Hie Val Val Phe Tyr Pro Thr Leu Lys Ser Leu Gln Val Arg Leu Glu
355 360 365
Leu Ala Arg Glu Leu Gly Val Gly Val Ser Ile Trp Glu Leu Gly Gln
370 375 380
Gly Leu Asp Tyr Phe Tyr Asp Leu Leu
385 390
<210> 97
<211> 196
<212> PRT
<213> Homo sapience
<400> 97
Met Trp Arg Val Pro Gly Thr Thr Arg Arg Pro Val Thr Gly Glu Ser
1 5 10 15
Pro Gly Met His Arg Pro Glu Ala Met Leu Leu Leu Leu Thr Leu Ala
20 25 30
Leu Leu Gly Gly Pro Thr Trp Ala Gly Lys Met Tyr Gly Pro Gly Gly
40 45
Gly Lys Tyr Phe Ser Thr Thr Glu Asp Tyr Asp His Glu Ile Thr Gly
30 50 55 60
Leu Arg Val Ser Val Gly Leu Leu Leu Val Lys Ser Val Gln Val Lys
65 70 75 g0
Leu Gly Asp Ser Trp Asp Val Lys Leu Gly Ala Leu Gly Gly Asn Thr
85 90 95
35 Gln Glu Val Thr Leu Gln Pro Gly Glu Tyr Ile Thr Lys Val Phe Val
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
109/177
loo los llo
Ala Phe Gln Ala Phe Leu Arg Gly Met Val Met Tyr Thr Ser Lys Asp
115 120 125
Arg Tyr Phe Tyr Phe Gly Lys Leu Asp Gly Gln Ile Ser Ser Ala Tyr
130 135 140
Pro Ser Gln Glu Gly Gln Val Leu Val Gly Ile Tyr Gly Gln Tyr Gln
145 150 155 160
Leu Leu Gly Ile Lys Ser Ile Gly Phe Glu Trp Asn Tyr Pro Leu Glu
165 170 175
Glu Pro Thr Thr Glu Pro Pro Val Asn Leu Thr Tyr Ser Ala Asn Ser
180 185 190
Pro Val Gly Arg
195
<210> 98
<211> 107
<212> PRT
<213> Homo sapience
<400> 98
Met Glu Gln Lys Leu Val GIu Glu Ile Leu Gln Ala Ile Thr Met Ser
1 5 10 15
Thr Asp Thr Gly Val Ser Leu Pro Ser Tyr Glu Glu Asp Gln Gly Ser
20 25 30
Lys Leu Ile Arg Lys Ala Lys Glu Ala Pro Phe Val Pro Val Gly Ile
40 45
Ala Gly Phe Ala Ala Ile Val Ala Tyr Gly Leu Tyr Lys Leu Lys Ser
50 55 60
Arg Gly Asn Thr Lys Met Ser Ile His Leu Ile His Met Arg Val Ala
30 65 70 75 80
Ala Glu Gly Phe Val Val Gly Ala Met Thr Val Gly Met Gly Tyr Ser
85 90 95
Met Tyr Arg Glu Phe Trp Ala Lys Pro Lys Pro
100 105
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
110/177
<210> 99
<211> 350
<212> PRT
<213> Homo sapience
<400> 99
Met Ser Glu Val Lys Ser Arg Lys Lys Ser Gly Pro Lys Gly Ala Pro
1 5 10 1S
Ala Ala Glu Pro Gly Lys Arg Ser Glu Gly Gly Lys Thr Pro Val Ala
20 25 30
Arg Ser Ser Gly Gly Gly Gly Trp Ala Asp Pro Arg Thr Cys Leu Ser
35 40 45
Leu Leu Ser Leu Gly Thr Cys Leu Gly Leu Ala Trp Phe Val Phe Gln
50 55 60
Glri Ser Glu Lys Phe Ala Lys Val Glu Asn Gln Tyr Gln Leu Leu Lys
65 70 75 80
Leu Glu Thr Asn Glu Phe Gln Gln Leu Gln Ser Lys Ile Ser Leu Ile
85 90 95
Ser Glu Lys Trp Gln Lys Ser Glu Ala Ile Met Glu Gln Leu Lys Ser
100 105 110
Phe Gln Ile Ile Ala His Leu Lys Arg Leu Gln Glu Glu Ile Asn Glu
115 120 12S
Val Lys Thr Trp Ser Asn Arg Ile Thr Glu Lys Gln Asp Ile Leu Asn
130 135 140
Asn Ser Leu Thr Thr Leu Ser Gln Asp Ile Thr Lys Val Asp Gln Ser
145 150 155 160
Thr Thr Ser Met Ala Lys Asp Val Gly Leu Lys Ile Thr Ser Val Lys
165 170 I75
Thr Asp Ile Arg Arg Ile Ser Gly Leu Val Thr Asp Val Ile Ser Leu
180 185 190
Thr Asp Ser Val Gln Glu Leu Glu Asn Lys Ile Glu Lys Val Glu Lys
195 200 205
Asn Thr Val Lys Asn Ile Gly Asp Leu Leu Ser Ser Ser Ile Asp Arg
210 215 220
Thr Ala Thr Leu Arg Lys Thr Ala Ser Glu Asn Ser Gln Arg Ile Asn
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
111/177
Z25 230 235 240
Ser Val Lys Lys Thr Leu Thr Glu Leu Lys Ser Asp Phe Asp Lys His
245 250 255
Thr Asp Arg Phe Leu Ser Leu Glu Gly Asp Arg Ala Lys Val Leu Lys
260 265 270
Thr Val Thr Phe Ala Asn Asp Leu Lys Pro Lys Val Tyr Asn Leu Lys
275 280 285
Lys Asp Phe Ser Arg Leu Glu Pro Leu Val Asn Asp Leu Thr Leu Arg
290 295 300
Ile Gly Arg Leu Val Thr Asp Leu Leu Gln Arg Glu Lys Glu Ile Ala
305 310 315 320
Phe Leu Ser Glu Lys Ile Ser Asn Leu Thr Ile Val Gln Ala Glu Ile
325 330 335
Lys Asp Ile Lys Asp Glu Ile Ala His Ile Ser Asp Met Asn
340 345 350
<210> 100
<211> 107
<212> PRT
<213> Homo sapience
<400> 100
Met Ser Ser Ala Gly Thr Ala Thr Pro Leu Glu Met Asp His Lys Leu
1 5 10 15
Thr Ser Gln Pro Gly Arg Pro Ser Phe Tyr Cys Asn Ser Arg His Ser
20 25 30
Ile Val Gly Ser Ser His Gln Leu Gly Phe Trp Phe Ser His Leu Glu
40 45
Ser Ser Gly Leu Lys Val Phe Gln Val Ser Leu Pro Cys Glu Cys Val
30 50 55 60
Asn Leu Pro Thr Arg Ile Ala Ser Val Val Leu Ser Leu Met Ser Leu
65 70 75 80
Leu Val Val Gly Gln Ala Pro Ala Trp Glu Gly Ser Leu Leu Arg Gly
85 90 95
35 Arg Pro Ala Gly Gly Ala His Leu Cys Ala Ala
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
112/1?7
100 105
<210> 101
<211> 1074
<212> DNA
<213> Homo Sapience
<400> 101
atggctccgcagaacctgagcaccttttgcctgttgctgctatacctcatcggggcggtg60
attgccggacgagatttctataagatcttgggggtgcctcgaagtgcctctataaaggat120
attaaaaaggcctataggaaactagccctgcagcttcatcccgaccggaaccctgatgat180
ccacaagcccaggagaaattccaggatctgggtgctgcttatgaggttctgtcagatagt240
gagaaacggaaacagtacgatacttatggtgaagaaggattaaaagatggtcatcagagc300
tcccatggagacattttttcacacttctttggggattttggtttcatgtttggaggaacc360
cctcgtcagcaagacagaaatattccaagaggaagtgatattattgtagatctagaagtc420
actttggaagaagtatatgcaggaaattttgtggaagtagttagaascaaacctgtggca480
aggcaggctcctggcaaacggaagtgcaattgtcggcaagagatgcggaccacccagctg540
ggccctgggcgcttccaaatgacccaggaggtggtctgcgacgaatgccctaatgtcaaa600
ctagtgaatgaagaacgaacgctggaagtagaaatagagcctggggtgagagacggcatg660
gagtacccctttattggagaaggtgagcctcacgtggatggggagcctggagatttacgg720
ttccgsatcaaagttgtcaagcacccaatatttgaaaggagaggagatgatttgtacaca780
aatgtgacaatctcattagttgagtcactggttggctttgagatggatattactcacttg840
gatggtcacaaggtacatatttcccgggataagatcaccaggccaggagcgaagctatgg900
aagaaaggggaagggctccccaactttgacaacaacaatatcaagggctctttgataatc960
acttttgatgtggattttccasaagaacagttaacagaggaagcgagagaaggtatcaaa1020
cagctactgaaacaagggtcagtgcagaaggtatacaatggactgcaaggatat 1074
<210> 102
<211> 678
<212> DNA
<213> Homo Sapience
<400> 102
atgaagatgg tcgcgccctg gacgcggttc tactccaaca gctgctgctt gtgctgccat 60
gtccgcaccg gcaccatcct gctcggcgtc tggtatctga tcatcaatgc tgtggtactg 120
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
113/177
ttgattttat tgagtgccctggctgatccggatcagtataacttttcaagttctgaactg180
ggaggtgact ttgagttcatggatgatgccaacatgtgcattgccattgcgatttctctt240
ctcatgatcc tgatatgtgctatggctacttacggagcgtacaagcaacgcgcagcctgg300
atcatcccat tcttctgttaccagatctttgactttgccctgaacatgttggttgcaatc360
actgtgctta tttatccaaactccattcaggaatacatacggceactgcctcctaatttt420
ccctacagag atgatgtcatgtcagtgaatcctacctgtttggtccttattattcttctg480
tttattagca ttatcttgacttttaagggttacttgattagctgtgtttggaactgctac540
cgatacatca atggtaggaactcctctgatgtcctggtttatgttaccagcaatgacact600
acggtgctgc tacccccgtatgatgatgccactgtgaatggtgctgccaaggagccaccg660
ccaccttacg tgtctgcc 678
<210> 103
<21I> 585
<212> DNA
<213> Homo Sapience
<400> 103
atgaggcttc tgctgcttct cctagtggcg gcgtctgcga tggtccggag cgaggcctcg 60
gccaatctgg gcggcgtgcc cagcaagaga ttaaagatgc agtacgccac ggggccgctg 120
ctcaagttcc agatttgtgtttcctgaggttataggcgggtgtttgaggagtacatgcgg180
gttattagcc agcggtacccagacatccgcattgaaggagagaattacctccctcaacca240
atatatagac acatagcatctttcctgtcagtcttcaaactagtattaataggcttaata300
attgttggca aggatccttttgctttctttggcatgcaagctcctagcatctggcagtgg360
ggccaagaaa ataaggtttatgcatgtatgatggttttcttcttgagcaacatgattgag420
aaccagtgta tgtcaacaggtgcatttgagataactttaaatgatgtacctgtgtggtct480
aagctggaat ctggtcaccttccatccatgcaacaacttgttcaaattcttgacaatgas540
atgaegctca atgtgcatatggattcaatcccacaccatcgatca 585
<210> 104
<21I> 1017
<212> DNA
<213> Homo Sapience
<400> 104
atgaactggg agctgctgct gtggctgctg gtgctgtgcg cgctgctcct gctcttggtg 60
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
114/177
cagctgctgc gcttcctgagggctgacggcgacctgacgctactatgggccgagtggcag120
ggacgacgcc cagaatgggagctgactgatatggtggtgtgggtgactggagcctcgagt180
ggaattggtg aggagctggcttaccagttgtctaaactaggagtttctcttgtgctgtca240
gccagaagag tgcatgagctggaaagggtgaaaagaagatgcctagagaatggcaattta300
aaagaasaag atatacttgttttgccccttgacctgaccgacactggttcccatgaagcg360
gctaccaaag ctgttctccaggagtttggtagaatcgacattctggtcaacaatggtgga420
atgtcccagc gttctctgtgcatggataccagcttggatgtctacagaaagctaatagag480
cttaactact tagggacggtgtccttgacaaaatgtgttctgcctcacatgatcgagagg540
aagcaaggaa agattgttactgtgaatagcatcctgggtatcatatctgtacctctttcc600
attggatact gtgctagcasgcatgctctccggggtttttttaatggccttcgaecagae660
cttgccacat acccaggtat aatagtttct aacatttgcc caggacctgt gcactcaaat 720
attgtggaga attccctagc tggagaagtc acaaagacta taggcaataa tggagaccag 780
tcccacaaga tgacaaccag tcgttgtgtg cggctgatgt taatcagcat ggccaatgat 840
ttgaaagaag tttggatctc agaacaacct ttcttgttag taacatattt gtggcaatac 900
atgccaacct gggcctggtg gataaccaac aagatgggga agaaaaggat tgagaacttt 960
sagagtggtg tggatgcaga ctcttcttat tttaaaatct ttaagacaaa acatgac 1017
<210> 105
<211> 1461
<212> DNA
<213> Homo Sapience
<400> 105
atggatggga cagagacccg gcagcggagg ctggacagct gtggcaagcc aggggagctg 60
gggcttcctc accccctcag cacaggagga ctccctgtag cctcagaaga tggagctctc 120
agggcccctg agagccaaagcgtgacccccaagccactggagactgagcctagcagggag180
accgcctggt ccataggccttcaggtgaccgtgcccttcatgtttgcaggcctgggactg240
tcctgggccg gcatgcttctggactatttccagcactggcctgtgtttgtggaggtgaaa300
gaccttttga cattggtgccgcccctggtgggcctgaaggggaacctggagatgacactg360
gcatccagac tctccacagctgccaacactggacaaattgatgacccccaggagcagcac420
agagtcatca gcagcaacct ggccctcatc caggtgcagg ccactgtcgt ggggctcttg 480
gctgctgtgg ctgcgctgct gttgggcgtg gtgtctcgag aggaagtgga tgtcgccaag 540
gtggagttgc tgtgtgccag cagtgtcctc actgccttcc ttgcagcctt tgccctgggg 600
gtgctgatgg tctgtatagt gattggtgct cgaaagctcg gggtcaaccc agacaacatt 660
gccacgccca ttgcagccag cctgggagac ctcatcacac tgtccattct ggctttggtt 720
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
115/177
agcagcttct tctacagaca caaagatagt cggtatctga cgccgctggt ctgcctcagc 780
tttgcggctc tgaccccagt gtgggtcctc attgccaagc agagcccacc catcgtgaag 840
atcctgaagt ttggctggtt cccaatcatc ctggccatgg tcatcagcag tttcggagga 900
ctcatcttga gcaaaaccgt ttctasacag cagtacaaag gcatggcgat atttaccccc 960
gtcatatgtg gtgttggtgg caatctggtg gccattcaga ccagccgaat ctcaacctac 1020
ctgcacatgt ggagtgcacc tggcgtcctg cccctccaga tgaagaaatt ctggcccaac 1080
ccgtgttcta ctttctgcac gtcagasatc aattccatgt cagctcgagt cctgctcttg 1140
ctggtggtcc caggccatct gattttcttc tacatcatct acctggtgga gggtcagtca 1200
gtcataaaca gccagacctt tgtggtgctc tacctgctgg caggcctgat ccaggtgaca 1260
atcctgctgt acctggcaga agtgatggtt cggctgactt ggcaccaggc cctggatcct' 1320
gacaaccact gcatccccta ccttacaggg ctgggggacc tgctcggtac tggcctcctg 1380
gcactctgct ttttcactga ctggctactg aagagcaagg cagagctggg tggcatctca 1440
gaactggcat ctggacctcc c 1461
<210> 106
<211> 1179
<212> DNA
<213> Homo Sapience
<400> 106
atgcggacac tcttcaacct cctctggctt gccctggcct gcagccctgt tcacactacc 60
ctgtcaaagt cagatgccaa aaaagccgcc tcaaegacgc tgctggagaa gagtcagttt 120
tcagataagc cggtgcaaga ccggggtttg gtggtgacgg acctcasagc tgagagtgtg 180
gttcttgagc atcgcagcta ctgctcggca aaggcccggg acagacactt tgctggggat 240
gtactgggct atgtcactccatggaacagccatggctacgatgtcaccaaggtctttggg300
agceagttca cacagatctcacccgtctggctgcagctgaagagacgtggccgtgagatg360
tttgaggtca cgggcctccacgacgtggaccaagggtggatgcgagctgtcaggaagcat420
gccaagggcc tgcacatagtgcctcggctcctgtttgaggactggacttacgatgatttc480
cggaacgtct tagacagtgaggatgagatagaggagctgagcaagaccgtggtccaggtg540
gcaaagaacc agcatttcgatggcttcgtggtggaggtctggaaccagctgctaagccag600
sagcgcgtgg gcctcatccacatgctcacccacttggccgaggctctgcaccaggcccgg660
ctgctggccc tcctggtcatcccgcctgccatcacccccgggaccgaccagctgggcatg720
ttcacgcaca aggagtttgagcagctggcccccgtgctggatggtttcagcctcatgacc780
tacgactact ctacagcgcatcagcctggccctaatgcacccctgtcctgggttcgagcc840
tgcgtccagg tcctggacccgsagtccaagtggcgaagcaaaatcctcctggggctcaac900
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
116/177
ttctatggta tggactacgcgacctccaaggatgcccgtgagcctgttgtcggggccagg960
tacatccaga cactgaaggaccacaggccccggatggtgtgggacagccaggcctcagag1020
cacttcttcg agtacaagaagagccgcagtgggaggcacgtcgtcttctacccaaccctg1080
aagtccctgc aggtgcggctggagctggcccgggagctgggcgttggggtctctatctgg1140
gagctgggcc agggcctggactacttctacgacctgctc 1179
<210> 107
<211> 588
<212> DNA
<213> Homo Sapience
<400> 107
atgtggaggg tgcccggcac aaccagacgc ccagtcacag gcgagagccc tgggatgcac 60
cggccagagg ccatgctgct gctgctcacg cttgccctcc tggggggccc cacctgggca 120
gggaagatgt atggccctggaggaggcaagtatttcagcaccactgaagactacgaccat180
gaastcacag ggctgcgggtgtctgtaggtcttctcctggtgaaaagtgtccaggtgaaa240
cttggagact cctgggacgtgaaactgggagccttaggtgggaatacccaggaagtcacc300
ctgcagccag gcgaatacatcacaaaagtctttgtcgccttccaagctttcctccggggt360
atggtcatgt acaccagcaaggaccgctatttctattttgggaagcttgatggccagatc420
tcctctgcct accccagccaagaggggcaggtgctggtgggcatctatggccagtatcaa480
ctccttggca tcaagagcattggctttgaatggaattatccactagaggagccgaccact540
gagccaccag ttaatctcacatactcagcasactcacccgtgggtcgc 588
<210> 108
<211> 321
<212> DNA
<213> Homo Sapience
<400> 108
atggagcaga agcttgtggaggagattcttcaagcaatcactatgtcaacagacacaggt60
gtttcccttc cttcatatgaggaagatcagggatcaaaactcattcgaaaagctaaagag120
gcaccattcg tacccgttggaatagcgggttttgcagcaattgttgcatatggattatat180
aaactgaaga gcaggggaaatactaaastgtccattcatctgatccacatgcgtgtggca240
gcccaaggct ttgttgtaggagcaatgactgttggtatgggctattccatgtatcgggaa300
ttctgggcaa aacctaagcct 321
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
117/177
<210> 109
<211> 1050
<212> DNA
<213> Homo Sapience
<400> 109
atgtctgaggtgaagagccggaagaagtcggggcccaagggagcccctgctgcggagccc60
gggaagcggagcgagggcgggaagacccccgtggcccggagcagcggaggcgggggctgg120
gcagacccccgaacgtgcctgagcctgctgtcgctggggacgtgcctgggcctggcctgg180
tttgtatttcagcagtcagaaaaatttgcaaaggtggaaaaccaataccagttactgaaa240
ctagaaaccaatgaattccaacaacttcaaagtaaaatcagtttaatttcagaaaagtgg300
cagaaatctgaagctatcatggaacaattgaagtcttttcaastaattgctcatctasag360
cgtctacaggaagsaattaatgaggtaaaaacttggtccaataggataactgaaaaacag420
gatatactgaacaacagtctgacgacgctttctcaagacattacaaaagtagaccaaagt480
acaacttccatggcaaasgatgttggtctcsagattacaagtgtaaaaacagatatacga540
cggatttcaggtttagtaactgatgtaatatcattgacagattctgtgcaagaactagaa600
sataaaatagagaaagtagaaaaeaatacagtaaaaaatataggtgatcttctttcaagc660
agtattgatcgaacagcaacgctccgasagacagcatctgaaaattcacaaagaattaac720
tctgttaagaagacgctaaccgaactasagagtgacttcgacaaacatacagatagattt780
ctaagcttagaaggtgacagagccaaagttctgaagacagtgacttttgcaaatgatcta840
asaccaseggtgtataatctaaagaaggacttttcccgtttagaaccattagtasatgat900
ttaacactacgcattgggagattggttaccgacttactacaaagagagaaagaaattgct960
ttcttaagtgaaaasatatctaatttaacaatagtccaagctgagattaaggatattaaa1020
gatgaaatagcacacatttcagatatgaat 1050
<210> 110
<211> 321
<212> DNA
<213> HomoSapience
<400> 110
atgtcctcag caggcacagc aacccctctg gaaatggatc acaaactcac ttctcagcca 60
ggcaggccaa gcttctattg taacagtagg cacagtatag tcggatcatc acatcagctg 120
ggtttttggt ttagtcatct agagtcgtct ggactaaagg tctttcaggt ctccttgccc 180
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
11$/17?
tgtgagtgcg tgascctccc cacccgaatt gcctcagttg tcctgagcct catgtctctc 240
ctggtggtgg gccaggcccc tgcatgggaa gggagcctgc tgcggggcag gccagctggg 300
ggtgctcacc tatgcgcagc a 321
<210> 111
<211> 1619
<212> DNA
<213> Homo Sapience
<220>
IO <221> CDS
<222> (158)...(1234)
<400> 111
agaagagggg gctagctagc tgtctctgcg gaccagggag acccccgcgc ccccccggtg 60
I5 tgaggcggcc tcacagggcc gggtgggctg gcgagccgac gcggcggcgg aggaggctgt 120
gaggagtgtg tggaacagga cccgggacag aggaacc atg get ccg cag aac ctg 175
Met Ala Pro Gln Asn Leu
1 5
agc accttttgc ctgttgctgcta tacctcatcggggcg attgcc 223
gtg
20 Ser ThrPheCys LeuLeuLeuLeu TyrLeuIleGlyAlaVal IleAla
10 15 ~ 20
gga cgagatttc tataagatcttg ggggtgcctcgaagtgcc tctata 271
Gly ArgAspPhe TyrLysIleLeu GlyValProArgSerAla SerIle
25 30 35
25 aag gatattaaa saggcctatagg aaactagccctgcagctt catccc 319
Lys AspIleLys LysAlsTyrArg LysLeuAlaLeuGlnLeu HisPro
40 45 50
gac cggaaccct gatgatccacaa gcccaggagaaattccag gatctg 367
Asp ArgAsnPro AspAspProGln AlaGlnGluLysPheGln AspLeu
30 55 60 65 70
ggt getgettat gaggttctgtca gatagtgagaaacggaaa cagtac 415
Gly AlaAlaTyr GluValLeuSer AspSerGluLysArgLys GlnTyr
75 80 85
gat acttatggt gasgaaggatta aaagatggtcatcagagc tcccat 463
35 Asp Thr Tyr Gly Glu Glu Gly Leu Lys Asp Gly His Gln Ser Ser His
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
119/177
90 95 100
gga gac att ttt tca cac ttc ttt ggg gat ttt ggt ttc atg ttt gga 511
Gly Asp Ile Phe Ser His Phe Phe Gly Asp Phe Gly Phe Met Phe Gly
105 110 115
gga acc cct cgt cag caa gac aga aat att cca aga gga agt gat att 559
Gly Thr Pro Arg Gln Gln Asp Arg Asn Ile Pro Arg Gly Ser Asp Ile
120 125 130
att gta gat cta gaa gtc act ttg gaa gaa gta tat gca gga aat ttt 607
Ile Val Asp Leu Glu Val Thr Leu Glu Glu Val Tyr Ala Gly Asn Phe
135 140 145 ~5n
gtg gaa gta gtt aga aac asa cct gtg gca agg cag get cct ggc aaa 655
Val Glu Val Val Arg Asn Lys Pro Val Ala Arg Gln Ala Pro Gly Lys
155 160 165
cgg aag tgc aat tgt cgg caa gag atg cgg acc acc cag ctg ggc cct 703
Arg Lys Cys Asn Cys Arg Gln Glu Met Arg Thr Thr Gln Leu Gly Pro
170 175 180
ggg cgc ttc caa atg acc cag gag gtg gtc tgc gac gaa tgc cct sat 751
Gly Arg Phe Gln Met Thr Gln Glu Val Val Cys Asp Glu Cys Pro Asn
185 190 195
gtc aaa cta gtg aat gaa gaa cga acg ctg gaa gta gaa ata gag cct 799
Val Lys Leu Val Asn Glu Glu Arg Thr Leu Glu Val Glu Ile Glu Pro
200 205 210
ggg gtg aga gac ggc atg gag tac ccc ttt att gga gaa ggt gag cct 847
Gly Val Arg Asp Gly Met Glu Tyr Pro Phe Ile Gly Glu Gly Glu Pro
215 220 225 230
cac gtg gat ggg gag cct gga gat tta cgg ttc cga atc aas gtt gtc 895
His Val Asp Gly Glu Pro Gly Asp Leu Arg Phe Arg Ile Lys Val Val
235 240 245
aag cac cca ata ttt gaa agg aga gga gat gat ttg tac aca aat gtg ' 943
Lys His Pro Ile Phe Glu Arg Arg Gly Asp Asp Leu Tyr Thr Asn Val
250 255 260
aca atc tca tta gtt gag tca ctg gtt ggc ttt gag atg gat att act 991
Thr Ile Ser Leu Val Glu Ser Leu Val Gly Phe Glu Met Asp Ile Thr
265 270 275
cac ttg gat ggt cac aag gta cat att tcc cgg gat aag atc acc agg 1039
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/0392'9
120/177
His Leu Asp Gly His Lys Val His Ile Ser Arg Asp Lys Ile Thr Arg
280 285 290
cca gga gcg aag cta tgg aag aaa ggg gaa ggg ctc ccc eac ttt gac 1087
Pro Gly Ala Lys Leu Trp Lys Lys Gly Glu Gly Leu Pro Asn Phe Asp
295 300 305 310
aac aac aat atc aag ggc tct ttg ata atc act ttt gat gtg gat ttt 1135
Asn Asn Asn Ile Lys Gly Ser Leu Ile Ile Thr Phe Asp Val Asp Phe
315 320 325
cca aaa gaa cag tta aca gag gaa gcg aga gaa ggt atc aaa cag cta 1183
Pro Lys Glu Gln Leu Thr Glu Glu Ala Arg Glu Gly Ile Lys Gln Leu
330 335 340
ctg aaa caa ggg tca gtg cag aag gta tac aat gga ctg caa gga tat 1231
Leu Lys Gln Gly Ser Val Gln Lys Val Tyr Asn Gly Leu Gln Gly Tyr
345 350 355
tgagagtga actttgttta ataagcgatatttattatct1290
ataaeattgg aaataagtga
gcaaggtttttttgtgtgtgtttttgtttttattttcaatatgcaagttaggcttaattt1350
ttttatctaatgatcatcatgaaatgaataagagggcttaagaatttgtccatttgcatt1410
cggaaaagaatgaccagcaaaaggtttactaatacctctccctttggggatttaatgtct1470
ggtgctgccgcctgagtttcaagaattasagctgcaagaggactccaggagcasaagasa1530
cacaatatagagggttggagttgttagcaatttcattcaaaatgcceactggagaagtct1590
gtttttaastacattttgttgttattttt 1619
<210> 112
<211> 2054
<212> DNA
<213> HomoSapience
<220>
<221> CDS
<222> (254)...(934)
<400> 112
cacatggcca agtccgcccc gccccctccc cgtccccgcc gctgcagcgg tcgccttcgg 60
agcgaagggt accgacccgg cagaagctcg gagctctcgg ggtatcgagg aggcaggccc 120
gcgggcgcac gggcgagcgg gccgggagcc ggagcggcgg aggagccggc agcagcggcg 180
cggcgggctc caggcgaggc ggtcgacgct cctgaaaact tgcgcgcgcg ctcgcgccac 240
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
121/177
tgcgcccgga gcg atg sag atg gtc gcg ccc tgg acg cgg ttc tac tcc 289
Met Lys Met Val Ala Pro Trp Thr Arg Phe Tyr Ser
1 5 10
aac agc tgc tgc ttg tgc tgc cat gtc cgc acc ggc acc atc ctg ctc 337
Asn Ser Cys Cys Leu Cys Cys His Val Arg Thr Gly Thr Ile Leu Leu
20 25
ggc gtc tgg tat ctg atc atc aat get gtg gta ctg ttg att tta ttg 385
Gly Val Trp Tyr Leu Ile Ile Asn Ala Val Val Leu Leu Ile Leu Leu
30 35 ~ 40
10 agt gcc ctg get gat ccg gat cag tat aac ttt tca agt tct gaa ctg 433
Ser Ala Leu Ala Asp Pro Asp Gln Tyr Asn Phe Ser Ser Ser Glu Leu
45 50 55 60
gga ggt gac ttt gag ttc atg gat gat gcc aac atg tgc att gcc att 481
Gly Gly Asp Phe Glu Phe Met Asp Asp Ala Asn Met Cys Ile Ala Ile
15 65 70 75
gcg att tct ctt ctc atg atc ctg ata tgt get atg get act tac gga 529
Ala Ile Ser Leu Leu Met Ile Leu Ile Cys Ala Met Ala Thr Tyr Gly
80 85 90
gcg tac aag caa cgc gca gcc tgg atc atc cca ttc ttc tgt tac cag 577
Ala Tyr Lys Gln Arg Ala Ala Trp Ile Ile Pro Phe Phe Cys Tyr Gln
95 100 105
atc ttt gac ttt gcc ctg aac atg ttg gtt gca atc act gtg ctt att 625
Ile Phe Asp Phe Ala Leu Asn Met Leu Val Ala Ile Thr Val Leu Ile
110 115 120
tat cca aac tcc att cag gaa tac ata cgg caa ctg cct cct eat ttt 673
Tyr Pro Asn Ser Ile Gln Glu Tyr Ile Arg Gln Leu Pro Pro Asn Phe
125 130 135 140
ccc tac aga gat gat gtc atg tca gtg aat cct acc tgt ttg gtc ctt 721
Pro Tyr Arg Asp Asp Val Met Ser Val Asn Pro Thr Cys Leu Val Leu
145 150 155
att att ctt ctg ttt att agc att atc ttg act ttt aag ggt tac ttg 769
Ile Ile Leu Leu Phe Ile Ser Ile Ile Leu Thr Phe Lys Gly Tyr Leu
160 165 170
att agc tgt gtt tgg aac tgc tac cga tac atc aat ggt agg aac tcc 8I7
Ile Ser Cys Val Trp Asn Cys Tyr Arg Tyr Ile Asn Gly Arg Asn Ser
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
122/1??
175 180 185
tct gat gtc ctg gtt tat gtt acc agc aat gac act acg gtg ctg cta 865
Ser Asp Val Leu Val Tyr Val Thr Ser Asn Asp Thr Thr Val Leu Leu
190 195 200
ccc ccg tat gat gat gcc act gtg eat ggt get gcc eag gag cca ccg 913
Pro Pro Tyr Asp Asp Ala Thr Val Asn Gly Ala Ala Lys Glu Pro Pro
205 2I0 215 220
cca cct tac gtg tct gcc taagccttca agtgggcgga gctgagggc 960
Pro Pro Tyr Val Ser Ala
225
agcagcttga ctttgcagac atctgagcaa tagttctgtt atttcacttt tgccatgagc 1020
ctctctgagc ttgtttgttg ctgaaatgct actttttaaa atttagatgt tagattgaaa 1080
actgtagttt tcaacatatg ctttgctgga acactgtgat agattaactg tagsattctt 1140
cctgtacgat tggggatata atgggcttca ctaaccttcc ctaggcattg aaacttcccc 1200
caaatctgat ggacctagaagtctgcttttgtacctgctgggccccasagttgggcattt1260
ttctctctgt tccctctcttttgaaaatgtaaaataaaaccasaaatagacaactttttc1320
ttcagccatt ccagcatagagaacaaaaccttatggaaacaggaatgtcaattgtgtaat1380
cattgttcta attaggtaaatagaagtccttatgtatgtgttacaagaatttcccccaca1440
acatccttta tgactgaagttcaatgacagtttgtgtttggtggtasaggattttctcca1500
tggcctgaat taagaccattagaaagcaccaggccgtgggagcagtgaccatctgctgac1560
tgttcttgtg gatcttgtgtccagggacatggggtgacatgcctcgtatgtgttagaggg1620
tggaatggat gtgtttggcgctgcatgggatctggtgcccctcttctcctggattcacat1680
ccccacccag ggcccgcttttactaagtgttctgccctagattggttcaaggaggtcatc1740
caactgactt tatcaagtggaattgggatatatttgatatacttctgcctaacaacatgg1800
aaaagggttt tcttttccctgcaagctacatcctactgctttgaacttccaagtatgtct1860
agtcaccttt taaaatgtaaacattttcagaasaatgaggattgccttccttgtatgcgc1920
tttttacctt gactacctgaattgcaagggatttttatatattcatatgttacasagtca1980
gcaactctcc tgttggttcattattgaatgtgctgtaaattaagttgtttgcaattaaaa2040
caaggtttgc ccac 2054
<210>113
<211>1380
<212>DNA
<213>Homo Sapience
<220>
CA 02336225 2001-O1-24
WO 00105367 PCT/JP99/03929
123/177
<221> CDS
<222> (43)...(630)
<400> 113
gcagtctgtc tgagggcggc cgaagtggct ggctcattta ag atg agg ctt ctg 54
Met Arg Leu Leu
1
ctg ctt ctc cta gtg gcg gcg tct gcg atg gtc cgg agc gag gcc tcg 102
Leu Leu Leu Leu Val Ala Ala Ser Ala Met Val Arg Ser Glu Ala Ser
5 10 15 2p
gcc aat ctg ggc ggc gtg ccc agc aag aga tta aag atg cag tac gcc 150
Ala Asn Leu Gly Gly Val Pro Ser Lys Arg Leu Lys Met Gln Tyr Ala
25 30 35
acg ggg ccg ctg ctc aag ttc cag att tgt gtt tcc tga ggt tat agg 198
Thz Gly Pro Leu Leu Lys Phe Gln Ile Cys Val Ser Xaa Gly Tyr Arg
40 45 50
cgg gtg ttt gag gag tac atg cgg gtt att agc cag cgg tac cca gac 246
Arg Val Phe Glu Glu Tyr Met Arg VaI Ile Ser Gln Arg Tyr Pro Asp
55 60 65
atc cgc att gaa gga gag aat tac ctc cct caa cca ata tat aga cac 294
Ile Arg Ile Glu Gly Glu Asn Tyr Leu Pro Gln Pro Ile Tyr Arg His
70 75 80
ata gca tct ttc ctg tca gtc ttc saa cta gta tta ata ggc tta ata 342
Ile Ala Ser Phe Leu Ser Val Phe Lys Leu Val Leu Ile Gly Leu Ile
85 90 95 100
att gtt ggc aag gat cct ttt get ttc ttt ggc atg caa get cct agc 390
Ile Val Gly Lys Asp Pro Phe Ala Phe Phe Gly Met Gln Ala Pro Ser
105 110 11 S
atc tgg cag tgg ggc caa gaa aat aag gtt tat gca tgt atg atg gtt 438
Ile Trp Gln Trp Gly Gln Glu Asn Lys Val Tyr Ala Cys Met Met Val
120 125 130
ttc ttc ttg agc aac atg att gag eac cag tgt atg tca aca ggt gca 486
Phe Phe Leu Ser Asn Met Ile Glu Asn Gln Cys Met Ser Thr Gly Ala
135 140 145
ttt gag ata act tta aat gat gta cct gtg tgg tct aag ctg gaa tct 534
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929-
124/177
Phe Glu Ile Thr Leu Asn Asp Val Pro Val Trp Ser Lys Leu Glu Ser
150 155 160
ggt cac ctt gtt att ctt 582
ctt cca caa gac aat
tcc atg gaa
caa caa
Gly His Leu Val Ile Leu
Leu Pro Gln Asp Asn
Ser Met Glu
Gln Gln
165 1 70 175 180
atg sag at atg tca atc cac cat 627
ctc aat gat cca cga tca
gtg c
Met Lys is Met Ser Ile His His
Leu Asn Asp Pro Arg Ser
VaI H
185 190 195
tag caccacctat 680
cagcactgaa
aactcttttg
cattaaggga
tcattgcaag
agcagcgtgactgacattatg~aggcctgtactgaagacagcaagctgttagtacagacc740
agatgctttcttggcaggctcgttgtacctcttggaaaacctcaatgcaagatagtgttt800
cagtgctggcatattttggaattctgcacattcatggagtgcaataatactgtatagctt860
tccccacctcccacaaaatcacccagttaatgtgtgtgtgtgtttttttttttaaggtaa920
acattactacttgtasctttttttcttagtcatatttgaaaaagtagaaaattgagttac980
aatttgattttttttecaaagatgtctgttsaatctgttgtgcttttatatgaatatttg1040
ttttttatagtttaaaattgatcctttgggaatccagttgaagttcccasatactttata1100
agagtttatcagacatctctaatttggccatgtccagtttatacagtttacaaaatatag1160
cagatgcaagattatgggggaaatcctatattcagagtactctataaatttttgtgtatg1220
tgtgtatgtgcgtgtgattaccagagaactactaaanaaaccaactgctttttaastcct1280
attgtgtagttasagtgtcatgccttgaccaatctaatgaattgattaattaactgggcc1340
tttatacttaactaaataaasaactaagcagatatgagtt 1380
<210> 114
<211> 1292
<212> nrrA
<213> Homo Sapience
<220>
<221> CDS
<222> {113)...(1132)
<400> 114
aaaagtgcgg ctctgggctg gccgaagggg tggcgctgcg atcccgcagg gcagcgacgc 60
gactctggtg cgggccgtct tcttcccccc gagctgggcg tgcgcggccg ca atg aac I18
Met Asn
1
CA 02336225 2001-O1-24
WO 00/05367 PC'T/JP99/03929
125177
tgg gag ctg ctg ctg tgg ctg ctg gtg ctg tgc gcg ctg ctc ctg ctc 166
Trp Glu Leu Leu Leu Trp Leu Leu Val Leu Cys Ala Leu Leu Leu Leu
10 15
ttg gtg cag ctg ctg cgc ttc ctg agg get gac ggc gac ctg acg cta 214
5 Leu Val Gln Leu Leu Arg Phe Leu Arg Ala Asp Gly Asp Leu Thr Leu
20 25 30
cta tgg gcc gag tgg cag gga cga cgc cca gaa tgg gag ctg act gat 262
Leu Trp Ala Glu Trp Gln Gly Arg Arg Pro Glu Trp Glu Leu Thr Asp
35 40 45 50
atg gtg gtg tgg gtg act gga gcc tcg agt gga att ggt gag gag ctg 310
Met Val Val Trp Val Thr Gly Ala Ser Ser Gly Ile Gly Glu Glu Leu
55 60 65
get tac cag ttg tct aaa cts gga gtt tct ctt gtg ctg tca gcc aga 358
Ala Tyr Gln Leu Ser Lys Leu Gly Val Ser Leu Val Leu Ser Ala Arg
70 75 so
aga gtg cat gag ctg gas agg gtg aaa aga aga tgc cta gag aat ggc 406
Arg Val His Glu Leu Glu Arg Val Lys Arg Arg Cys Leu Glu Asn Gly
B5 90 95
aat tta aaa gaa saa gat ata ctt gtt ttg ccc ctt gac ctg acc gac 454
Asn Leu Lys Glu Lys Asp Ile Leu Val Leu Pro Leu Asp Leu Thr Asp
100 105 110
act ggt tcc cat gaa gcg get acc aaa get gtt ctc cag gag ttt ggt 502
Thr Gly Ser His Glu Ala Ala Thr Lys Ala Val Leu Gln Glu Phe Gly
115 120 125 130
aga atc gac att ctg gtc aac aat ggt gga atg tcc cag cgt tct ctg 550
Arg Ile Asp Ile Leu Val Asn Asn Gly Gly Met Ser Gln Arg Ser Leu
135 140 145
tgc atg gat acc agc ttg gat gtc tac aga aag cta ata gag ctt aac 598
Cys Met Asp Thr Ser Leu Asp Val Tyr Arg Lys Leu Ile Glu Leu Asn
150 155 160
tac tta ggg acg gtg tcc ttg aca aaa tgt gtt ctg cct cac atg atc 646
Tyr Leu Gly Thr Val Ser Leu Thr Lys Cys Val Leu Pro His Met IIe
165 170 175
gag agg aag caa gga aag att gtt act gtg aat agc atc ctg ggt atc 694
Glu Arg Lys Gln Gly Lys Ile Val Thr Val Asn Ser Ile Leu Gly Ile
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
126/177
180 185 190
ata tctgtacctctttccatt ggatactgtgetagcaag catgetctc 742
Ile SerValProLeuSerIle GlyTyrCysAlaSerLys HisAlaLeu
195 200 205 210
cgg ggtttttttsatggcctt cgaacagaacttgccaca tacccaggt 790
Arg GlyPhePheAsnGlyLeu ArgThrGluLeuAlaThr TyrProGly
215 220 225
ata atagtttctaacatttgc ccaggacctgtgcaatca aatattgtg 838
Ile IleValSerAsnIleCys ProGlyProValGlnSer AsnIleVal
230 235 240
gag aattccctagetggagae gtcacaasgactataggc aataatgga 886
Glu AsnSerLeuAlaGlyGlu ValThrLysThrIleGly AsnAsnGly
245 250 255
gac cagtcccacaagatgaca accagtcgttgtgtgcgg ctgatgtta 934
Asp GlnSerHisLysMetThr ThrSerArgCysValArg LeuMetLeu
260 265 270
atc agcatggccaatgatttg aaagaagtttggatctca gaacaacct 982
Ile SerMetAlaAsnAspLeu LysGluValTrpIleSer GluGlnPro
275 280 285 290
ttc ttgttagtaacatatttg tggcaatacatgccaacc tgggcctgg 1030
Phe LeuLeuValThrTyrLeu TrpGlnTyrMetProThr TrpAlaTrp
295 300 305
tgg ataaccaacaagatgggg aagsaaaggattgagsac tttaagagt 1078
Trp IleThrAsnLysMetGly LysLysArgIleGluAsn PheLysSer
310 315 320
ggt gtggatgcagactcttct tattttaaaatctttaag acaaaacat 1126
Gly ValAspAlaAspSerSer TyrPheLysIlePheLys ThrLysHis
325 330 335
gac tgaaaagagc tctgtactt tggagggaaa aatggaaa ac
1180
a ttcaagccac a
Asp
tgaaaacagc aatcttctta tgcttctgaa taatcaaaga ctaetttgtg gttttacttt 1240
ttaatagata tgactttgct tccaacatgg aatgasataa aaaataagta at 1292
<210> 115
CA 02336225 2001-O1-24
WO 00/05367 PCT/JP99/03929
12?/177
<211> 2168
<212> DNA
<213> Homo Sapience
<220>
<221> CDS
<222> (56)...(1519)
<400>
115
tttccgccgc cgcctgggag cccagctgtg 55
gggacccggg cccag
ctgccaggcg
atg gatggg acagagacc cggcagcggaggctggac agctgtggcaag 103
Met AspGly ThrGluThr ArgGlnArgArgLeuAsp SerCysGlyLys
1 5 10 15
cca ggggag ctggggctt cctcaccccctcagcaca ggaggactccct 151
Pro GlyGlu LeuGlyLeu ProHisProLeuSerThr GlyGlyLeuPro
20 25 30
gta gcctca gasgatgga getetcagggcccctgag agccaaagcgtg 199
Val AlaSer GluAspGly AlaLeuArgAlaProGlu SerGlnSerVal
35 40 45
acc eccsag ccactggag actgagcctagcagggag accgcctggtcc 247
Thr ProLys ProLeuGlu ThrGluProSerArgGlu ThrAlaTrpSer
50 55 60
ata ggcctt caggtgacc gtgcccttcatgtttgca ggcctgggactg 295
Ile GlyLeu GlnValThr ValProPheMetPheAla GlyLeuGlyLeu
65 70 75 80
tcc tgggcc ggcatgctt ctggactatttccagcac tggcctgtgttt 343
Ser TrpAla GlyMetLeu LeuAspTyrPheGlnHis TrpProValPhe
85 90 95
gtg gaggtg aaagacctt ttgacattggtgccgccc ctggtgggcctg 391
Val GluVal LysAspLeu LeuThrLeuValProPro LeuValGlyLeu
100 105 110
aag gggaac ctggagatg acactggcatccagactc tccacagetgcc 439
Lys GlyAsn LeuGluMet ThrLeuAlaSerArgLeu SerThrAlaAla
115 120 125
aac actgga caaattgat gacccccaggagcagcac agagtcatcagc 487
Asn Thr Gly Gln Ile Asp Asp Pro Gln Glu Gln His Arg Val Ile Ser
CA 02336225 2001-O1-24
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