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CA 02441755 2003-09-22
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Human Secreted Proteins
Field of the Invention
The present invention relates to human secreted proteins/polypeptides, and
isolated nucleic
acid molecules encoding said proteins/polypeptides, useful for detecting,
preventing, diagnosing,
prognosticating, treating, and/or ameliorating hematopoietic and hematologic
diseases and
disorders. Antibodies that bind these polypeptides are also encompassed by the
present invention.
Also encompassed by the invention are vectors, host cells, and recombinant and
synthetic methods
for producing said polynucleotides, polypeptides, and/or antibodies. The
invention further
encompasses screening methods for identifying agonists and antagonists of
polynucleotides and
polypeptides of the invention. The present invention further encompasses
methods and
compositions for inhibiting or enhancing the production and function of the
polypeptides of the
present invention.
Background of the Invention
Blood is composed of a fluid component, plasma, in which are suspended red
blood cells,
white blood cells, and platelets. This suspension, circulating through the
cardiovascular system,
forms the basis of the immune system, provides all of the body's tissues with
oxygen and
nutrients, and removes carbon dioxide and other metabolic byproducts for
excretion.
Immune cells, red blood cells, and platelets, are derived from common
precursor stem cells
and develop through a process known as hematopoiesis. During fetal life
hematopoiesis occurs in
the liver and spleen, but in the adult, hematopoiesis occurs primarily in the
bone marrow and
thymus. The stem cells from which all blood cells are derived proliferate and
differentiate into the
various blood cell lineages, (e.g., lymphoid cells (B or T cells), myeloid
cells (basophils,
eosinophils, neutrophils, macrophages, mast cells), thrombocytes (platelets),
or erythrocytes (red
blood cells)) in response to cytokines and other signals received from cells
(e.g., stromal cells) in
the bone marrow microenvironment. Many of the cytokines that promote the
growth and
differentiation of hematopoietic stem cells are known as "colony stimulating
factors". For
example, interleukin-3 (IL-3, and also known as multi~olony stimulating
factor) and granulocyte
macrophage colony stimulating 'factor (GM-CSF), which are released by
activated macrophages
and T cells, stimulate the production of macrophages and granulocytes
(myelopoiesis). Stem cell
factor (SCF, c-kit ligand) is a growth factor for primitive lymphoid and
myeloid hematopoietic
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bone marrow progenitor cells expressing the early cell surface marker CD34.
Other hematopoietic
cytokines/growth factors include, but are not limited to macrophage colony
stimulating factor (M-
CSF), granulocyte colony stimulating factor (G-CSF), and erythropoietin (EPO).
Interleukins-1, 6,
and 7 have also been shown to function as hematopoietic growth
factors/cytokines. Deficiencies
in the quantities of mature red or white blood cells, either as a result of
insufficient production or
excessive destruction, may result in anemias and/or immunodeficiencies.
In addition to the cellular component of the blood, there are a remarkable
variety of soluble
blood-borne proteins that serve important physiological functions.
Descriptions of some of the
functional classes of blood proteins, along with representative members of
these classes, are given
below.
Coagulation factors
The formation of insoluble protein aggregates at the site of vascular injury
or inflammation,
termed coagulation, is the result of multiple interacting coagulation factors
(Dahlback, B., Lancet
355:1627-32). This cascade of interdependent proteins (including Factors V,
VIII, IX, X XI, and
XII) results in the production of the protease, thrombin. Thrombin converts
blood-soluble
fibrinogen into fibrin, which polymerizes into insoluble clots that are
stabilized by the activity of
Factor XIII. This process is balanced by the activity of coagulation
inhibitors such as antithrombin
III, heparin cofactor II, Protein C and Protein S. Imbalance between pro-
clotting factors and
coagulation inhibitors leads to potentially serious medical conditions,
including improper wound
healing and the bleeding disorders hemophilia A and B, as well as excessive
clotting disorders
such as thrombosis (e.g. cerebral, coronary, and placental), pulmonary
embolus, stroke, and
coronary artery disease. For a more extensive review see Triplett, D., Clin
Chem 46:1260-9.
linmunoproteins
Blood plasma contains a number of proteins that contribute to the immune
response.
Immunoglobulin antibodies are glycoproteins with similar structural domains,
which bind to
specific antigenic invaders and trigger other components of the immune system.
The complement
cascade, a network of about 20 interacting proteins, is activated by antigen-
antibody complexes
and results in the lysis of infected cells, as well as other important immune
functions.
Immunoproteins are important tools for the diagnosis and treatment of
infection, cancer, and other
disorders. For more detailed discussion of immunoproteins see Meri, J. and
Jarva, H., Vox Sang
74 suppl. 2:291-302 and Chapter 23 of Molecular Biology of the Cell, 3'a
Edition, edited by
Alberts, B. et al.
Hormones
The blood serves as a major vehicle for hormones and other secreted signaling
molecules
that act at a site distant to their release. A number of peptide hormones
function as regulators of
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homeostatic processes. For example, parathyroid hormone and calcitonin
oppositely regulate
serum levels of calcium. Blood-borne peptide hormones that regulate
carbohydrate metabolism
include insulin, glucagon, and adrenocorticotropin hormone. Vasopressin,
angiotensin, and
bradykinin are hormones that modulate vasodilation and blood pressure.
Follicle-stimulating
hormone and leutinizing hormone play important roles in both male and female
reproductive
functions. Dysfunction of these hormones can lead to a wide spectrum of
disorders, including
osteoporosis, diabetes, psychiatric disorders, hypoglycemia, obesity,
infertility, as well as hypo-
and hypertension.
Cytokines
Cytokines are a class of circulating proteins that act primarily as
intercellular signaling
molecules regulating hematopoiesis, angiogenesis, and immune system functions.
One subgroup
of cytokines, the hematopoietins, regulates hematopoietic stem cell
differentiation to maintain the
proper number and proportions of each blood cell type. For example, the
production of
erythrocytes is stimulated by the release of erythropoietin from the kidneys
in response to
decreased blood oxygen levels. Similarly, thrombopoietin stimulates the
proliferation and
differentiation of megakaryocytes, leading to increased platelet production.
Another cytokine
subgroup, the chemokines, is secreted by cells of the immune system, and act
to coordinate the
immune response to an invading antigen. This is a large and diverse class of
proteins, and
includes RANTES, eotaxin, lymphotactin, MIP-1, and the interleukins. Many of
these
polypeptides have uses in the diagnosis and treatment of immunological
disorders and infection
(Holldack. J. et al., Med Ped Oncol Suppl 2:2-9; Chapter 23, Immunolo~y,
edited by Elgert, K.).
Carrier Proteins
A number of soluble proteins found in blood function as carriers of other
molecules such as
nutrients and waste products. Carrier proteins can also bind exogenously
delivered drugs and
influence pharmacokinetic properties such as serum half life and tissue
adsorption. Serum
albumin, comprising about half of the protein found in blood plasma, regulates
osmotic pressure of
blood, as well as binds many bioactive molecules. Transferrin is a blood
carrier protein that
regulates iron levels, while ceruloplasmin regulates copper levels. .
Thus there exists a clear need for novel polynucleotides and polypeptides (as
well as
antibodies, agonists, and antagonists) useful in diagnostic and therapeutic
methods for detecting,
preventing, diagnosing, prognosticating, treating, and/or ameliorating
hematopoietic and
hematologic diseases and disorders; such as, for example, leukemias,
lymphomas, hemophiliac,
anemias, immunodeficiency disorders (including A>DS), amongst many other
conditions. See,
e.g., "Blood Related Disorders" and "Immune Activity" sections, infra.
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Summary of the Invention
The present invention encompasses human secreted proteins/polypeptides, and
isolated
nucleic acid molecules encoding said proteins/polypeptides, useful for
detecting, preventing,
diagnosing, prognosticating, treating, and/or ameliorating hematopoietic and
hematologic diseases
and disorders. Antibodies that bind these polypeptides are also encompassed by
the present
invention; as are vectors, host cells, and recombinant and synthetic methods
for producing said
polynucleotides, polypeptides, and/or antibodies. The invention further
encompasses screening
methods for identifying agonists and antagonists of polynucleotides and
polypeptides of the
invention. The present invention also encompasses methods and compositions for
inhibiting or
enhancing the production and function of the polypeptides of the present
invention.
Detailed Description
Polynucleotides and Polyneptides of the Invention
Description of Table 1A
Table 1A summarizes information concerning certain polypnucleotides and
polypeptides of
the invention. The first column provides the gene number in the application
for each clone
identifier. The second column provides a unique clone identifier, "Clone
>Z7:", for a cDNA clone
related to each contig sequence disclosed in Table 1A. Third column, the cDNA
Clones identified
in the second column were deposited as indicated in the third column (i.e. by
ATCC Deposit No:Z
and deposit date). Some of the deposits contain multiple different clones
corresponding to the
same gene. In the fourth column, "Vector" refers to the type of vector
contained in the
corresponding cDNA Clone identified in the second column. In the fifth column,
the nucleotide
sequence identified as "NT SEQ ID NO:X" was assembled from partially
homologous
("overlapping") sequences obtained from the corresponding cDNA clone
identified in the second
column and, in some cases, from additional related cDNA clones. The
overlapping sequences
were assembled into a single contiguous sequence of high redundancy (usually
three to five
overlapping sequences at each nucleotide position), resulting in a final
sequence identified as SEQ
ID NO:X. In the sixth column, "Total NT Seq." refers to the total number of
nucleotides in the
contig sequence identified as SEQ 1D NO:X." The deposited clone may contain
all or most of
these sequences, reflected by the nucleotide position indicated as "5' NT of
Clone Seq." (seventh
column) and the "3' NT of Clone Seq." (eighth column) of SEQ ID NO:X. In the
ninth column,
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the nucleotide position of SEQ ID NO:X of the putative start codon
(methionine) is identified as
"5' NT of Start Codon." Similarly , in column ten, the nucleotide position of
SEQ >D NO:X of the
predicted signal sequence is identified as "5' NT of First AA of Signal Pep."
In the eleventh
column, the translated amino acid sequence, beginning with the methionine, is
identified as "AA
SEQ ID NO:Y," although other reading frames can also be routinely translated
using known
molecular biology techniques. The polypeptides produced by these alternative
open reading
frames are specifically contemplated by the present invention.
In the twelfth and thirteenth columns of Table 1A, the first and last amino
acid position of
SEQ ID NO:Y of the predicted signal peptide is identified as "First AA of Sig
Pep" and "Last AA
of Sig Pep." In the fourteenth column, the predicted first amino acid position
of SEQ ID NO:Y of
the secreted portion is identified as "Predicted First AA of Secreted
Portion". The amino acid
position of SEQ )D NO:Y of the last amino acid encoded by the open reading
frame is identified in
the fifteenth column as "Last AA of ORF".
SEQ ID NO:X (where X may be any of the polynucleotide sequences disclosed in
the
sequence listing) and the translated SEQ )D NO:Y (where Y may be any of the
polypeptide
sequences disclosed in the sequence listing) are sufficiently accurate and
otherwise suitable for a
variety of uses well known in the art and described further below. For
instance, SEQ )D NO:X is
useful for designing nucleic acid hybridization probes that will detect
nucleic acid sequences
contained in SEQ ID NO:X or the cDNA contained in the deposited clone. These
probes will also
hybridize to nucleic acid molecules in biological samples, thereby enabling a
variety of forensic
and diagnostic methods of the invention. Similarly, polypeptides identified
from SEQ ID NO:Y
may be used, for example, to generate antibodies which bind specifically to
proteins containing the
polypeptides and the secreted proteins encoded by the cDNA clones identified
in Table 1A and/or
elsewhere herein
Nevertheless, DNA sequences generated by sequencing reactions can contain
sequencing
errors. The errors exist as misidentified nucleotides, or as insertions or
deletions of nucleotides in
the generated DNA sequence. The erroneously inserted or deleted nucleotides
cause frame shifts
in the reading frames of the predicted amino acid sequence. In these cases,
the predicted amino
acid sequence diverges from the actual amino acid sequence, even though the
generated DNA
sequence may be greater than 99.9°Io identical to the actual DNA
sequence (for example, one base
insertion or deletion in an open reading frame of over 1000 bases).
Accordingly, for those applications requiring precision in the nucleotide
sequence or the
amino acid sequence, the present invention provides not only the generated
nucleotide sequence
identified as SEQ ID NO:X, and the predicted translated amino acid sequence
identified as SEQ
1D NO:Y, but also a sample of plasmid DNA containing a human cDNA of the
invention
deposited with the ATCC, as set forth in Table 1A. The nucleotide sequence of
each deposited
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plasmid can readily be determined by sequencing the deposited plasmid in
accordance with known
methods
The predicted amino acid sequence can then be verified from such deposits.
Moreover, the
amino acid sequence of the protein encoded by a particular plasmid can also be
directly
determined by peptide sequencing or by expressing the protein in a suitable
host cell containing
the deposited human cDNA, collecting the protein, and determining its
sequence.
Also provided in Table 1A is the name of the vector which contains the cDNA
plasmid.
Each vector is routinely used in the art. The following additional information
is provided for
convenience.
Vectors Lambda Zap (U.5. Patent Nos. 5,128,256 and 5,286,636), Uni-Zap XR
(U.5.
Patent Nos. 5,128, 256 and 5,286,636), Zap Express (U.S. Patent Nos. 5,128,256
and 5,286,636),
pBluescript (pBS) (Short, J. M. et al., Nucleic Acids Res. 16:7583-7600
(1988); Alting-Mees, M.
A. and Short, J. M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Along-Mees,
M. A. et al.,
Strategies 5:58-61 (1992)) are commercially available from Stratagene Cloning
Systems, Inc.,
11011 N. Torrey Pines Road, La Jolla, CA, 92037. pBS contains an ampicillin
resistance gene and
pBK contains a neomycin resistance gene. Phagemid pBS may be excised from the
Lambda Zap
and Uni-Zap XR vectors, and phagemid pBK may be excised from the Zap Express
vector. Both
phagemids may be transformed into E. coli strain XL-1 Blue, also available
from Stratagene
Vectors pSportl, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0, were obtained
from Life Technologies, Inc., P. O. Box 6009, Gaithersburg, MD 20897. All
Sport vectors contain
an ampicillin resistance gene and may be transformed into E. coli strain
DH10B, also available
from Life Technologies. See, for instance, Gruber, C. E., et al., Focus 15:59
(1993). Vector
lafmid BA (Bento Soares, Columbia University, New York, NY) contains an
ampicillin resistance
gene and can be transformed into E. coli strain XL-1 Blue. Vector pCR~2.1,
which is available
from Invitrogen, 1600 Faraday Avenue, Carlsbad, CA 92008, contains an
ampicillin resistance
gene and may be transformed into E. coli strain DH10B, available from Life
Technologies. See,
for instance, Clark, J. M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D.
et al.,
BiolTechnology 9: ( 1991 ).
The present invention also relates to the genes corresponding to SEQ )D NO:X,
SEQ >D
NO:Y, and/or a deposited cDNA (cDNA Clone )D). The corresponding gene can be
isolated in
accordance with known methods using the sequence information disclosed herein.
Such methods
include, but are not limited to, preparing probes or primers from the
disclosed sequence and
identifying or amplifying the corresponding gene from appropriate sources of
genomic material.
Also provided in the present invention are allelic variants, orthologs, and/or
species
homologs. Procedures known in the art can be used to obtain full-length genes,
allelic variants,
splice variants, full-length coding portions, orthologs, and/or species
homologs of genes
corresponding to SEQ )D NO:X and SEQ m NO:Y using information from the
sequences
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disclosed herein or the clones deposited with the ATCC. For example, allelic
variants and/or
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 for
allelic variants and/or
the desired homologue.
The present invention provides a polynucleotide comprising, or alternatively
consisting of,
the nucleic acid sequence of SEQ ID NO:X and/or a cDNA contained in ATCC
Deposit No.Z.
The present invention also provides a polypeptide comprising, or
alternatively, consisting of, the
polypeptide sequence of SEQ ID NO:Y, a polypeptide encoded by SEQ ID NO:X,
and/or a
polypeptide encoded by a cDNA contained in ATCC deposit No.Z. Polynucleotides
encoding a
polypeptide comprising, or alternatively consisting of the polypeptide
sequence of SEQ )D NO:Y,
a polypeptide encoded by SEQ ID NO:X and/or a polypeptide encoded by the cDNA
contained in
ATCC Deposit No.Z, are also encompassed by the invention. The present
invention further
encompasses a polynucleotide comprising, or alternatively consisting of the
complement of the
nucleic acid sequence of SEQ ID NO:X, and/or the complement of the coding
strand of the cDNA
contained in ATCC Deposit No.Z.
Description of Table 1B (Comprised of Tables 1B.1 and 1B.2)
Table 1B.1 and Table 1B.2 summarize some of the polynucleotides encompassed by
the invention (including cDNA clones related to the sequences (Clone ID:),
contig sequences
(contig identifier (Contig ID:) and contig nucleotide sequence identifiers
(SEQ )D NO:X)) and
further summarizes certain characteristics of these polynucleotides and the
polypeptides encoded
thereby. The first column of Tables 1B.1 and 1B.2 provide the gene numbers in
the application for
each clone identifier. The second column of Tables 1B.1 and 1B.2 provide
unique clone
identifiers, "Clone ID:", for cDNA clones related to each contig sequence
disclosed in Table 1A
and/or Table 1B. The third column of Tables 1B.1 and 1B.2 provide unique
contig identifiers,
"Contig ID:" for each of the contig sequences disclosed in these tables. The
fourth column of
Tables 1B.1 and 1B.2 provide the sequence identifiers, "SEQ >D NO:X", for each
of the contig
sequences disclosed in Table 1A and/or 1B.
Table 1B.1
The fifth column of Table 1B.1, "ORF (From-To)", provides the location (i.e.,
nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO:X
that delineates
the preferred open reading frame (ORF) that encodes the amino acid sequence
shown in the
sequence listing and referenced in Table 1B.1 as SEQ ID NO:Y (column 6).
Column 7 of Table
1B.1 lists residues comprising predicted epitopes contained in the
polypeptides encoded by each of
the preferred ORFs (SEQ ID NO:Y). Identification of potential immunogenic
regions was
performed according to the method of Jameson and Wolf (CABIOS, 4; 181-186
(1988));
specifically, the Genetics Computer Group (GCG) implementation of this
algorithm, embodied in
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the program PEPTIDESTRUCTURE (Wisconsin Package v10.0, Genetics Computer Group
(GCG), Madison, Wisc.). This method returns a measure of the probability that
a given residue is
found on the surface of the protein. Regions where the antigenic index score
is greater than 0.9
over at least 6 amino acids are indicated in Table 1B.1 as "Predicted
Epitopes". In particular
embodiments, polypeptides of the invention comprise, or alternatively consist
of, one, two, three,
four, five or more of the predicted epitopes described in Table 1B.1. It will
be appreciated that
depending on the analytical criteria used to predict antigenic determinants,
the exact address of the
determinant may vary slightly. Column 8 of Table 1B.1 ("Cytologic Band")
provides the
chromosomal location of polynucleotides corresponding to SEQ >Z7 NO:X.
Chromosomal location
was determined by finding exact matches to EST and cDNA sequences contained in
the NCBI
(National Center for Biotechnology Information) UniGene database. Given a
presumptive
chromosomal location, disease locus association was determined by comparison
with the Morbid
Map, derived from Online Mendelian Inheritance in Man (Online Mendelian
Inheritance in Man,
OMIMTM. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins
University
(Baltimore, MD) and National Center for Biotechnology Information, National
Library of
Medicine (Bethesda, MD) 2000. World Wide Web URL:
http://www:ncbi.nlm.nih.gov/omim/). If
the putative chromosomal location of the Query overlaps with the chromosomal
location of a
Morbid Map entry, an OMIM identification number is disclosed in Table 1B.1,
column 9 labeled
"OM1M Disease References)". A key to the OMIM reference identification numbers
is provided
in Table 5.
Table 1B.2
Column 5 of Table 1B.2, "Tissue Distribution" shows the expression profile of
tissue, cells,
and/or cell line libraries which express the polynucleotides of the invention.
The first code
number shown in Table 1B.2 column 5 (preceding the colon), represents the
tissue/cell source
identifier code corresponding to the key provided in Table 4. Expression of
these polynucleotides
was not observed in the other tissues and/or cell libraries tested. The second
number in column 5
(following the colon), represents the number of times a sequence corresponding
to the reference
polynucleotide sequence (e.g., SEQ ID NO:X) was identified in the
corresponding tissue/cell
source. Those tissue/cell source identifier codes in which the first two
letters are "AR" designate
information generated using DNA array technology. Utilizing this technology,
cDNAs were
amplified by PCR and then transferred, in duplicate, onto the array. Gene
expression was assayed
through hybridization of first strand cDNA probes to the DNA array. cDNA
probes were generated
from total RNA extracted from a variety of different tissues and cell lines.
Probe synthesis was
performed in the presence of 33P dCTP, using oligo(dT) to prime reverse
transcription. After
hybridization, high stringency washing conditions were employed to remove non-
specific hybrids
from the array. The remaining signal, emanating from each gene target, was
measured using a
Phosphorimager. Gene expression was reported as Phosphor Stimulating
Luminescence (PSL)
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which reflects the level of phosphor signal generated from the probe
hybridized to each of the gene
targets represented on the array. A local background signal subtraction was
performed before the
total signal generated from each array was used to normalize gene expression
between the
different hybridizations. The value presented after "[array code]:" represents
the mean of the
duplicate values, following background subtraction and probe normalization.
One of skill in the
art could routinely use this information to identify normal and/or diseased
tissues) which show a
predominant expression pattern of the corresponding polynucleotide of the
invention or to identify
polynucleotides which show predominant and/or specific tissue and/or cell
expression.
Description of Table 1C
Table 1C summarizes additional polynucleotides encompassed by the invention
(including
cDNA clones related to the sequences (Clone ID:), contig sequences (contig
identifier (Contig
)D:) contig nucleotide sequence identifiers (SEQ ID NO:X)), and genomic
sequences (SEQ ID
NO:B). The first column provides a unique clone identifier, "Clone ID:", for a
cDNA clone
related to each contig sequence. The second column provides the sequence
identifier, "SEQ lD
NO:X", for each contig sequence. The third column provides a unique contig
identifier, "Contig
ID:" for each contig sequence. The fourth column, provides a BAC identifier
"BAC ID NO:A" for
the BAC clone referenced in the corresponding row of the table. The fifth
column provides the
nucleotide sequence identifier, "SEQ ID NO:B" for a fragment of the BAC clone
identified in
column four of the corresponding row of the table. The sixth column, "Exon
From-To", provides
the location (i.e., nucleotide position numbers) within the polynucleotide
sequence of SEQ ID
NO:B which delineate certain polynucleotides of the invention that are also
exemplary members of
polynucleotide sequences that encode polypeptides of the invention (e.g.,
polypeptides containing
amino acid sequences encoded by the polynucleotide sequences delineated in
column six, and
fragments and variants thereof).
Description of Table 1D
Table 1D: In preferred embodiments, the present invention encompasses a method
of
detecting, preventing, diagnosing, prognosticating, treating, and/or
ameliorating hematopoietic and
hematologic diseases and disorders; comprising administering to a patient in
which such treatment,
prevention, or amelioration is desired a protein, nucleic acid, or antibody of
the invention (or
fragment or variant thereof) represented by Table 1A, Table 1B, and Table 1C,
in an amount
effective to detect, prevent, diagnose, prognosticate, treat, and/or
ameliorate the disease or
disorder.
As indicated in Table 1D, the polynucleotides, polypeptides, agonists, or
antagonists of the
present invention (including antibodies) can be used in assays to test for one
or more biological
activities. If these polynucleotides and polypeptides do exhibit activity in a
particular assay, it is
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likely that these molecules may be involved in the diseases associated with
the biological activity.
Thus, the polynucleotides or polypeptides, or agonists or antagonists thereof
(including antibodies)
could be used to treat the associated disease.
Table 1D provides information related to biological activities for
polynucleotides and
polypeptides of the invention (including antibodies, agonists, and/or
antagonists thereof). Table
1D also provides information related to assays which may be used to test
polynucleotides and
polypeptides of the invention (including antibodies, agonists, and/or
antagonists thereof) for the
corresponding biological activities. The first column ("Gene No.") provides
the gene number in
the application for each clone identifier. The second column ("cDNA Clone
)D:") provides the
unique clone identifier for each clone as previously described and indicated
in Tables 1A, 1B, and
1C. The third column ("AA SEQ 1D NO:Y") indicates the Sequence Listing SEQ 1D
Number for
polypeptide sequences encoded by the corresponding cDNA clones (also as
indicated in Tables
1A, 1B, and 2). The fourth column ("Biological Activity") indicates a
biological activity
corresponding to the indicated polypeptides (or polynucleotides encoding said
polypeptides). The
fifth column ("Exemplary Activity Assay") further describes the corresponding
biological activity
and provides information pertaining to the various types of assays which may
be performed to test,
demonstrate, or quantify the corresponding biological activity. Table 1D
describes the use of
FMAT technology, inter alia, for testing or demonstrating various biological
activities.
Fluorometric microvolume assay technology (FMAT) is a fluorescence-based
system which
provides a means to perform nonradioactive cell- and bead-based assays to
detect activation of cell
signal transduction pathways. This technology was designed specifically for
ligand binding and
immunological assays. Using this technology, fluorescent cells or beads at the
bottom of the well
are detected as localized areas of concentrated fluorescence using a data
processing system.
Unbound flurophore comprising the background signal is ignored, allowing for a
wide variety of
homogeneous assays. FMAT technology may be used for peptide ligand binding
assays,
immunofluorescence, apoptosis, cytotoxicity, and bead-based immunocapture
assays. See,
Miraglia S et. al., "Homogeneous cell and bead based assays for highthroughput
screening using
flourometric microvolume assay technology," Journal of Biomolecular Screening;
4:193-204
( 1999). In particular, FMAT technology may be used to test, confirm, and/or
identify the ability of
polypeptides (including polypeptide fragments and variants) to activate signal
transduction
pathways. For example, FMAT technology may be used to test, confirm, and/or
identify the
ability of polypeptides to upregulate production of immunomodulatory proteins
(such as, for
example, interleukins, GM-CSF, Rantes, and Tumor Necrosis factors, as well as
other cellular
regulators (e.g. insulin)).
Table 1D also describes the use of kinase assays for testing, demonstrating,
or quantifying
biological activity. In this regard, the phosphorylation and de-
phosphorylation of specific amino
acid residues (e.g. Tyrosine, Serine, Threonine) on cell-signal transduction
proteins provides a fast,
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reversible means for activation and de-activation of cellular signal
transduction pathways.
Moreover, cell signal transduction via phosphorylation/de-phosphorylation is
crucial to the
regulation of a wide variety of cellular processes (e.g. proliferation,
differentiation, migration,
apoptosis, etc.). Accordingly, kinase assays provide a powerful tool useful
for testing, confirming,
and/or identifying polypeptides (including polypeptide fragments and variants)
that mediate cell
signal transduction events via protein phosphorylation. See e.g., Forrer, P.,
Tamaskovic R., and
Jaussi, R. "Enzyme-Linked Immunosorbent Assay for Measurement of JNK, ERK, and
p38 Kinase
Activities" Biol. Chem. 379(8-9): 1101-1110 (1998).
Description of Table 1E
Polynucleotides encoding polypeptides of the present invention can be used in
assays to
test for one or more biological activities. One such biological activity which
may be tested
includes the ability of polynucleotides and polypeptides of the invention to
stimulate up-regulation
or down-regulation of expression of particular genes and proteins. Hence, if
polynucleotides and
polypeptides of the present invention exhibit activity in altering particular
gene and protein
expression patterns, it is likely that these polynucleotides and polypeptides
of the present invention
may be involved in, or capable of effecting changes in, diseases associated
with the altered gene
and protein expression profiles. Hence, polynucleotides, polypeptides, or
antibodies of the present
invention could be used to treat said associated diseases.
TaqMan~ assays may be performed to assess the ability of polynucleotides (and
polypeptides they encode) to alter the expression pattern of particular
"target" genes. TaqMan~
reactions are performed to evaluate the ability of a test agent to induce or
repress expression of
specific genes in different cell types. TaqMan~ gene expression quantification
assays
("TaqMan~ assays") are well known to, and routinely performed by, those of
ordinary skill in the
art. TaqMan~ assays are performed in a two step reverse transcription /
polymerase chain
reaction (RT-PCR). In the first (RT) step, cDNA is reverse transcribed from
total RNA samples
using random hexamer primers. In the second (PCR) step, PCR products are
synthesized from the
cDNA using gene specific primers.
To quantify gene expression the Taqman~ PCR reaction exploits the 5' nuclease
activity
of AmpliTaq Gold~ DNA Polymerase to cleave a Taqman~ probe (distinct from the
primers)
during PCR. The Taqman~ probe contains a reporter dye at the 5'-end of the
probe and a
quencher dye at the 3' end of the probe. When the probe is intact, the
proximity of the reporter
dye to the quencher dye results in suppression of the reporter fluorescence.
During PCR, if the
target of interest is present, the probe specifically anneals between the
forward and reverse primer
sites. AmpliTaq Fold DNA Polymerase then cleaves the probe between the
reporter and quencher
when the probe hybridizes to the target, resulting in increased fluorescence
of the reporter (see
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Figure 2). Accumulation of PCR products is detected directly by monitoring the
increase in
fluorescence of the reporter dye.
After the probe fragments are displaced from the target, polymerization of the
strand
continues. The 3'-end of the probe is blocked to prevent extension of the
probe during PCR. This
process occurs in every cycle and does not interfere with the exponential
accumulation of product.
The increase in fluorescence signal is detected only if the target sequence is
complementary to the
probe and is amplified during PCR. Because of these requirements, any
nonspecific amplification
is not detected.
For test sample preparation, vector controls or constructs containing the
coding sequence
for the gene of interest are transfected into cells, such as for example 293T
cells, and supernatants
collected after 48 hours. For cell treatment and RNA isolation, multiple
primary human cells or
human cell lines are used; such cells may include but are not limited to,
Normal Human Dermal
Fibroblasts, Aortic Smooth Muscle, Human Umbilical Vein Endothelial Cells,
HepG2, Daudi,
Jurkat, U937, Caco, and THP-1 cell lines. Cells are plated in growth media and
growth is arrested
by culturing without media change for 3 days, or by switching cells to low
serum media and
incubating overnight. Cells are treated for 1, 6, or 24 hours with either
vector control supernatant
or sample supernatant (or purified/partially purified protein preparations in
buffer). Total RNA is
isolated; for example, by using Trizol extraction or by using the Ambion
RNAqueous(TM)-4PCR
RNA isolation system. Expression levels of multiple genes are analyzed using
TAQMAN, and
expression in the test sample is compared to control vector samples to
identify genes induced or
repressed. Each of the above described techniques are well known to, and
routinely performed by,
those of ordinary skill in the art.
Table 1E indicates particular disease classes and preferred indications for
which
polynucleotides, polypeptides, or antibodies of the present invention may be
used in detecting,
diagnosing, preventing, treating and/or ameliorating said diseases and
disorders based on "target"
gene expression patterns which may be up- or down-regulated by polynucleotides
(and the
encoded polypeptides) corresponding to each indicated cDNA Clone m (shown in
Table 1E,
Column 2).
Thus, in preferred embodiments, the present invention encompasses a method of
detecting, diagnosing, preventing, treating, and/or ameliorating a disease or
disorder listed in the
"Disease Class" and/or "Preferred Indication" columns of Table 1E; comprising
administering to a
patient in which such detection, diagnosis, prevention, or treatment is
desired a protein, nucleic
acid, or antibody of the invention (or fragment or variant thereof) in an
amount effective to detect,
diagnose, prevent, treat, or ameliorate the disease or disorder. The first and
second columns of
Table 1D show the "Gene No." and "cDNA Clone >D No.", respectively, indicating
certain nucleic
acids and proteins (or antibodies against the same) of the invention
(including polynucleotide,
polypeptide, and antibody fragments or variants thereof) that may be used in
detecting, diagnosing,
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preventing, treating, or ameliorating the diseases) or disorders) indicated in
the corresponding
row in the "Disease Class" or "Preferred Indication" Columns of Table 1E.
In another embodiment, the present invention also encompasses methods of
detecting,
diagnosing, preventing, treating, or ameliorating a disease or disorder listed
in the "Disease Class"
or "Preferred Indication" Columns of Table 1E; comprising administering to a
patient
combinations of the proteins, nucleic acids, or antibodies of the invention
(or fragments or variants
thereof), sharing similar indications as shown in the corresponding rows in
the "Disease Class" or
"Preferred Indication" Columns of Table 1E.
The "Disease Class" Column of Table 1E provides a categorized descriptive
heading
for diseases, disorders, and/or conditions (more fully described below) that
may be detected,
diagnosed, prevented, treated, or ameliorated by a protein, nucleic acid, or
antibody of the
invention (or fragment or variant thereof).
The "Preferred Indication" Column of Table 1E describes diseases, disorders,
and/or
conditions that may be detected, diagnosed, prevented, treated, or ameliorated
by a protein, nucleic
acid, or antibody of the invention (or fragment or variant thereof).
The "Cell Line" and "Exemplary Targets" Columns of Table 1E indicate
particular cell
lines and target genes, respectively, which may show altered gene expression
patterns (i.e., up- or
down-regulation of the indicated target gene) in Taqman assays, performed as
described above,
utilizing polynucleotides of the cDNA Clone ID shown in the corresponding row.
Alteration of
expression patterns of the indicated "Exemplary Target" genes is correlated
with a particular
"Disease Class" and/or "Preferred Indication" as shown in the corresponding
row under the
respective column headings.
The "Exemplary Accessions" Column indicates GenBank Accessions (available
online
through the National Center for Biotechnology Information (NCBI) at
httn://www.ncbi.nlm.nih.~ov/) which correspond to the "Exemplary Targets"
shown in the
adjacent row.
The recitation of "Cancer" in the "Disease Class" Column indicates that the
corresponding nucleic acid and protein, or antibody against the same, of the
invention (or fragment
or variant thereof) may be used for example, to detect, diagnose, prevent,
treat, and/or ameliorate
neoplastic diseases and/or disorders (e.g., leukemias, cancers, etc., as
described below under
"Hyperproliferative Disorders")
The recitation of "Immune" in the "Disease Class" column indicates that the
corresponding nucleic acid and protein, or antibody against the same, of the
invention (or fragment
or variant thereof), may be used for example, to detect, diagnose, prevent,
treat, and/or ameliorate
diseases and/or disorders relating to neoplastic diseases (e.g., as described
below under
"Hyperproliferative Disorders"), blood disorders (e.g., as described below
under "Immune
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Activity" "Cardiovascular Disorders" and/or "Blood-Related Disorders"), and
infections (e.g., as
described below under "Infectious Disease").
The recitation of "Angiogenesis" in the "Disease Class" column indicates that
the
corresponding nucleic acid and protein, or antibody against the same, of the
invention (or fragment
or variant thereof), may be used for example, to detect, diagnose, treat,
prevent, and/or ameliorate
diseases and/or disorders relating to neoplastic diseases (e.g., as described
below under
"Hyperproliferative Disorders"), diseases and/or disorders of the
cardiovascular system (e.g., as
described below under "Cardiovascular Disorders"), diseases and/or disorders
involving cellular
and genetic abnormalities (e.g., as described below under "Diseases at the
Cellular Level"),
diseases and/or disorders involving angiogenesis (e.g., as described below
under "Anti-
Angiogenesis Activity"), to promote or inhibit cell or tissue regeneration
(e.g., as described below
under "Regeneration"), or to promote wound healing (e.g., as described below
under "Wound
Healing and Epithelial Cell Proliferation").
The recitation of "Diabetes" in the "Disease Class" column indicates that the
corresponding nucleic acid and protein, or antibody against the same, of the
invention (or fragment
or variant thereof), may be used for example, to detect, diagnose, treat,
prevent, and/or ameliorate
diabetes (including diabetes mellitus types I and II), as well as diseases
and/or disorders associated
with, or consequential to, diabetes (e.g. as described below under "Endocrine
Disorders," "Renal
Disorders," and "Gastrointestinal Disorders").
Description of Table 2
Table 2 summarizes homology and features of some of the polypeptides of the
invention.
The first column provides a unique clone identifier, "Clone ID:",
corresponding to a cDNA clone
disclosed in Table 1A or Table 1B. The second column provides the unique
contig identifier,
"Contig >D:" corresponding to contigs in Table 1B and allowing for correlation
with the
information in Table 1B. The third column provides the sequence identifier,
"SEQ 1D NO:X", for
the contig polynucleotide sequence. The fourth column provides the analysis
method by which the
homology/identity disclosed in the Table was determined. Comparisons were made
between
polypeptides encoded by the polynucleotides of the invention and either a non-
redundant protein
database (herein referred to as "NR"), or a database of protein families
(herein referred to as
"PFAM") as further described below. The fifth column provides a description of
the PFAM/NR
hit having a significant match to a polypeptide of the invention. Column six
provides the
accession number of the PFAM/NR hit disclosed in the fifth column. Column
seven,
"Score/Percent Identity", provides a quality score or the percent identity, of
the hit disclosed in
columns five and six. Columns 8 and 9, "NT From" and "NT To" respectively,
delineate the
polynucleotides in "SEQ 117 NO:X" that encode a polypeptide having a
significant match to the
PFAM/NR database as disclosed in the fifth and sixth columns. In specific
embodiments
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polypeptides of the invention comprise, or alternatively consist of, an amino
acid sequence
encoded by a polynucleotide in SEQ 1D NO:X as delineated in columns 8 and 9,
or fragments or
variants thereof.
Description of Table 3
Table 3 provides polynucleotide sequences that may be disclaimed according to
certain
embodiments of the invention. The first column provides a unique clone
identifier, "Clone 1D",
for a cDNA clone related to contig sequences disclosed in Table 1B. The second
column provides
the sequence identifier, "SEQ 1D NO:X", for contig sequences disclosed in
Table 1A and/or Table
1B. The third column provides the unique contig identifier, "Contig ID:", for
contigs disclosed in
Table 1B. The fourth column provides a unique integer 'a' where 'a' is any
integer between 1 and
the final nucleotide minus 15 of SEQ ID NO:X, and the fifth column provides a
unique integer 'b'
where 'b' is any integer between 15 and the final nucleotide of SEQ ID NO:X,
where both a and b
correspond to the positions of nucleotide residues shown in SEQ ID NO:X, and
where b is greater
than or equal to a + 14. For each of the polynucleotides shown as SEQ ID NO:X,
the uniquely
defined integers can be substituted into the general formula of a-b, and used
to describe
polynucleotides which may be preferably excluded from the invention. In
certain embodiments,
preferably excluded from the invention are at least one, two, three, four,
five, ten, or more of the
polynucleotide sequences) having the accession numbers) disclosed in the sixth
column of this
Table (including for example, published sequence in connection with a
particular BAC clone). In
further embodiments, preferably excluded from the invention are the specific
polynucleotide
sequences) contained in the clones corresponding to at least one, two, three,
four, five, ten, or
more of the available material having the accession numbers identified in the
sixth column of this
Table (including for example, the actual sequence contained in an identified
BAC clone).
Description of Table 4
Table 4 provides a key to the tissue/cell source identifier code disclosed in
Table 1B.2,
column 5. Column 1 of Table 4 provides the tissue/cell source identifier code
disclosed in Table
1B.2, Column 5. Columns 2-5 provide a description of the tissue or cell
source. Note that
"Description" and "Tissue" sources (i.e. columns 2 and 3) having the prefix
"a_" indicates organs,
tissues, or cells derived from "adult" sources. Codes corresponding to
diseased tissues are
indicated in column 6 with the word "disease." The use of the word "disease"
in column 6 is non-
limiting. The tissue or cell source may be specific (e.g. a neoplasm), or may
be disease-associated
(e.g., a tissue sample from a normal portion of a diseased organ).
Furthermore, tissues and/or cells
lacking the "disease" designation may still be derived from sources directly
or indirectly involved
in a disease state or disorder, and therefore may have a further utility in
that disease state or
disorder. In numerous cases where the tissue/cell source is a library, column
7 identifies the vector
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used to generate the library.
Description of Table 5
Table 5 provides a key to the OMIM reference identification numbers disclosed
in Table
IB.1, column 9. OMIM reference identification numbers (Column 1) were derived
from Online
Mendelian Inheritance in Man (Online Mendelian Inheritance in Man, OMIM.
McKusick-Nathans
Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and
National Center
for Biotechnology Information, National Library of Medicine, (Bethesda, MD)
2000. World Wide
Web URL: http://www.ncbi.nlm.nih.gov/omimn. Column 2 provides diseases
associated with the
cytologic band disclosed in Table 1B.1, column 8, as determined using the
Morbid Map database.
Description of Table 6
Table 6 summarizes some of the ATCC Deposits, Deposit dates, and ATCC
designation
numbers of deposits made with the ATCC in connection with the present
application. These
deposits were made in addition to those described in the Table 1A.
Description of Table 7
Table 7 shows the cDNA libraries sequenced, and ATCC designation numbers and
vector
information relating to these cDNA libraries.
The first column shows the first four letters indicating the Library from
which each library
clone was derived. The second column indicates the catalogued tissue
description for the
corresponding libraries. The third column indicates the vector containing the
corresponding
clones. The fourth column shows the ATCC deposit designation for each libray
clone as indicated
by the deposit information in Table 6.
Definitions
The following definitions are provided to facilitate understanding of certain
terms used
throughout this specification.
In the present invention, "isolated" refers to material removed from its
original environment
(e.g., the natural environment if it is naturally occurring), and thus is
altered "by the hand of man"
from its natural state. For example, an isolated polynucleotide could be part
of a vector or a
composition of matter, or could be contained within a cell, and still be
"isolated" because that
vector, composition of matter, or particular cell is not the original
environment of the
polynucleotide. The term "isolated" does not refer to genomic or cDNA
libraries, whole cell total
or mRNA preparations, genomic DNA preparations (including those separated by
electrophoresis
and transferred onto blots), sheared whole cell genomic DNA preparations or
other compositions
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where the art demonstrates no distinguishing features of the
polynucleotide/sequences of the
presentinvention.
In the present invention, a "secreted" protein refers to those proteins
capable of being
directed to the ER, secretory vesicles, or the extracellular space as a result
of a signal sequence, as
well as those proteins released into the extracellular space without
necessarily containing a signal
sequence. If the secreted protein is released into the extracellular space,
the secreted protein can
undergo extracellular processing to produce a "mature" protein. Release into
the extracellular
space can occur by many mechanisms, including exocytosis and proteolytic
cleavage.
As used herein, a "polynucleotide" refers to a molecule having a nucleic acid
sequence
encoding SEQ >D NO:Y or a fragment or variant thereof (e.g., the polypeptide
delinated in
columns fourteen and fifteen of Table 1A); a nucleic acid sequence contained
in SEQ )D NO:X (as
described in column 5 of Table 1A and/or column 3 of Table IB) or the
complement thereof; a
cDNA sequence contained in Clone 117: (as described in column 2 of Table IA
and/or Table 1B
and contained within a library deposited with the ATCC); a nucleotide sequence
encoding the
polypeptide encoded by a nucleotide sequence in SEQ ID NO:B as defined in
column 6 (EXON
From-To) of Table 1C or a fragment or variant thereof; or a nucleotide coding
sequence in SEQ )D
NO:B as defined in column 6 of Table 1C or the complement thereof. For
example, the
polynucleotide can contain the nucleotide sequence of the full length cDNA
sequence, including
the 5' and 3' untranslated sequences, the coding region, as well as fragments,
epitopes, domains,
and variants of the nucleic acid sequence. Moreover, as used herein, a
"polypeptide" refers to a
molecule having an amino acid sequence encoded by a polynucleotide of the
invention as broadly
defined (obviously excluding poly-Phenylalanine or poly-Lysine peptide
sequences which result
from translation of a polyA tail of a sequence corresponding to a cDNA).
In the present invention, "SEQ ID NO:X" was often generated by overlapping
sequences
contained in multiple clones (contig analysis). A representative clone
containing all or most of the
sequence for SEQ ID NO:X is deposited at Human Genome Sciences, Inc. (HGS) in
a catalogued
and archived library. As shown, for example, in column 2 of Table 1B, each
clone is identified by
a cDNA Clone ID (identifier generally referred to herein as Clone >D:). Each
Clone ID is unique to
an individual clone and the Clone )D is all the information needed to retrieve
a given clone from
the HGS library. Table 7 provides a list of the deposited cDNA libraries. One
can use the Clone
ID: to determine the library source by reference to Tables 6 and 7. Table 7
lists the deposited
cDNA libraries by name and links each library to an ATCC Deposit. Library
names contain four
characters, for example, "HTWE." The name of a cDNA clone (Clone ll~) isolated
from that
library begins with the same four characters, for example "HTWEP07". As
mentioned below,
Table 1A and/or Table 1B correlates the Clone )D names with SEQ ID NO:X. Thus,
starting with
an SEQ )D NO:X, one can use Tables 1A, 1B, 6, 7, and 9 to determine the
corresponding Clone
1D, which library it came from and which ATCC deposit the library is contained
in. Furthermore,
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it is possible to retrieve a given cDNA clone from the source library by
techniques known in the
art and described elsewhere herein. The ATCC is located at 10801 University
Boulevard,
Manassas, Virginia 20110-2209, USA. The ATCC deposits were made pursuant to
the terms of the
Budapest Treaty on the international recognition of the deposit of
microorganisms for the purposes
of patent procedure.
In specific embodiments, the polynucleotides of the invention are at least 15,
at least 30, at
least 50, at least 100, at least 125, at least 500, or at least 1000
continuous nucleotides but are less
than or equal to 300 kb, 200 kb, 100 kb, 50 kb, 15 kb, 10 kb, 7.5kb, 5 kb, 2.5
kb, 2.0 kb, or 1 kb, in
length. In a further embodiment, polynucleotides of the invention comprise a
portion of the
coding sequences, as disclosed herein, but do not comprise all or a portion of
any intron. In
another embodiment, the polynucleotides comprising coding sequences do not
contain coding
sequences of a genomic flanking gene (i.e., 5' or 3' to the gene of interest
in the genome). In other
embodiments, the polynucleotides of the invention do not contain the coding
sequence of more
than 1000, 500, 250, 100, 50, 25, 20, 15, 10, 5, 4, 3, 2, or 1 genomic
flanking gene(s).
A "polynucleotide" of the present invention also includes those
polynucleotides capable of
hybridizing, under stringent hybridization conditions, to sequences contained
in SEQ 117 NO:X, or
the complement thereof (e.g., the complement of any one, two, three, four, or
more of the
polynucleotide fragments described herein), the polynucleotide sequence
delineated in columns 7
and 8 of Table 1A or the complement thereof, the polynucleotide sequence
delineated in columns
8 and 9 of Table 2 or the complement thereof, and/or cDNA sequences contained
in Clone >D:
(e.g., the complement of any one, two, three, four, or more of the
polynucleotide fragments, or the
cDNA clone within the pool of cDNA clones deposited with the ATCC, described
herein), and/or
the polynucleotide sequence delineated in column 6 of Table 1C or the
complement thereof.
"Stringent hybridization conditions" refers to an overnight incubation at 42
degree C in a solution
comprising 50% formamide, Sx SSC (750 mM NaCI, 75 mM trisodium citrate), 50 mM
sodium
phosphate (pH 7.6), 5x Denhardt's solution, 10% dextran sulfate, and 20 p,g/ml
denatured, sheared
salmon sperm DNA, followed by washing the filters in O.lx SSC at about 65
degree C.
Also contemplated are nucleic acid molecules that hybridize to the
polynucleotides of the
present invention at lower stringency hybridization conditions. Changes in the
stringency of
hybridization and signal detection are primarily accomplished through the
manipulation of
formamide concentration (lower percentages of formamide result in lowered
stringency); salt
conditions, or temperature. For example, lower stringency conditions include
an overnight
incubation at 37 degree C in a solution comprising 6X SSPE (20X SSPE = 3M
NaCI; 0.2M
NaH2P04; 0.02M EDTA, pH 7.4), 0.5% SDS, 30% formamide, 100 ug/ml salmon sperm
blocking
DNA; followed by washes at 50 degree C with 1XSSPE, 0.1% SDS. In addition, to
achieve even
lower stringency, washes performed following stringent hybridization can be
done at higher salt
concentrations (e.g. 5X SSC).
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Note that variations in the above conditions may be accomplished through the
inclusion
and/or substitution of alternate blocking reagents used to suppress background
in hybridization
experiments. Typical blocking reagents include Denhardt's reagent, BLOTTO,
heparin, denatured
salmon sperm DNA, and commercially available proprietary formulations. The
inclusion of
specific blocking reagents may require modification of the hybridization
conditions described
above, due to problems with compatibility.
Of course, a polynucleotide which hybridizes only to polyA+ sequences (such as
any 3'
terminal polyA+ tract of a cDNA shown in the sequence listing), or to a
complementary stretch of
T (or Ln residues, would not be included in the definition of
"polynucleotide," since such a
polynucleotide would hybridize to any nucleic acid molecule containing a poly
(A) stretch or the
complement thereof (e.g., practically any double-stranded cDNA clone generated
using oligo dT
as a primer).
The polynucleotide of the present invention can be composed of any
polyribonucleotide or
polydeoxribonucleotide, which may be unmodified RNA or DNA or modified RNA or
DNA. For
example, polynucleotides can be composed of single- and double-stranded DNA,
DNA that is a
mixture of single- and double-stranded regions, single- and double-stranded
RNA, and RNA that
is mixture of single- and double-stranded regions, hybrid molecules comprising
DNA and RNA
that may be single-stranded or, more typically, double-stranded or a mixture
of single- and double-
stranded regions. In addition, the polynucleotide can be composed of triple-
stranded regions
comprising RNA or DNA or both RNA and DNA. A polynucleotide may also contain
one or
more modified bases or DNA or RNA backbones modified for stability or for
other reasons.
"Modified" bases include, for example, tritylated bases and unusual bases such
as inosine. A
variety of modifications can be made to DNA and RNA; thus, "polynucleotide"
embraces
chemically, enzymatically, or metabolically modified forms.
In specific embodiments, the polynucleotides of the invention are at least 15,
at least 30, at
least 50, at least 100, at least 125, at least 500, or at least 1000
continuous nucleotides but are less
than or equal to 300 kb, 200 kb, 100 kb, 50 kb, 15 kb, 10 kb, 7.Skb, 5 kb, 2.5
kb, 2.0 kb, or 1 kb, in
length. In a further embodiment, polynucleotides of the invention comprise a
portion of the
coding sequences, as disclosed herein, but do not comprise all or a portion of
any intron. In
another embodiment, the polynucleotides comprising coding sequences do not
contain coding
sequences of a genomic flanking gene (i.e., 5' or 3' to the gene of interest
in the genome). In other
embodiments, the polynucleotides of the invention do not contain the coding
sequence of more
than 1000, 500, 250, 100, 50, 25, 20, 15, 10, 5, 4, 3, 2, or 1 genomic
flanking gene(s).
"SEQ ID NO:X" refers to a polynucleotide sequence described in column 5 of
Table 1A,
while "SEQ )D NO:Y" refers to a polypeptide sequence described in column 10 of
Table 1A. SEQ
m NO:X is identified by an integer specified in column 6 of Table 1A. The
polypeptide sequence
SEQ 117 NO:Y is a translated open reading frame (ORF) encoded by
polynucleotide SEQ m
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NO:X. The polynucleotide sequences are shown in the sequence listing
immediately followed by
all of the polypeptide sequences. Thus, a polypeptide sequence corresponding
to polynucleotide
sequence SEQ 1D N0:2 is the first polypeptide sequence shown in the sequence
listing. The
second polypeptide sequence corresponds to the polynucleotide sequence shown
as SEQ 1D N0:3,
and so on.
The polypeptide of the present invention can be composed of amino acids joined
to each
other by peptide bonds or modified peptide bonds, i.e., peptide isosteres, and
may contain amino
acids other than the 20 gene-encoded amino acids. The polypeptides may be
modified by either
natural processes, such as posttranslational processing, or by chemical
modification techniques
which are well known in the art. Such modifications are well described in
basic texts and in more
detailed monographs, as well as in a voluminous research literature.
Modifications can occur
anywhere in a polypeptide, including the peptide backbone, the amino acid side-
chains and the
amino or carboxyl termini. It will be appreciated that the same type of
modification may be
present in the same or varying degrees at several sites in a given
polypeptide. Also, a given
polypeptide may contain many types of modifications. Polypeptides may be
branched, for
example, as a result of ubiquitination, and they may be cyclic, with or
without branching. Cyclic,
branched, and branched cyclic polypeptides may result from posttranslation
natural processes or
may be made by synthetic methods. Modifications include acetylation,
acylation, ADP-
ribosylation, amidation, covalent attachment of flavin, covalent attachment of
a heme moiety,
covalent attachment of a nucleotide or nucleotide derivative, covalent
attachment of a lipid or lipid
derivative, covalent attachment of phosphotidylinositol, cross-linking,
cyclization, disulfide bond
formation, demethylation, formation of covalent cross-links, formation of
cysteine, formation of
pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor
formation,
hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation,
proteolytic
processing, phosphorylation, prenylation, racemization, selenoylation,
sulfation, transfer-RNA
mediated addition of amino acids to proteins such as arginylation, and
ubiquitination. (See, for
instance, PROTEINS - STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E.
Creighton, W. H. Freeman and Company, New York (1993); POSTTRANSLATIONAL
COVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press, New
York, pgs. 1-12 (1983); Seifter et al., Meth. Enzymol. 182:626-646 (1990);
Rattan et al., Ann.
N.Y. Acad. Sci. 663:48-62 (1992)).
"SEQ >D NO:X" refers to a polynucleotide sequence described, for example, in
Tables 1A,
Table 1B, or Table 2, while "SEQ >D NO:Y" refers to a polypeptide sequence
described in column
11 of Table 1A and or column 6 of Table 1B.1,. SEQ ID NO:X is identified by an
integer specified
in column 4 of Table 1B. The polypeptide sequence SEQ ID NO:Y is a translated
open reading
frame (ORF) encoded by polynucleotide SEQ ID NO:X. "Clone )17:" refers to a
cDNA clone
described in column 2 of Table 1A and/or 1B.
CA 02441755 2003-09-22
WO 03/038063 PCT/US02/08277
"A polypeptide having functional activity" refers to a polypeptide capable of
displaying one
or more known functional activities associated with a full-length (complete)
protein. Such
functional activities include, but are not limited to, biological activity
(e.g. activity useful in
treating, preventing and/or ameliorating hematopoietic and hematologic
diseases and disorders),
antigenicity (ability to bind [or compete with a polypeptide for binding] to
an anti-polypeptide
antibody), immunogenicity (ability to generate antibody which binds to a
specific polypeptide of
the invention), ability to form multimers with polypeptides of the invention,
and ability to bind to a
receptor or ligand for a polypeptide.
The polypeptides of the invention can be assayed for functional activity (e.g.
biological
activity) using or routinely modifying assays known in the art, as well as
assays described herein.
Specifically, one of skill in the art may routinely assay secreted
polypeptides (including fragments
and variants) of the invention for activity using assays as described in the
examples section below.
"A polypeptide having biological activity" refers to a polypeptide exhibiting
activity similar
to, but not necessarily identical to, an activity of a polypeptide of the
present invention, including
mature forms, as measured in a particular biological assay, with or without
dose dependency. In
the case where dose dependency does exist, it need not be identical to that of
the polypeptide, but
rather substantially similar to the dose-dependence in a given activity as
compared to the
polypeptide of the present invention (i.e., the candidate polypeptide will
exhibit greater activity or
not more than about 25-fold less and, preferably, not more than about tenfold
less activity, and
most preferably, not more than about three-fold less activity relative to the
polypeptide of the
presentinvention).
TABLES
Table 1A
Table 1A summarizes information concerning certain polypnucleotides and
polypeptides of
the invention. The first column provides the gene number in the application
for each clone
identifier. The second column provides a unique clone identifier, "Clone ID:",
for a cDNA clone
related to each contig sequence disclosed in Table 1A. Third column, the cDNA
Clones identified
in the second column were deposited as indicated in the third column (i.e. by
ATCC Deposit No:Z
and deposit date). Some of the deposits contain multiple different clones
corresponding to the
same gene. In the fourth column, "Vector" refers to the type of vector
contained in the
corresponding cDNA Clone identified in the second column. In the fifth column,
the nucleotide
sequence identified as "NT SEQ ID NO:X" was assembled from partially
homologous
("overlapping") sequences obtained from the corresponding cDNA clone
identified in the second
column and, in some cases, from additional related cDNA clones. The
overlapping sequences
were assembled into a single contiguous sequence of high redundancy (usually
three to five
21
CA 02441755 2003-09-22
WO 03/038063 PCT/US02/08277
overlapping sequences at each nucleotide position), resulting in a final
sequence identified as SEQ
ID NO:X. In the sixth column, "Total NT Seq." refers to the total number of
nucleotides in the
contig sequence identified as SEQ >D NO:X." The deposited clone may contain
all or most of
these sequences, reflected by the nucleotide position indicated as "5' NT of
Clone Seq." (seventh
column) and the "3' NT of Clone Seq." (eighth column) of SEQ )D NO:X. In the
ninth column,
the nucleotide position of SEQ m NO:X of the putative start codon (methionine)
is identified as
"5' NT of Start Codon." Similarly , in column ten, the nucleotide position of
SEQ ID NO:X of the
predicted signal sequence is identified as "5' NT of First AA of Signal Pep."
In the eleventh
column, the translated amino acid sequence, beginning with the methionine, is
identified as "AA
SEQ 1D NO:Y," although other reading frames can also be routinely translated
using known
molecular biology techniques. The polypeptides produced by these alternative
open reading
frames are specifically contemplated by the present invention.
In the twelfth and thirteenth columns of Table 1A, the first and last amino
acid position of
SEQ >D NO:Y of the predicted signal peptide is identified as "First AA of Sig
Pep" and "Last AA
of Sig Pep." In the fourteenth column, the predicted first amino acid position
of SEQ >D NO:Y of
the secreted portion is identified as "Predicted First AA of Secreted
Portion". The amino acid
position of SEQ >D NO:Y of the last amino acid encoded by the open reading
frame is identified in
the fifteenth column as "Last AA of ORF".
SEQ )D NO:X (where X may be any of the polynucleotide sequences disclosed in
the
sequence listing) and the translated SEQ >D NO:Y (where Y may be any of the
polypeptide
sequences disclosed in the sequence listing) are sufficiently accurate and
otherwise suitable for a
variety of uses well known in the art and described further below. For
instance, SEQ 1D NO:X is
useful for designing nucleic acid hybridization probes that will detect
nucleic acid sequences
contained in SEQ 117 NO:X or the cDNA contained in the deposited clone. These
probes will also
hybridize to nucleic acid molecules in biological samples, thereby enabling a
variety of forensic
and diagnostic methods of the invention. Similarly, polypeptides identified
from SEQ ID NO:Y
may be used, for example, to generate antibodies which bind specifically to
proteins containing the
polypeptides and the secreted proteins encoded by the cDNA clones identified
in Table 1A and/or
elsewhere herein
Nevertheless, DNA sequences generated by sequencing reactions can contain
sequencing
errors. The errors exist as misidentified nucleotides, or as insertions or
deletions of nucleotides in
the generated DNA sequence. The erroneously inserted or deleted nucleotides
cause frame shifts
in the reading frames of the predicted amino acid sequence. In these cases,
the predicted amino
acid sequence diverges from the actual amino acid sequence, even though the
generated DNA
sequence may be greater than 99.9% identical to the actual DNA sequence (for
example, one base
insertion or deletion in an open reading frame of over 1000 bases).
22
CA 02441755 2003-09-22
WO 03/038063 PCT/US02/08277
Accordingly, for those applications requiring precision in the nucleotide
sequence or the
amino acid sequence, the present invention provides not only the generated
nucleotide sequence
identified as SEQ >D NO:X, and the predicted translated amino acid sequence
identified as SEQ
ID NO:Y, but also a sample of plasmid DNA containing a human cDNA of the
invention
deposited with the ATCC, as set forth in Table 1A. The nucleotide sequence of
each deposited
plasmid can readily be determined by sequencing the deposited plasmid in
accordance with known
methods
The predicted amino acid sequence can then be verified from such deposits.
Moreover, the
amino acid sequence of the protein encoded by a particular plasmid can also be
directly
determined by peptide sequencing or by expressing the protein in a suitable
host cell containing
the deposited human cDNA, collecting the protein, and determining its
sequence.
Also provided in Table 1A is the name of the vector which contains the cDNA
plasmid.
Each vector is routinely used in the art. The following additional information
is provided for
convenience.
Vectors Lambda Zap (U.S. Patent Nos. 5,128,256 and 5,286,636), Uni-Zap XR
(U.S.
Patent Nos. 5,128, 256 and 5,286,636), Zap Express (U.S. Patent Nos. 5,128,256
and 5,286,636),
pBluescript (pBS) (Short, J. M. et al., Nucleic Acids Res. 16:7583-7600
(1988); Alting-Mees, M.
A. and Short, J. M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Aping-Mees,
M. A. et al.,
Strategies 5:58-61 (1992)) are commercially available from Stratagene Cloning
Systems, Inc.,
11011 N. Torrey Pines Road, La Jolla, CA, 92037. pBS contains an ampicillin
resistance gene and
pBK contains a neomycin resistance gene. Phagemid pBS may be excised from the
Lambda Zap
and Uni-Zap XR vectors, and phagemid pBK may be excised from the Zap Express
vector. Both
phagemids may be transformed into E. coli strain XL-1 Blue, also available
from Stratagene
Vectors pSportl, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0, were obtained
from Life Technologies, Inc., P. O. Box 6009, Gaithersburg, MD 20897. All
Sport vectors contain
an ampicillin resistance gene and may be transformed into E. coli strain
DH10B, also available
from Life Technologies. See, for instance, Gruber, C. E., et al., Focus 15:59
(1993). Vector
lafmid BA (Bento Soares, Columbia University, New York, NY) contains an
ampicillin resistance
gene and can be transformed into E. coli strain XL-1 Blue. Vector pCR~2.1,
which is available
from Invitrogen, 1600 Faraday Avenue, Carlsbad, CA 92008, contains an
ampicillin resistance
gene and may be transformed into E. coli strain DH10B, available from Life
Technologies. See,
for instance, Clark, J. M., Nuc. Acids Res. 16: 9677-9686 ( 1988) and Mead, D.
et al.,
Bio/fechnology 9: (1991).
The present invention also relates to the genes corresponding to SEQ ID NO:X,
SEQ ID
NO:Y, and/or a deposited cDNA (cDNA Clone )D). The corresponding gene can be
isolated in
accordance with known methods using the sequence information disclosed herein.
Such methods
23
CA 02441755 2003-09-22
WO 03/038063 PCT/US02/08277
include, but are not limited to, preparing probes or primers from the
disclosed sequence and
identifying or amplifying the corresponding gene from appropriate sources of
genomic material.
Also provided in the present invention are allelic variants, orthologs, and/or
species
homologs. Procedures known in the art can be used to obtain full-length genes,
allelic variants,
splice variants, full-length coding portions, orthologs, and/or species
homologs of genes
corresponding to SEQ m NO:X and SEQ )D NO:Y using information from the
sequences
disclosed herein or the clones deposited with the ATCC. For example, allelic
variants and/or
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 for
allelic variants and/or
the desired homologue.
The present invention provides a polynucleotide comprising, or alternatively
consisting of,
the nucleic acid sequence of SEQ )D NO:X and/or a cDNA contained in ATCC
Deposit No.Z.
The present invention also provides a polypeptide comprising, or
alternatively, consisting of, the
polypeptide sequence of SEQ )D NO:Y, a polypeptide encoded by SEQ m NO:X,
and/or a
polypeptide encoded by a cDNA contained in ATCC deposit No.Z. Polynucleotides
encoding a
polypeptide comprising, or alternatively consisting of the polypeptide
sequence of SEQ )D NO:Y,
a polypeptide encoded by SEQ >D NO:X and/or a polypeptide encoded by the cDNA
contained in
ATCC Deposit No.Z, are also encompassed by the invention. The present
invention further
encompasses a polynucleotide comprising, or alternatively consisting of the
complement of the
nucleic acid sequence of SEQ 1D NO:X, and/or the complement of the coding
strand of the cDNA
contained in ATCC Deposit No.Z.
24
CA 02441755 2003-09-22
WO 03/038063 PCT/US02/08277
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CA 02441755 2003-09-22
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74
CA 02441755 2003-09-22
WO 03/038063 PCT/US02/08277
Table 1B (Comprised of Tables 1B.1 and 1B.2)
The first column in Table 1B.1 and Table 1B.2 provides the gene number in the
application corresponding to the clone identifier. The second column in Table
1B.1 and Table 1B.2
provides a unique "Clone ID:" for the cDNA clone related to each contig
sequence disclosed in
Table 1B.1 and Table 1B.2. This clone ID references the cDNA clone which
contains at least the
5' most sequence of the assembled contig and at least a portion of SEQ 1D NO:X
as determined by
directly sequencing the referenced clone. The referenced clone may have more
sequence than
described in the sequence listing or the clone may have less. In the vast
majority of cases,
however, the clone is believed to encode a full-length polypeptide. In the
case where a clone is not
full-length, a full-length cDNA can be obtained by methods described elsewhere
herein. The third
column in Table 1B.1 and Table 1B.2 provides a unique "Contig )D"
identification for each contig
sequence. The fourth column in Table 1B.1 and Table 1B.2 provides the "SEQ ID
NO:" identifier
for each of the contig polynucleotide sequences disclosed in Table 1B.
Table 1B.1
The fifth column in Table 1B.1, "ORF (From-To)", provides the location (i.e.,
nucleotide position numbers) within the polynucleotide sequence "SEQ ID NO:X"
that delineate
the preferred open reading frame (ORF) shown in the sequence listing and
referenced in Table
1B.1, column 6, as SEQ ID NO:Y. Where the nucleotide position number "To" is
lower than the
nucleotide position number "From", the preferred ORF is the reverse complement
of the
referenced polynucleotide sequence. The sixth column in Table 1B.1 provides
the corresponding
SEQ ID NO:Y for the polypeptide sequence encoded by the preferred ORF
delineated in column 5.
In one embodiment, the invention provides an amino acid sequence comprising,
or alternatively
consisting of, a polypeptide encoded by the portion of SEQ ID NO:X delineated
by "ORF (From-
To)". Also provided are polynucleotides encoding such amino acid sequences and
the
complementary strand thereto. Column 7 in Table 1B.1 lists residues comprising
epitopes
contained in the polypeptides encoded by the preferred ORF (SEQ ID NO:Y), as
predicted using
the algorithm of Jameson and Wolf, (1988) Comp. Appl. Biosci. 4:181-186. The
Jameson-Wolf
antigenic analysis was performed using the computer program PROTEAN (Version
3.11 for the
Power Macintosh, DNASTAR, Inc., 1228 South Park Street Madison, WI). In
specific
embodiments, polypeptides of the invention comprise, or alternatively consist
of, at least one, two,
three, four, five or more of the predicted epitopes as described in Table 1B.
It will be appreciated
that depending on the analytical criteria used to predict antigenic
determinants, the exact address
of the determinant may vary slightly.
Column 8 in Table 1B.1 provides a chromosomal map location for certain
polynucleotides of the invention. Chromosomal location was determined by
finding exact matches
CA 02441755 2003-09-22
WO 03/038063 PCT/US02/08277
to EST and cDNA sequences contained in the NCBI (National Center for
Biotechnology
Information) UniGene database. Each sequence in the UniGene database is
assigned to a "cluster";
all of the ESTs, cDNAs, and STSs in a cluster are believed to be derived from
a single gene.
Chromosomal mapping data is often available for one or more sequences) in a
UniGene cluster;
this data (if consistent) is then applied to the cluster as a whole. Thus, it
is possible to infer the
chromosomal location of a new polynucleotide sequence by determining its
identity with a mapped
UniGene cluster.
A modified version of the computer program BLASTN (Altshul, et al., J. Mol.
Biol.
215:403-410 (1990), and Gish, and States, Nat. Genet. 3:266-272) (1993) was
used to search the
UniGene database for EST or cDNA sequences that contain exact or near-exact
matches to a
polynucleotide sequence of the invention (the 'Query' ). A sequence from the
UniGene database
(the 'Subject') was said to be an exact match if it contained a segment of 50
nucleotides in length
such that 48 of those nucleotides were in the same order as found in the Query
sequence. If all of
the matches that met this criteria were in the same UniGene cluster, and
mapping data was
available for this cluster, it is indicated in Table 1B under the heading
"Cytologic Band". Where a
cluster had been further localized to a distinct cytologic band, that band is
disclosed; where no
banding information was available, but the gene had been localized to a single
chromosome, the
chromosome is disclosed.
Once a presumptive chromosomal location was determined for a polynucleotide of
the
invention, an associated disease locus was identified by comparison with a
database of diseases
which have been experimentally associated with genetic loci. The database used
was the Morbid
Map, derived from OMIMTM and National Center for Biotechnology Information,
National
Library of Medicine (Bethesda, MD) 2000;. If the putative chromosomal location
of a
polynucleotide of the invention (Query sequence) was associated with a disease
in the Morbid Map
database, an OMIM reference identification number was noted in column 9, Table
1B.1, labelled
"OMIM Disease Reference(s). Table 5 is a key to the OMIM reference
identification numbers
(column 1), and provides a description of the associated disease in Column 2.
Table 1B.2
Column 5, in Table 1B.2, provides an expression profile and library code:count
for each of
the contig sequences (SEQ ID NO:X) disclosed in Table 1B, which can routinely
be combined
with the information provided in Table 4 and used to determine the tissues,
cells, andlor cell line
libraries which predominantly express the polynucleotides of the invention.
The first number in
Table 1B.2, column 5 (preceding the colon), represents the tissue/cell source
identifier code
corresponding to the code and description provided in Table 4. The second
number in column 5
(following the colon) represents the number of times a sequence corresponding
to the reference
76
CA 02441755 2003-09-22
WO 03/038063 PCT/US02/08277
polynucleotide sequence was identified in the corresponding tissue/cell
source. Those tissue/cell
source identifier codes in which the first two letters are "AR" designate
information generated
using DNA array technology. Utilizing this technology, cDNAs were amplified by
PCR and then
transferred, in duplicate, onto the array. Gene expression was assayed through
hybridization of
first strand cDNA probes to the DNA array. cDNA probes were generated from
total RNA
extracted from a variety of different tissues and cell lines. Probe synthesis
was performed in the
presence of 33P dCTP, using oligo (dT) to prime reverse transcription. After
hybridization, high
stringency washing conditions were employed to remove non-specific hybrids
from the array. The
remaining signal, emanating from each gene target, was measured using a
Phosphorimager. Gene
expression was reported as Phosphor Stimulating Luminescence (PSL) which
reflects the level of
phosphor signal generated from the probe hybridized to each of the gene
targets represented on the
array. A local background signal subtraction was performed before the total
signal generated from
each array was used to normalize gene expression between the different
hybridizations. The value
presented after "[array code]:" represents the mean of the duplicate values,
following background
subtraction and probe normalization. One of skill in the art could routinely
use this information to
identify normal and/or diseased tissues) which show a predominant expression
pattern of the
corresponding polynucleotide of the invention or to identify polynucleotides
which show
predominant and/or specific tissue and/or cell expression.
77
CA 02441755 2003-09-22
WO 03/038063 PCT/US02/08277
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DEMANDE OU BREVET VOLUMINEUX
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