Note: Descriptions are shown in the official language in which they were submitted.
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METHODS FOR MONITORING DRUG ACTIVITIES IN VIV~
[0001] This application incorporates by reference the entire disclosures of
U~.S.
Provisional Application Serial No. 60/446,133, filed February 11, 2003 and
entitled
"Methods for Monitoring Drug Activities ifZ Tlivo," U.S. Provisional
Application Serial No.
60/459,782, filed April 3, 2003 and entitled "Methods for Diagnosing RCC
and/or Solid
Tumors," and U.S. Provisional Application, filed January 23, 2004 and
entitled."Methods
for Prognosis and Treatment of Solid Tumors" (by Michael Burczynski, et al.).
In addition,
this application incorporates by reference all materials recorded in compact
discs labeled .
"Copy 1 - Sequence Listing Part," "Copy 2 - Sequence Listing Part" and "Copy 3
-
Sequence Listing Part," each of which includes "Sequence Listing.ST25.txt"
(3,647 KB,
created February 9, 2004). Furthermore, this application incorporates by
reference all
materials recorded in compact discs labeled °'Copy 1 - Tables Part,"
"Copy 2 - Tables Part"
and "Copy 3 - Tables Part," each of which includes "Table 1 (the Qualifier
Table).txt" (210
KB, created February 9, 2004).
TECHNICAL FIELD
[0002] This invention relates to methods, systems and equipment useful for
monitoring ira vivo activities of CCI-779 or other drugs.
BACKGROUND
[0003] CCI-779 is an ester analog of the immunosuppressant rapamycin and as
such
is a potent, selective inhibitor of the mammalian target of rapamycin. The
mammalian
target of rapamycin (mTOR) activates multiple signaling pathways, including
phosphorylation of p70s6kinase, which results in increased translation of 5'
TOP mRNAs
encoding proteins involved in translation and entry into the G 1 phase of the
cell cycle. By
virtue of its inhibitory effects on mTOR and cell cycle control, CCI-779 may
function as a
cytostatic and immunosuppressive agent. CCI-779 has been used as an anticancer
drag,and
is currently being evaluated for indications in clinical trials for treating
various oncology
and inflammatory diseases. These diseases include, but are not limited to,
renal cell
carcinoma (RCC), prostate cancer, gliomas, lung cancer, and non-Hodgkin's
lymphoma.
SUMMARY OF THE INVENTION
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SUMMARY OF THE INVENTION
[0004] One of the main objectives of clinical pharmacogenomic studies is to
identify
suitable markers for monitoring ih vivo activities of CCI-779 or other drugs.
The present
invention employs easily-obtained tissues, such as peripheral blood, as
surrogate tissues for
the detection of in vivo activities of CCI-779 or other drugs.
[0005] In one aspect, the present invention provides methods that are useful
for
detecting irZ vivo activities of CCI-779 or other drugs. The methods include
comparing an
i
expression profile of at least one drug activity gene in a peripheral blood
sample of a patient
of interest to a reference expression profile of the gene, where the gene is
differentially
expressed in peripheral blood mononuclear cells (PBMCs) of patients who have a
non-
blood disease and are subject to a drug therapy as compared to PBMCs isolated
from the
patients prior to the drug therapy. In many embodiments, the patient of
interest has the non-
blood disease and is being treated by the drug therapy.
[0006] In one embodiment, the drug therapy is an anti-cancer therapy, such as
CCI-
779 therapy, and the non-blood disease is a solid tumor, such as RCC, prostate
cancer, or
headlneck cancer. In another embodiment, the drug activity genes of the
present invention
are selected from Table 5.
[0007] The peripheral blood samples used in the present invention can be,
without
limitation, whole blood samples or samples comprising enriched PBMCs. Other
peripheral
blood samples that include PBMCs can also be employed in the present
invention.
[0008] The expression profiles of the drug activity genes can be determined by
various means, such as quantitative RT-PCR, Northern Blot, in situ
hybridization, slot-
blotting, nuclease protection assay, nucleic acid arrays, enzyme-linked
immunosorbent
assays (ELISAs), radioimmunoassay (RIAs), fluorescence-activated cell sorters
(FACSs), or
Western Blots. In addition, two-dimensional SDS-polyacrylamide gel
electrophoresis and
other high-through nucleic acid or protein detection techniques can also be
used.
[0009] In many embodiments, the reference expression profile and the
expression
profile being compared are prepared using the same or comparable methodology.
In one
example, the reference expression profile is an average baseline expression
profile of drug
activity genes in peripheral blood samples isolated from patient or patients
prior to a drug
treatment. In another example, the reference expression profile is an
expression profile of
drug activity genes in peripheral blood samples of the patient of interest.
The reference
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expression profile and the expression profile being compared can be obtained
from
peripheral blood samples isolated at different time points in a drug
treatment.
[0010] In one embodiment, the drug activity genes used in the present
invention are
over-expressed (or under-expressed) in PBMCs of patient who have a non-blood
disease as
compared to PBMCs of humans who do not have the non-blood disease. The drug
therapy
being investigated can down-regulate (or up-regulate) the expression of the
drug activity
genes in PBMCs of patients who have the non-blood disease.
(0011] In another embodiment, the expression of the drug activity genes in
PBMCs
can be stimulated (or suppressed) by phytohemagglutinin (PHA). The drug
therapy being
investigated can down-regulate (or up-regulate) the expression of these genes
in PHA-
treated PBMCs.
[0012] In another aspect, the present invention provides other methods that
are
useful for detecting in vivo activities of CCI-779 or other drugs. . The
methods include
comprises comparing an expression profile of at least one drug activity gene
in a peripheral
blood sample of a patient of interest to a reference expression profile of the
gene, where the
RNA transcripts) of the drug activity gene can hybridize under stringent or
nucleic acid
array hybridization conditions to one or more qualifiers selected from the
Qualifier Table.
(0013] In yet another aspect, the present invention provides methods useful
for
identifying drug activity genes. The methods include detecting the gene
expression profile
in peripheral blood samples of patients who have a non-blood disease and are
subject to a
drug therapy, and comparing the gene expression profile to a baseline .gene
expression
profile in peripheral blood samples isolated before the drug therapy. Drug
activity genes
whose expression levels in peripheral blood samples can be modulated by the
drug therapy
can therefore be identified.
[0014] In still another aspect, the present invention provides kits useful for
detecting
in vivo activities of CCI-779 or other drugs. In one embodiment, the kits
include a plurality
of polynucleotides, and each polynucleotide can hybridize under stringent or
nucleic acid
array hybridization conditions to an RNA transcript, or the complement
thereof, of a
different respective drug activity gene. In another embodiment, the kits
include a plurality
of antibodies, and each antibody can bind to a polypeptide encoded by a
different respective
drug activity gene. The drug activity genes can be selected, without
limitation, from Table
5.
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[0015] In still yet another aspect, the present invention provides nucleic
acid arrays
useful for detecting in vivo activities of CCI-779 or other drugs. A
substantial portion of all
polypeptide probes on the nucleic acid array can hybridize under stringent or
nucleic acid
array hybridization conditions to RNA transcripts, or the complements thereof,
of drug
activity genes.
[0016] Other features, objects, and advantages of the present invention are
apparent
in the detailed description that follows. It should be understood, however,
that the detailed
description, while indicating preferred embodiment, of the invention, are
given by way of
illustration only, not limitation. Various changes and modifications within
the scope of the
invention will become apparent to those skilled in the art from the detailed
description.
DETAILED DESCRIPTION
[0017] The present invention provides methods useful for the detection of ih
vivo
activities of CCI-779 or other drugs. Numerous drug activity genes can be
identified by the
present invention. The expression profiles of these genes in PBMCs can be
modulated by
CCI-779 or other drugs. Accordingly, these genes can be used as surrogate
markers for
monitoring drug activities in vivo. In one embodiment, the methods of the
present invention
include comparing the expression profile of at least one drug activity gene in
a peripheral
blood sample of a patient of interest to a reference expression profile of the
same drug
activity gene. The patient of interest has a non-blood disease, such as RCC,
prostate cancer,
or another solid tumor, and is being treated by a drug therapy. A change in
the peripheral
blood expression profile of the drug activity gene is indicative of the in
vivo activity of the
drug therapy. In many cases, the reference expression.profile can be
determined by using
baseline peripheral blood samples isolated from patients prior to the drug
therapy.
Peripheral blood samples amenable to the present invention include, but are
not limited to,
whole blood samples or samples comprising enriched PBMCs. Expression profiles
of drug
activity genes can be detected using a variety of methods, such as
quantitative RT-PCT,
Northern Blot, ira situ hybridization, nucleic acid arrays, enzyme-linked
immunosorbent
assay (ELISA), radioimmunoassay (RIA), FACS (fluorescence-activated cell
sorter), or
Western Blot. The drug activity genes of the present invention may also be
used for
assessing the efficiency of a drug therapy.
[0018] Various aspects of the invention are described in further detail in the
following sections. The use of sections is not meant to limit the invention.
Each section
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and subsection may apply to any aspect of the invention. In this application,
the use of "or"
means "and/or" unless stated otherwise. Also, the use of the singular includes
the plural
unless stated otherwise:
A. General Methods for Identifying Drn~ Activity Genes
[0019] The availability of the human genome sequence, together with new
developments in technology, such as DNA microarrays, proteomics and
computational
biology, allows systemic gene expression studies for various diseases. The
present
invention employs the systematic gene expression analysis technique to
identify genes
whose expression in peripheral blood can be modulated by a therapeutic agent
such as CCI-
779. These genes are herein referred to as "drug activity genes." The genes
whose
expression levels in peripheral blood can be modified by CCI-779 are refereed
to as "CCI-
779 activity genes."
(0020] Drug activity genes can be identified by comparing peripheral blood
gene
expression profiles before and after a drug treatment. Numerous methods are
available for
detecting and comparing gene expression profiles.
[0021] For instance, gene expression profiles can be detected by measuring the
levels of RNA transcripts in peripheral blood samples. In one embodiment,
total RNAs or
polyA+ RNAs are isolated from peripheral blood samples using conventional
means. The
isolated RNAs can be amplified to produce cDNAs or cRNAs. Peripheral blood
gene
expression profiles can be determined by measuring the amount of the amplified
cDNAs or
cRNAs.
[0022] Peripheral blood gene expression profiles can also be determined by
measuring the levels of polypeptides in peripheral blood samples. The amounts
of
polypeptides in peripheral samples can be detected using various methods, such
as ELISAs,
RIAs, FACSs, Western Blots or other immunoassays. In addition, two-dimensional
gel
electrophoresis/mass spectrometry or other high-throughput protein sequencing
and
identification methods can be used.
(0023] In one embodiment, nucleic acid arrays are used for detecting or
comparing
gene expression profiles in peripheral blood samples isolated at different
stages of a
therapeutic treatment. Nucleic acid arrays allow for quantitative detection of
the expression
levels of a large number of genes at one time. Examples of nucleic acid arrays
include, but
are not limited to, Genechip° microarrays from Affymetrix (Santa Clara,
CA), cDNA
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microarrays from Agilent Technologies (Palo Alto, CA), and bead arrays
described in U.S.
Patent Nos. 6,288,220 and 6,391,62.
[0024] The polynucleotides to be hybridized to nucleic acid arrays can be
labeled
with one or more labeling moieties to allow for detection of hybridized
polynucleotide
complexes. The labeling moieties can include compositions that are detectable
by
spectroscopic, photochemical, biochemical, bioelectronic, immunochemical,
electrical,
optical or chemical means. Exemplary labeling moieties include radioisotopes,
chemiluminescent compounds, labeled binding proteins, heavy metal atoms,
spectroscopic
markers such as fluorescent markers and dyes, magnetic labels, linked enzymes,
mass
spectrometry tags, spin labels, electron transfer donors and acceptors, and
the like.
Unlabeled polynucleotides can also be employed. The polynucleotides can be
DNA, RNA,
or a modified form thereof.
[0025] Hybridization reactions can be performed in absolute or differential
hybridization formats. In the absolute hybridization format, polynucleotides
derived from
one sample, such as a peripheral blood sample isolated from a cancer patient
at a particular
treatment stage, are hybridized to the probes in a nucleic acid array. Signals
detected after
the formation of hybridization complexes correlate to the polynucleotide
levels in the
sample. In the differential hybridization format, polynucleotides derived from
two
biological samples, such as one isolated from a cancer patient at a first
stage of treatment
and the other isolated from the same patient but at a second stage of
treatment, are labeled
with different labeling moieties. A mixture of these differently labeled
polynucleotides is
added to a nucleic acid array. The nucleic acid array is then examined under
conditions in
which the emissions from the two different labels are individually detectable.
In one
embodiment, the fluorophores Cy3 and Cy5 (Amersham Pharmacia Biotech,
Piscataway
N.J.) are used as the labeling moieties for the differential hybridization
format.
[0026] Signals gathered from nucleic acid arrays can be analyzed using
commercially available software, such as those provide by Affymetrix or
Agilent
Technologies. Controls, such as for scan sensitivity, probe labeling and
cDNAIcRNA
quantitation, can be included in the hybridization experiments. In many
embodiments, the
nucleic acid array expression signals are scaled or normalized before being
subject to
further analysis. For instance, the expression signals for each gene can be
normalized to
take into account variations in hybridization intensities when more than one
array is used
under similar test conditions. Signals for individual polynucleotide complex
hybridization
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can also be normalized using the intensities derived from internal
normalization controls
contained on each array. In addition, genes with relatively consistent
expression levels
across the samples can be used to normalize the expression levels of other
genes. In one
embodiment, the expression levels of the genes are normalized across the
samples such that
the mean is zero and the standard deviation is one. In another embodiment, the
expression
data detected by nucleic acid arrays are subject to a variation flter which
excludes genes
showing minimal or insignificant variation across all samples.
[0027] A variety of peripheral blood samples can be used in the present
invention.
In one embodiment, the peripheral blood samples are whole blood samples. In
another
embodiment, the peripheral blood samples comprise enriched PBMCs. By
"enriched," it
means that the percentage of PBMCs in the sample is higher than that in whole
blood. In
many cases, the PBMC percentage in an enriched sample is at least 1, 2, 3, 4,
5 or more
times higher than that in whole blood. In many other cases, the PBMC
percentage in an
enriched sample is at least 90%, 95%, 98%, 99%, 99.5%, or more. Blood samples
containing enriched PBMCs can be prepared using any method known in the art,
such as
Ficoll gradients centrifugation or CPTs (cell purification tubes).
[0028] Peripheral blood samples used in the present can be isolated at any
stage of a
drug treatment (including baseline samples isolated before the drug
treatment). For
instance, the samples can be isolated from patients at 1 day, 2 days, 3 days,
4 days, 5 days, 6
days, 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, or 16 weeks after initiation
of a drug
treatment. Other time points can also be used for isolating blood samples for
monitoring or
assessing ifa vivo drug activities.
[0029] In many embodiments, the patients being treated by a drug therapy of
interest
have a non-blood disease, such as a solid tumor. Solid tumors amenable to the
present
invention include, but are not limited, RCC, prostate cancer, head/neck
cancer, ovarian
cancer, testicular cancer, brain tumor, breast cancer, lung cancer, colon
cancer, pancreas
cancer, stomach cancer, bladder cancer, skin cancer, cervical cancer, uterine
cancer, and
liver cancer. In one embodiment, the solid tumors have the following
characteristics: (1) a
mass of hyperproliferating cells of clonal origin, and (2) acquisition of an
aggressively
invasive phenotype, where cancer cells leave the tissue of origin and
establish new tumor
metastases at distant sites. In one example, the patients have RCC.
[0030] Any cancer or disease treatment can be evaluated by the present
invention.
Exemplary cancer treatments include the use of cytokines, such as interferon
or interleukin
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2. In addition, chemotherapy drugs can be used, either individually or in
combination with
other drugs, cytokines or therapies. Suitable chemotherapy drugs include, but
are not
limited to, CCI-779, AN-238, vinblastine, floxuridine, 5-fluorouracil, and
tamoxifen.
AN238 is a cytotoxic agent which has 2-pyrrolinodoxorubicin linked to a
somatostatin
(SST) carrier octapeptide. AN238 can be targeted to SST receptors on the
surface of RCC
tumor cells. Moreover, monoclonal antibodies, antiangiogenesis drugs, and anti-
growth
factor drugs can be employed to treat cancers.
[0031] The gene expression profile in peripheral blood samples isolated at one
stage
of a drug treatment can be compared to that at another stage of the drug
treatment. Drug
activity genes that are differentially expressed in PBMCs at one stage of the
treatment
relative to another stage of treatment can therefore be identified. In one
embodiment, the
PBMC expression level of a drug activity gene is substantially higher at one
stage than at
another stage. For instance, an average PBMC expression level of a drug
activity gene at
one stage can be at least 1.5, 2, 3, 4, 5, 10, 20, or more times of that at
another stage. In
another embodiment, the PBMC expression level of a drug activity gene is
substantially
lower at one stage than at another stage. For instance, an average PBMC
expression level
of a drug activity gene at one stage can be no greater than 0.67, 0.5, 0.33,
0.25, 0.1, 0.05, or
less times of that at another stage.
[0032] In yet another embodiment, drug activity genes can be identified using
clustering algorithms based on the nucleic acid array gene expression data.
For instance,
unsupervised cluster analyses can be used to analyze and categorize genes
which have
differential expression patterns between different drug treatment stages.
Algorithms for
unsupervised cluster analysis include, but are not limited to, self organized
maps (SOMs),
principle component analysis, average linkage clustering, and hierarchical
clustering.
[0033] Supervised cluster analysis can also be used to organize and identify
drug
activity genes. Algorithms for supervised cluster analysis include, but are
not limited to,
nearest neighbors test, support vector machines, and SPLASH. Either two-class
or multi-
class correlation metrics can be used.
B. Identification of CCI-779 Activity Genes
[0034] In one embodiment, HG-U95Av2 gene chips (manufactured by Affymetrix)
were used for detecting and comparing the levels of RNA transcripts in PBMC-
enriched
peripheral blood samples. Peripheral blood samples were isolated from RCC
patients at
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different stages of CCI-779 treatment (See Example 1). The CCI-779 treatment
included
intravenous administration of 25, 75 or 250 mg of CCI-779 once weekly.
Peripheral blood
samples were isolated from RCC patients immediately before the initial
administration of
CCI-779, and then 8 weeks and 16 weeks thereafter.
[0035] cRNA were prepared from the isolated PBMC samples and hybridized to
HG-U95Av2 genechips. Hybridization signals were collected for each
oligonucleotide
probe on the genechips. Signals from the oligonucleotide probes of the same
qualifier were
averaged. Qualifiers that produce different hybridization signals in samples
isolated at
different treatment time points were identified. Examples of these identified
qualifiers are
illustrated in Table 1 ("the Qualifier Table").
[0036] In general, each qualifier in the Qualifier Table corresponds to at
least one
CCI-779 activity gene, and the RNA transcripts of the gene can hybridize under
stringent or
nucleic acid array hybridization conditions to the qualifier. As used herein,
"hybridize to a
qualifier" means to hybridize to at least one oligonucleotide probe of the
qualifier. In many
embodiments, the RNA transcripts of a CCI-779 activity gene can hybridize
under stringent
or nucleic acid array hybridization conditions to at least 2, 4, 6~ 8, 10, 12,
14 or 16
oligonucleotide probes of the corresponding qualifier.
[0037] Table 2 lists the expression profiles of some qualifiers that produced
different hybridization signals for PBMC samples isolated at different
treatment stages.
Each expression profile in Table 2 ("Baseline," "8wks Average," or "l6wks
Average") was
an average of PBMC samples of 110 RCC patients. Each expression profile under
"Baseline," "8wks Average," and "l6wks Average" represented the hybridization
signals on
the respective qualifier for PBMC samples isolated immediately before the
initial CCI-779
administration, 8 weeks after the initial administration, and 16 weeks after
the initial
administration, respectively. The p-value of an ANOVA analysis was provided
for each
qualifier. The p-value suggests the statistical significance of the difference
observed
between the expression profiles obtained at different CCI-779 treatment
stages. Lesser p-
values indicate more statistical significance for the differences observed
between different
treatment stages.
Table 2. PBMC Gene Expression Profiles at Different CCI-779 Treatment Stakes
Baseline g~'~'ks l6wks ~~VA
Qualifier (n=110) Average Average p_Value CPS
(n=110) (n=110)
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Baseline gwks l6wks ~pVA
Qualifier (n=110) Average Average p_Value
(n=110) (n=110)
34768 at 7.90 19.4 20.8 2.5E-11 1
36097 at 113 195 247 8.OE-11 2
36675 r at 62.2 109 144 8.4E-11 3
37940 f at 6.95 22.7 28.8 S.lE-10 4
34338 at 16.0 29.3 35.4 5.9E-10 5
38991 at 27.2 15.2 ~ 12.9 1.3E-09 6
38976 at 42.6 103.7 139 4.6E-09 7
37905 r at 32 19.0 13.9 6.OE-09 8
38780 at 11.9 23.1 32.0 7.1E-09 9
41215 s at 48.4 91 113 7.1 E-0910
35956 s at 11.1 3.81 4.19 9.3E-09 11
32332 at 8.14 18.6 21.9 l.lE-08 13
41551 at 8.48 14.0 19.3 1.8E-O8 14
39332 at 21.9 10 9.14 1.9E-08 15
40778 at 6.19 11.7 15.6 1.9E-08 16
32232 at 9.81 16.2 19.7 4.5E-O8 17
34310 at 11.3 19.1 26.3 5.8E-08 18
1184 at 24.4 56.6 76.0 8.3E-08 19
35688_g at 10.1 20.2 15.7 8.4E-08 20
38981 at 6.48 14.4 16.2 8.9E-08 21
37391 at 173 89.3 28.4 1.3E-07 23
39593 at 9.10 38.5 62.6 1.4E-07 24
32505 at 8.62 4.62 4.24 1.6E-07 25
AFFX- 36.3 10.1 11.9 1.8E-07 26
M27830 5
at
35666 at 19.8 11.4 9.76 2.OE-07 27
39061 at 18.6 37.0 47.0 2.1E-07 28
39748 at 29.9 14.8 12.2 2.5E-07 29
40505 at 12.8 26.1 37.0 2.7E-07 30
38597 f at 15.6 7.48 6.95 3.3E-07 31
39545 at 13.0 34.2 43.8 3.3E-07 32
34268 at 14.3 33.3 48.9 4.2E-07 33
38816 at 13.3 7.05 5.62 4.8E-07 34
38732 at 8.95 16.2 18.b S.OE-07 35
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Baseline gwks l6wks ~pVA
Qualifier (n=110) Average Average p_Value Cpl
(n=110 (n=110
40607 at 9 23.8 36.4 S.lE-07 36
37200 at 29.3 70.6 111 6.5E-07 37
283 at 13.8 26.8 34.8 6.6E-07 38
40757 at 10.8 33.0 56.1 7.1E-07 39
384 at 19.2 36.0 51.7 9.OE-07 41
40814 at 19 12.2 9.24 9.4E-07 42
37027 at 31.8 60.0 85.0 9.4E-07 43
1760 s at 12.1 7.52 5.57 l.lE-06 44
1292 at 16.3 37.4 39.8 l.lE-06 45
38287 at 26.5 54.9 79.8 1.2E-06 46
41591 at 10.9 6.90 4.76 1.3E-06 47
32475 at 4.62 9.05 12.7 1.3E-06 48
40782 at 36.4 23.9 8.29 1.4E-06 49
503 at 19.7 33.3 43.2 1.5E-06 50
875_g at 132 68.7 10.5 1.5E-06 51
37185 at 288 160 34.0 1.6E-06 52
32282 at 10.9 4.57 4.95 1.7E-06 53
40981 at 9.10 4.05 4.10 1.9E-06 54
34782 at 74.0 46.2 24.6 1.9E-06 55
37373 at 11.9 19.4 24.0 2.OE-06 56
40018 at 8 4.67 3.57 2.1E-06 57
31638 at 7.19 12.9 16.0 2.1E-06 58
38191 at 14.4 3.14 3.38 2.4E-06 59
33396 at 44.2 73.2 91.0 2.6E-06 60
38104 at 4.33 6.76 8.76 2.6E-06 61
32193 at 7.90 16.3 24.1 2.8~-06 62
38350 f at 4.90 8.95 10.4 2.8E-06 63
1985 s at 5.57 9.19 11.9 2.9E-06 64
38598 at 10.5 3.71 3.05 3.3E-06 65
.
41446 f at 17.6 38.9 44.8 3.3E-06 66
41436 at 15.8 9.71 7.05 3.3E-06 67
36672 at 7 17.2 26 3.4E-06 68
38717 at 6.62 15.1 21.0 3.7E-06 70
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Baseline g~'~s l6Wks AlVOVA
Qualifier (n=110) Average Average p_Value CpS
(n=110) (n=110
32183 at 36.3 22.6 14.9 3.8E-06 71
32737 at 14.2 26.4 36.9 4.3E-06 72
40140 at 24.5 16.9 11.9 4.6E-06 73
40818 at 23.9 14.1 10 4.7E-06 74
34787 at 15.7 24.8 ~ 37.2 4.9E-06 75
38652 at 7.05 13.5 ~ 15.5 S.OE-06 76
41812 s at 5.76 10.5 12.7 S.lE-06 77
31622 f at 18.5 34.9 38.3 6.3E-06 78
40828 at 30.7 24.3 14.9 6.7E-06 79
39693 at 3.76 9.10 11.0 7.7E-06 80
40994 at 12.2 8.67 5.29 7.8E-06 81
39802 at 24 13.6 5.19 9.1E-06 83
40567 at 39.1 65.4 96.8 1.OE-05 84
38518 at 16.7 11.9 6.67 l.lE-05 85
1368 at 17.9 11.3 4 l.lE-05 87
41653 at 8.29 4.57 3.29 1.3E-05 88
41669 at 13.2 8.43 5.10 1.3E-05 89
36488 at 7.81 17.7 25.5 1.4E-05 90
1005 at 61.6 129 166 1.5E-05 91
36495 at 71.2 37.3 26.4 1.7E-05 92
40579 at 7.67 4.24 3.43 1.7E-05 93
36607 at 6.05 11.9 16.2 2.OE-05 94
34311 at 15.8 24.8 34.9 2.1 E-0595
35785 at 92.4 71.7 45.3 2.1E-05 96
40622 r at 45 24:4 20.9 2.2E-05 97
33777 at 7.43 20.9 31.7 2.2E-05 98
38220 at 5.71 11.4 16.8 2.5E-05 99
1665 s at 6.86 26.5 39.9 2.6E-05 100
1693 s at 321 244 91.2 2.9E-05 101
32612 at 5.90 8.86 12.1 2.9E-05 102
41045 at 16.7 33.4 48.8 3.OE-05 103
37233 at 19.9 9.52 2.86 3.OE-05 104
37967 at 61.3 132 159 3.1E-05 105
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Baseline gwks l6wks ~pVA
Qualifier (n=110) Average Average p_Value CPS
(n=110) (n=110)
2049 s at 11.9 - 26.9 32.8 3.3E-05 106
39997 at 24.3 38.5 49.0 3.4E-05 107
41332 at 8.14 13.7 18.1 3.4E-05 108
115 at 51.5 35.0 9.19 3.6E-05 109
40964 at 7.62 3.29 3.10 3.7E-05 110
35303 at 25.8 19.6 12.0 4.OE-05 111
40742 at 10 28.8 37.4 4.1E-05 112
37955 at 4.14 5.81 8.38 4.4E-05 113
39698 at 4.10 6.52 9.29 4.5E-05 114
32586 at 6.05 9.67 12.4 4.5E-05 115
40159 r at 10.5 20.9 46.6 S.OE-05 116
32635 at 8.24 3.95 3.57 S.OE-05 117
35840 at 5.05 7.86 11.8 S.lE-05 118
37661 at 21.2 13.3 6.48 S.lE-05 119
411 i at 29.2 40.1 65.6 S.lE-05 120
35012 at 20.4 40.3 74.9 5.2E-05 121
38760 f at 9.33 16.0 21.4 5.3E-05 122
36474 at 9.48 5.81 4.48 5.3E-05 123
41440 at 4.24 9.3 8 9.10 5.4E-05 124
39953 i at 23.1 9.14 7.71 5.8E-05 125
245 at 45.8 62.2 103 6.OE-05 126
37181 at 3.67 5.90 7.52 6.OE-05 127
39799 at 31.3 21.3 7.90 6.2E-05 128
39320 at 6.48 12.4 16.1 6.4E-05 129
794 at 5.29 10.2 14.0 6.4E-05 130
36091 at 7.33 11.7 18.7 6.6E-05 131
37187 at 66.8 45.1 11.7 7.2E-05 133
~
38338 at 8.76 14.2 18.3 7.2E-05 134
34760 at 14.3 23.0 31.0 7.3E-05 135
33133 at 7.67 12.3 16.3 7.6E-05 136
32904 at 10.2 19.4 26.2 7.7E-..05137
37359 at 7.71 12.4 16.3 8.2E-05 138
40485 at 3.95 7.81 9.81 8.3E-05 139
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Baseline gwks l6wks ANOVA
Qualifier (n=110) Average Average p_Value CPS
(n=110) (n=110)
37215 at 6.86 11.3 19.4 8.4E-OS 140
40274 at 9.10 21 16.1 B.SE-OS 141
41174 at 12.9 9.95 5.71 8.8E-OS 143
1715 at 5.86 14.0 21.5 8.8E-OS 144
41503 at 10.1 7.71 ~ 4.90 8.9E-OS 145
40390 at 5.71 3.62 ~ 2.81 9.2E-OS 146
40811 at 13.8 10.5 6.81 9.3E-OS 147
31499 s at 11.7 24.6 41.3 9.3E-OS 148
34023 at 4.76 7.33 11.9 9.SE-OS 149
1125 s at 8.57 6.29 4.24 9.7E-OS 150
36617 at 15.4 34.2 43.7 9.9E-OS 151
36337 at 15.2 7.48 5.95 0.00010 152
36161 at 5.24 7.95 10.8 0.00010 153
1433-g at 22.0 15 8.62 0.00010 154
39043 at 64.8 96.1 134 0.00011 155
37311 at 67.7 94.7 139 0.00012 156
37009 at 16.3 25.9 41.7 0.00013 157
33942 s at 17.9 9.52 7.86 0..00013158
39641 at 3.67 9.86 10.9 0.00013 159
529 at 10.8 23.1 22.5 0.00013 160
32199 at 8.81 2.90 2.95 0.00014 161
1426 at 59.8 45.1 27.5 0.00014 162
31851 at 17 12.5 8.10 0.00014 163
34378 at 124 49.4 26.3 0.00014 164
36173 r at 6.90 2.52 3.81 0.00016 165
35275 at 5 2.29 2.81 0.00017 1.66
41184 s at 7.33 14.8 18.0 0.00018 168
38391 at 16.5 23.0 33.3 0.00018 170
39829 at 28.0 17.8 13.6 0.00019 171
37587 at 6.71 3.19 2.90 0.00020 172
34022 at 35.0 20.0 3.52 0.00020 173
34188 at 13.7 9.62 6.05 0.00022 175
37647 at 13.2 25.3 35.2 0.00022 176
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Baseline gwks l6wks ANOVA
Qualifier (n=110) Average Average p_Value CpS
(n=110) (n=110
40089 at 20.4 12.0 9.24 0.00023 177
39982 r at 7.52 4.76 2.95 0.00024 178
32202 at 3.14 5.57 8.48 0.00026 179
35036 at 7.33 2.71 2.81 0.00027 180
906 at 34.6 23.6 12.6 0.00027 181
36033 at 12.8 8.38 6.10 0.00028 182
36766 at 20.8 36.2 57.2 0.00029 183
38893 at 38.2 48.4 78.4 0.00029 184
37374 at 3.86 6.38 8 0.00030 185
36599 at 4.57 6.76 9.38 0.00030 186
464 s at 7.43 12.7 16.5 0.00030 187
32533 s at 6.05 13.1 17.0 0.00031 188
36496 at 7.62 11 15.9 0.00031 189
36280 at 7.62 13 18.4 0.00033 190
38126 at 16.2 8.86 7.71 0.00033 191
37011 at 22.4 38.9 52.2 0.00035 192
39166 s at 9.24 2.10 2.38 0.00037 193
1825 at 16.6 28.0 35.2 0.00040 195
41577 at 13.5 13.7 4.38 0.00041 196
33161 at 3.14 6.10 9.81 0.00042 197
31438 s at 11.5 14.7 23.4 0.00043 198
36372 at 5.05 12.6 19.7 0.00043 199
2094 s at 50.3 104 141 0.00045 200
32977 at 11.6 22.6 33.4 0.00048 201
32264 at 9.29 18.1. 20.2 0.00048 202
32184 at 9.90 16.4 20.0 0.00048 203
35674 at 4.52 7.67 12 0.00049 204
41249 at 5.43 8.90 14.3 0.00051 205
36762 at 8.33 3.95 4.43 0.00052 206
37146 at 13.3 5.24 4.90 0.00055 207
867 s at 13.7 7.24 3.57 0.00055 208
33500 i at 53.9 32.3 26.4 0.00056 209
1575 at 7.71 5.67 3.57 0.00056 210
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Baseline g~'~'ks l6wks ANOVA
Qualifier (n=110) Average Average p_Value OPS
(n=110) (n=110)
40088 at 22.4 18.7 10.2 0.00060 211
37742 at 6.19 9.81 14.5 0.00067 213
35992 at 13.1 9.33 5.19 0.00072 214
35710 s at 6.29 10.6 13.0 0.00073 216
39119 s at 12.2 18.1 ~ 31.3 0.00074 217
34857 at 14.9 9.43 ~ 6.29 0.00078 218
41198 at 26 46.0 67.8 0.00080 219
34476 r at 11.5 8.48 3.81 0.00084 220
35772 at 5.62 2.71 2.95 0.00086 221
34660 at 13.1 20.3 28.4 0.00090 222
35648 at 14.4 11.1 5.71 0.00097 223
AFFX-
HUMRGE 65.8 30.3 34.9 0.00099 225
1M10098 3
at
31324 at 7.43 3.71 3.48 0.00099 226
1395 at 7.19 12.7 14.7 0.0010 227
32066_g at 27.2 22.4 12.2 0.0010 228
1107 s at 20.0 39.8 60 0.0010 229
1097 s at 29.0 21.7 9.86 0.0011 230
35591 at 4.48 10 7.86 0.0011 231
32815 at 17.2 7.86 6.33 0.0011 232
36231 at 20.6 15.7 9.29 0.0011 233
38823 s at 10.8 9.76 5.10 0.0012 234
32618 at 6.05 9.43 12.3 0.0013 235
2092 s at 9.57 6.62 2.67 0.0014 236
37184 at 8.62 2.67 2.81 0.0014 237
37120 at 15.8 8.71 3.48 0.0014 238
1237 at 79.6 66.5 32.8 0.0015 239
37310 at 9.76 9.38 3.95 0.0016 241
40541 at 13.0 6.10 8.90 0.0016 242
31346 at 4.90 10.5 7.10 0.0017 244
37875 at 11.4 5.52 5.67 0.0017 245
38125 at 8.24 3.29 3.19 0.0018 246
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Baseline gwks l6wl~s p~~VA
Qualifier (n=110) Average Average p_Value CpS
(n=110) (n=110)
859 at 22.0 19.3 6.86 0.0019 247
35792 at 8.05 5.57 3.57 0.0020 249
34946 at 5.48 8.14 11.2 0.0020 250
33956 at 11.6 16.5 24.7 0.0023 253
32975_g at 8.86 4.90 4.29 0.0024 254
38582 at 6.95 2.90 3.24 0.0025 255
181_g at 12 19.2 29.4 0.0025 256
37864 s at 10.0 6.29 3.43 0.0028 257
34704 r at 8.71 4.86 4.24 0.0028 258
32163 f at 10.2 6.10 4.76 0.0029 259
41189 at 14 10 6.67 0.0030 260
41698 at 6.81 6.24 3.33 0.0030 261
40456 at 11.52 10.2 5.62 0.0031 262
41227 at 15.8 7.52 10.8 0.0033 263
36100 at 24.4 14.8 12.0 0.0035 264
36411 s at 16.2 8.19 7.90 0.0037 265
41167 at 10.7 6.33 5.33 0.0037 266
41819 at 4.48 6.71 9.29 0.0037 267
38389 at 3.76 6.95 10.2 0.0038 268
37975 at 14.9 35.2 41.1 0.0039 269
39640 at 14.7 6.10 7.95 0.0043 270
38010 at 7.38 3.90 3.33 0.0043 271
32675 at 9.33 13.0 20.0 0.0044 272
1531 at 8.52 4.52 3.90 0.0044 273
40646 at 6.81 12.5 19.4 0.0045 274
39474 s at 4.71 2.33 3.05 0.0047 275
34498 at 21 28.0 48.5 0.0053 276
37654 at 4.05 6.95 8.14 0.0053 277
408 at 24.4 18.2 3.48 0.0054 278
38340 at 16.7 12.9 8.10 0.0056 279
1937 at 31.6 13.0 9.62 0.0059 280
41638 at 13.3 8.38 6.10 0.0059 281
36138 at 21 32.5 42.5 0.0060 282
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Baseline 8wks l6wks ANOVA
Qualifier (n=110) Average Average p_Value CpS
(n=110) (n=110)
32407 f at 13.7 6.33 5.38 0.0061 283
38131 at 17 36.1 2.90 0.0063 284
39775 at 11.7 22.7 32.8 0.0064 285
318 at 5.19 6.19 10.6 0.0073 286
39402 at 83.1 87.2 12.4 0.0077 287
36543 at 7.57 5.62 ~ 2.67 0.0079 288
1788 s at 7.33 6.62 3.62 0.0091 289
34702 f at 10.6 4.67 3.86 0.0094 290
40951 at 5.71 2.76 2.86 0.0098 291
35313 at 5.43 3 2.38 0.010 292
1520 s at 105 112 16 0.011 293
40171 at 6.05 8.14 12.8 0.011 295
32162 r at 14.1 7.86 6 0.012 296
1369 s at 365 292 163 0.012 297
34490 f at 5.05 7.71 10.2 0.012 298
36710 at 8.81 13.5 22.2 0.013 300
37220 at 8.24 14.0 20.0 0.013 301
32003 at 9.05 5.29 4.38 0.013 302
1667 s at 14.4 9.57 7.14 0.013 303
731 f at 7.71 4.05 3.76 0.015 304
39448 r at 8.38 4 4.43 0.015 305
40385 at 7 11.0 2.67 0.017 306
37603 at 83.9 88.7 36.3 0.028 307
41046 s at 5.52 2.57 3.19 0.040 308
37456 at 16 30:0 37.6 0.039 309
31828 r at 9.52 2.52 6 0.047 310
[0038] Each qualifier has a corresponsding CCI-779 activity gene probe
sequence
(CPS), and each CPS can be derived from a corresponding SEQ ID NO depicted in
Table 3.
In manycases, each CPS consists of an unambiguous fragment, or the complement
thereof,
of the corresponding SEQ ID NO. In many other cases, each CPS also comprises
at least
one oligonucleotide probe of the corresponding qualifier. Each SEQ ID NO in
Table 3 is a
cDNA or genomic sequence, or the complement thereof, of a CCI-779 activity
gene
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represented by the qualifier that corresponds to the SEQ ID NO. Accordingly,
each SEQ ID
NO or its corresponding CPS can hybridize 'under stringent or nucleic acid
array
hybridization conditions to the RNA transcripts, or the complements thereof,
of the
represented CCI-779 activity gene.
(0039] Each SEQ ID NO may have an Entrez nucleotide sequence database
accession number (see Table 4). The Entrez nucleotide sequence database is
maintained by
the National Center of Biotechnology Information (NCBI), National Library of
Medicine,
Washington, DC. The database collects sequences from several sources,
including
GenBank, RefSeq, and PDB.
[0040] Any ambiguous residue ("n") in a SEQ ID NO can be determined by
numerous methods. In one embodiment, the ambiguous residues in a SEQ ID NO are
determined by aligning the SEQ ID NO to a corresponding genomic sequence
obtained
from a human genome sequence database. In another embodiment, the ambiguous
residues
in a SEQ ID NO are determined based on the sequence of the corresponding
Entrez
accession number. In yet another embodiment, the ambiguous residues are
determined by
re-sequencing the SEQ ID NO. In general, each "n" position in a SEQ ID NO
represents at
least one nucleotide selected from a, t, g, and c, or contains no nucleotide
residue.
Table 3. Qualifiers and Corresponding CPSs and SEO ID NOs
Qualifier CPS SEQ ID NO
34768 at 1 nucleotides 1777 to 2353 of SEQ ID NO:
1
36097 at 2 nucleotides 1273 to 1774 of SEQ ID NO:
2
36675 r at 3 nucleotides 338 to 744 of SEQ ID NO:
3
37940 f at 4 the complement of nucleotides 305 to
- - 502 of SEQ ID
NO: 4
34338 at 5 nucleotides 659 to 995 of ~SEQ ID NO:
5
38991 at 6 the complement of nucleotides 382 to
- 527 of SEQ ID
NO: 6
38976 at 7 nucleotides 1107 to 1517 of SEQ ID NO:
7
37905 r at 8 nucleotides 1451 to 1961 of SEQ ID NO:
8
38780 at 9 nucleotides 567 to 1095 of SEQ ID NO:
9
41215 s at 10 nucleotides 719 to 1049 of SEQ ID NO:
10
35956 s at 11 nucleotides 1360 to 1973 of SEQ ID NO:
11
32332 at 13 nucleotides 1190 to 1720 of SEQ ID NO:
12
41551 at 14 the complement of nucleotides 223 to
- 388 of 'SEQ ID
NO: 13
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Qualifier CPS SEQ ID NO
39332 at 15 nucleotides 1091 to 1182 of S~Q ID NO:
14
40778 at 16 nucleotides 498 to 938 of SEQ ID NO:
15
32232 at 17 nucleotides 484 to 963 of SEQ ID NO:
16
34310 at 18 SEQ ID NO: 17
1184 at 19 nucleotides 197 to 743 of SEQ ID NO:
18
35688-g at 20 SEQ ID NO: 19
38981 at 21 ~ SEQ ID NO: 20
37391 at 23 nucleotides X1022- 1395 of SEQ ID NO:
21
39593 at 24 the complement of nucleotides 14 to
- 199 of SEQ ID NO:
22
32505 at 25 nucleotides 4 to 223 of SEQ ID NO: 23
AFFX- 26 SEQ ID NO: 24
M27830 5 at
35666 at 27 nucleotides 30'50 to 3530 of SEQ ID
NO: 2~
39061 at 28 nucleotides 425 to 948 of SEQ ID NO:
26
39748 at 29 nucleotides 2675 to 3052 of SEQ ID NO:
27
40505 at 30 the complement of nucleotides 52 to
- 286 of SEQ ID NO:
28
38597 f at 31 nucleotides 2196 to 2257 of SEQ ID NO:
29
39545 at 32 SEQ ID NO: 30
34268 at 33 nucleotides 1088 to 1530 of SEQ ID NO:
31
38816 at 34 nucleotides 3244 to 3649 of SEQ ID NO:
32
38732 at 35 nucleotides 762-1229 of SEQ ID NO: 33
40607 at 36 nucleotides 5022-5382 of SEQ ID NO:
34
37200 at 37 nucleotides 1406-1932 of SEQ ID NO:
35
283 at 38 nucleotides 1426-1965 of SEQ Il~ NO:
36
40757 at 39 nucleotides 393-818 of SEQ ID NO: 37
384 at 41 SEQ ID NO: 38
40814 at 42 nucleotides 1123-1247 of SEQ ID NO:
39
37027 at 43 SEQ ID NO: 40
1760 s at 44 nucleotides 2049-2393 of SEQ ID NO:
41
1292 at 45 nucleotides 1126-1654 of SEQ ID NO:
42
38287 at 46 the complement ofnucleotides 8-451 of
SEQ ID NO: 43
41591 at 47 the complement of nucleotides 39-547
- of SEQ ID NO:
44
32475 at 48 nucleotides 1845--2329 of SEQ ID NO:
45
40782 at 49 nucleotides 886-1289 of SEQ ID NO: 46
503 at 50 nucleotides 13-342 of SEQ ID NO: 47
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Qualifier CPS SEQ ID NO
875_g at 51 nucleotides 562-886 of SEQ ID NO: 48
37185 at 52 nucleotides 1311-1761 of SEQ ID NO:
49
32282 at 53 nucleotides 2851-3265 of SEQ ID NO:
50
40981 at 54 nucleotides 2661-3257 of SEQ ID NO:
51
34782 at 55 the complement of nucleotides 529-952
- of SEQ ID NO:
52
37373 at 56 nucleotides 1339-1771 of SEQ ID NO:
53
40018 at 57 nucleotides 5780 to 6213 of SEQ ID NO:
54
31638 at 58 SEQ ID NO: 55
38191 at 59 the complement of nucleotides 171 -451
- of SEQ ID NO:
56
33396 at 60 SEQ ID NO: 57
38104 at 61 SEQ ID NO: 58
32193 at 62 SEQ ID NO: 59
38350 f at 63 SEQ ID N.O: 60
1985 s at 64 nucleotides 90-510 of SEQ ID NO: 61
38598 at 65 the complement of nucleotides 149-213
- of SEQ ID NO:
62
41446 f at 66 the complement of nucleotides 28-303
- - of SEQ ID NO:
63
41436 at 67 nucleotides 4687-4907 of SEQ ID NO:
64
36672 at 68 nucleotides 1509-1977 of SEQ ID NO:
65
38717 at 70 nucleotides 1355 to 1737 of SEQ ID NO:
66
32183 at 71 nucleotides 2195 to 2651 of SEQ ID NO:
67
32737 at 72 nucleotides 183 to 669 of SEQ ID NO:
68
40140 at 73 nucleotides 2828 to 3356 of SEQ ID NO:
69
40818 at 74 nucleotides 5138-5360 of SEQ ID NO:
70
34787 at 75 nucleotides 3428-3616 of SEQ ID NO:
71
38652 at 76 nucleotides 829-1333 of SEQ ID NO: 72
41812 s at 77 nucleotides 3618-4192 of SEQ ID NO:
73
31622 f at 78 SEQ ID NO: 74
40828 at 79 nucleotides 4472-4977 of SEQ ID NO:
75
39693 at g0 the complement of nucleotides 55-554
- of SEQ ID NO:
76
40994 at 81 nucleotides 2004 to 2502 of SEQ ID NO:
77
39802 at 83 nucleotides 444 to 991 of SEQ ID NO:
78
40567 at 84 nucleotides 3868 to 3916 of SEQ ID NO:
79
38518 at 85 nucleotides 3841-4076 of SEQ ID NO:
80
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Qualifier CPS _ SEQ ID NO
1368 at 87 nucleotides 4459-4885 of SEQ ID NO:
81
41653 at 88 nucleotides 110125 to 110701 of SEQ
ID NO: 82
41669 at 89 nucleotides 4596 to 5049 of SEQ ID NO:
83
36488 at 90 nucleotides 4959 to 5449 of SEQ ID NO:
84
1005 at 91 nucleotides 784 to 1318 of SEQ ID NO:
85
36495 at 92 SEQ ID NO: 86
40579 at 93 ; SEQ ID NO: 87
36607 at ~ 94 the complement of 201545 to 202131 of
SEQ ID NO: 88
34311 at 95 nucleotides 360 to 722 of SEQ ID NO:
89
35785 at 96 nucleotides 160 to 436 of SEQ ID NO:
90
40622 r at 97 SEQ ID NO: 91
33777 at 98 SEQ ID NO: 92
38220 at 99 nucleotides 3894 to 4357 of SEQ ID NO:
93
1665 s at 100 SEQ ID NO: 94
1693 s at 101 SEQ ID NO: 95
32612 at 102 nucleotides 2033 to 2405 of SEQ ID NO:
96
41045 at 103 nucleotides 1546 to 1973 of SEQ ID NO:
97
37233 at 104 SEQ ID NO: 98
37967 at 105 nucleotides 278 to 635 of SEQ ID NO:
99
2049 s at 106 nucleotides 842 to 1443 of SEQ ID NO:
100
39997 at 107 SEQ ID NO: 101
41332 at 108 nucleotides 635 to 1169 of SEQ ID NO:
102
115 at 109 nucleotides 3083-3605 of SEQ ID NO:
103
40964 at 110 SEQ ID NO: 104
35303 at 111 SEQ ID NO: 105
40742 at 112 nucleotides 1661 to 1912 of SEQ ID NO:
106
37955 at 113 nucleotides 669 to 730 of SEQ ID NO:
107
39698 at 114 nucleotides 599 to 1068 of SEQ ID NO:
108
32586 at 115 nucleotides 5059 to 5585 of SEQ ID NO:
109
40159 r at 116 nucleotides 970-1341 of SEQ ID NO: 110
32635 at 117 nucleotides 3240 to 3424 of SEQ ID NO:
111
35840 at 118 nucleotides 639 to 1163 of SEQ ID NO:
112
37661 at 119 nucleotides 4061-4398 of SEQ ID NO:
113
411 i at 120 nucleotides 281 to 318 of SEQ ID NO:
114
35012 at 121 nucleotides 1070 to 1667 of SEQ ID NO:
115
38760 f at 122 nucleotides 1014 to 1263 ofSEQ ID NO:
116
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Qualifier CPS SEQ ID NO
36474 at 123 nucleotides 3881 to 4038 of SEQ ID NO:
117
41440 at 124 nucleotides 655 to 933 of SEQ ID NO:
118
39953 i at 125 nucleotides 5549 to '5598 of SEQ ID
NO: 119
245 at 126 nucleotides 1795 to 2323 of SEQ ID NO:
120
37181 at 127 nucleotides 375 to 947 of SEQ ID NO:
121
39799 at 128 SEQ ID NO: 122
39320 at. 129 nucleotides 569 to 1121 of SEQ ID NO:
123
794 at 130 nucleotides 1484 to 2024 of SEQ ID NO:
124
36091 at 131 nucleotides 1806 to 1973 of SEQ ID NO:
125
37187 at 133 nucleotides 504-946 of SEQ ID NO: 126
38338 at 134 the complement of nucleotides 61 to
- 470 of SEQ ID NO:
127
34760 at 135 nucleotides 3404 to 3694 of SEQ ID NO:
128 .
33133 at 136 SEQ ID NO: 129
32904 at 137 SEQ ID NO: 130
37359 at 138 nucleotides 798 to 1300 of SEQ ID NO:
131
40485 at 139 the complement of nucleotides 35-188
- of SEQ ID NO:
132
37215 at 140 SEQ ID NO: 133
40274 at 141 nucleotides 561-736 of SEQ ID NO: 134
41174 at 143 nucleotides 3461 to 4011 of SEQ ID NO:
135
1715 at 144 nucleotides 1162 to 1402 of SEQ ID NO:
136
41503 at 145 nucleotides 3580 to 4066 of SEQ ID NO:
137
40390 at 146 nucleotides 978 to 1393 of SEQ ID NO:
138
40811 at 147 nucleotides 4475 to 4934 of SEQ ID NO:
139
31499 s at 148 nucleotides 251-854 of SEQ ID NO: 140
34023 at 149 nucleotides 570 to 1026 of SEQ ID NO:
141
1125 s at 150 SEQ ID NO: 142
36617 at 151 nucleotides 691 to 819 of SEQ ID NO:
143
36337 at 152 the complement of nucleotides 54-372
- of SEQ ID NO:
144
36161 at 153 nucleotides 5172 to 5682 of SEQ ID NO:
145
1433-g at 154 nucleotides 1907 to 2267 of SEQ ID NO:
146
39043 at 155 nucleotides 967 to 1366 of SEQ ID NO:
147
37311 at 156 SEQ ID NO: 148
37009 at 157 the complement of nucleotides 3527-3999
- of SEQ ID
NO: 149
33942 s at 158 nucleotides 3457 to 3843 of SEQ ID NO:
150
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Qualifier CPS SEQ ID NO
39641 at 159 nucleotides 759 to 1194 of SEQ ID NO:
151
529 at i 60 nucleotides 1995 to 2319 of SEQ ID NO:
152
32199 at 161 nucleotides 4778 to 5059 of SEQ ID NO:
153
1426 at 162 nucleotides 2046 to 2334 of SEQ ID NO:
154
31851 at 163 nucleotides 802 to 1201 of SEQ ID NO:
155
34378 at 164 nucleotides 1217-1314 of SEQ ID NO:
156
36173 r at 165 nucleotides 4756 to 4950 of SEQ ID NO:
157
35275 at 166 nucleotides 3552 to 3973 of SEQ ID NO:
158
41184 s at 168 SEQ ID NO: 159
38391 at 170 nucleotides 750 to 1184 of SEQ ID NO:
160
39829 at 171 nucleotides 799 to 1337 of SEQ ID NO:
161
37587 at 172 nucleotides 599 to 1167 of SEQ ID NO:
162
34022 at 173 nucleotides 426-993 of SEQ ID NO: 163
34188 at 175 nucleotides 1283 to 1708 of SEQ ID NO:
164
37647 at 176 nucleotides 1702 to 2244 of SEQ ID NO:
165
40089 at 177 nucleotides 1189 to 1234 of SEQ ID NO:
166
39982 r at 178 nucleotides 1075 to 1489 of SEQ ID NO:
167
32202 at 179 nucleotides 1928 to 2496 of SEQ ID NO:
168
35036 at 180 nucleotides 2895 to 3261 of SEQ ID NO:
169
906 at 181 nucleotides 1993 to 2533 of SEQ ID NO:
170
36033 at 182 nucleotides 562 to 916 of SEQ ID NO:
171
36766 at 183 nucleotides 167-666 of SEQ ID NO: 172
38893 at 184 nucleotides 29281 to 29344 of SEQ ID
NO: 173
37374 at 185 nucleotides 1465-1939 of SEQ ID NO:
174
36599 at 186 SEQ ID NO: 175
464 s at 187 nucleotides 869-1048 of SEQ ID NO: 176
32533 s at 188 nucleotides 91 - 464 of SEQ ID NO: 177
36496 at 189 nucleotides 1061-1514 of SEQ ID NO:
178
36280 at 190 nucleotides 535-953 of SEQ ID NO: 179
38126 at 191 SEQ ID NO: 180
37011 at 192 nucleotides 37 to 460 of SEQ ID NO:
181
39166 s at 193 nucleotides 1583-1790 of SEQ ID NO:
182
1825 at 195 nucleotides 6960-7542 of SEQ ID NO:
183
41577 at 196 nucleotides 5804-6213 of SEQ ID NO:
184
33161 at 197 the complement of nucleotides 1 to 270
of SEQ ID NO:
185
24
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Qualifier CPS SEQ ID NO
31438 s at 198 nucleotides 3247 - 3720 of SEQ ID NO:
186
36372 at 199 nucleotides 2437-3029 of SEQ ID NO:
187
2094 s at 200 nucleotides 2713 -3294 of SEQ ID NO:
188
32977 at 201 nucleotides 2074-2206 of SEQ ID NO:
189
32264 at 202 nucleotides 493-755 of SEQ ID NO: 190
32184 at 203 nucleotides 1691-2175 of SEQ ID NO:
191
35674 at 204 nucleotides 3798-4194 of SEQ ID NO:
192
41249 at 205 the complement of nucleotides 63.056-63481
- of SEQ ID
NO: 193
36762 at 206 nucleotides 1129-1630 of SEQ ID NO:
194
37146 at 207 nucleotides 5897-6262 of SEQ ID NO:
195
867 s at 208 nucleotides 1821-1945 of SEQ ID NO:
196
33500 i at 209 nucleotides 1253-1296 of SEQ ID NO:
197
1575 at 210 nucleotides 4240-4585 of SEQ ID NO:
198
40088 at 211 nucleotides 6655-7207 of SEQ ID NO:
199
37742 at 213 ~ nucleotides 1946-2278 of SEQ ID NO:
200
35992 at 214 nucleotides 1207-1652 of SEQ ID NO:
201
35710 s at 216 nucleotides 63-630 of SEQ ID NO: 202
39119 s at 217 nucleotides 408-727 of SEQ ID NO: 203
34857 at 218 nucleotides 1269-1779 of SEQ ID NO:
204
41198 at 219 nucleotides 1589-2106 of SEQ ID NO:
205
34476 r at 220 nucleotides 4012-4358 of SEQ ID NO:
206
35772 at 221 SEQ ID NO: 207
34660 at 222 the complement of nucleotides 40-615
- of SEQ ID NO:
208
35648 at 223 ' SEQ ID NO: 209
AFFX-HUMRGE 225 nucleotides 62-1969 of SEQ ID NO: 210
/M10098 3 at
31324 at 226 nucleotides 51-308 of SEQ ID NO: 211
1395 at 227 nucleotides 433-1039 of SEQ ID NO: 212
32066-g at 228 SEQ ID NO: 213
1107 s at 229 nucleotides 7-602 of SEQ ID NO: 214
1097 s at 230 SEQ ID NO: 215
35591 at 231 nucleotides 1711-2087 of SEQ ID NO:
216
32815 at 232 the complement of nucleotides 49-265
- of SEQ ID NO:
217
36231 at 233 SEQ ID NO: 218
38823 s at 234 the complement of nucleotides 57-557
of SEQ ID NO:
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Qualifier CPS SEQ ID NO
219
32618 at 235 nucleotides 489-909 of SEQ ID NO: 220
2092 s at 236 nucleotides 824-1229 of SEQ ID NO: 221
37184 at 237 nucleotides 1631-2037 of SEQ ID NO:
222
37120 at 238 nucleotides 1870-2379 of SEQ ID NO:
223
1237 at 239 nucleotides 658-1204 of SEQ ID NO: 224
37310 at 241 nucleotides 5668-7083 of SEQ ID NO:
225
40541 at 242 nucleotides 1030-1412 of SEQ ID NO:
226
31346 at 244 nucleotides 647-1187 of SEQ ID NO: 227
37875 at 245 nucleotides 2330-2672 of SEQ ID NO:
228
38125 at 246 nucleotides 2357-2473 of SEQ ID NO:
229
859 at 247 nucleotides 4693-5071 of SEQ ID NO:
230
35792 at 249 nucleotides 884-1174 of SEQ ID NO: 231
34946 at 250 nucleotides 386-895 of SEQ ID NO: 232
33956 at 253 nucleotides 90-594 of SEQ ID NO: 233
32975-g at 254 nucleotides 18770-18875 of SEQ ID NO:
234
38582 at 255 the complement of nucleotides 40 to
- 288 of SEQ ID NO:
235
181_g at 256 nucleotides 1464-1864 of SEQ ID NO:
236.
37864 s at 257 nucleotides 1108-1568 of SEQ ID NO:
237
34704 r at 258 SEQ ID NO: 238
32163 f at 259 SEQ ID NO: 239
41189 at 260 nucleotides 1161-1608 of SEQ ID NO:
240
41698 at 261 nucleotides 45240-45830 of SEQ ID NO:
241
40456 at 262 nucleotides 733-1310 of SEQ ID NO: 242
41227 at 263 nucleotides 35752-35804 of SEQ ID NO:
243
36100 at 264 nucleotides 2613-3118 of SEQ ID NO:
244
36411 s at 265 nucleotides 1623-2080 of SEQ ID NO:
245
41167 at 266 nucleotides 1596-2100 of SEQ ID NO:
246
41819 at 267 nucleotides 2242-2578 of SEQ ID NO:
247
38389 at 268 nucleotides 960-1377 of SEQ ID NO: 248
37975 at 269 nucleotides 3684-4231 of SEQ ID NO:
249
39640 at 270 nucleotides 2415-2938 of SEQ ID NO:
250
38010 at 271 nucleotides 1044-1494 of SEQ ID NO:
251
32675 at 272 nucleotides 972 - 1411 of SEQ ID NO:
252
1531 at 273 nucleotides 1b91-1891 of SEQ ID NO:
253
2b
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Qualifier CPS SEQ ID NO
40646 at 274 nucleotides 2496-3012 of SEQ ID NO:
254
39474 s at 275 nucleotides 22-507 of SEQ ID NO: 255
34498 at 276 nucleotides 1434-1983 of SEQ ID NO:
256
37654 at 277 nucleotides 1580-2043 of SEQ ID NO:
257
408 at 278 nucleotides 1412-1851 of SEQ ID NO:
258
38340 at 279 nucleotides 4103-4434 of SEQ ID NO:
259
1937 at 280 SEQ ID NO: 260
41638 at 281 nucleotides 1696-1922 of SEQ ID NO:
261
36138 at 282 nucleotides 943-1477 of SEQ ID NO: 262
32407 f at 283 nucleotides 3-280 of SEQ ID NO: 263
38131 at 284 nucleotides 1240-1517 of SEQ ID NO:
264
39775 at 285 nucleotides 18180 -18249 of SEQ ID NO:
265
318 at 286 nucleotides 601-838 of SEQ ID NO: 266
39402 at 287 nucleotides 927-1473 of SEQ ID NO: 267
36543 at 288 nucleotides 1723-2013 of SEQ ID NO:
268
1788 s at 289 nucleotides 1622-2058 of SEQ ID NO:
269
34702 f at 290 nucleotides 534-575 of SEQ ID NO: 270
40951 at 291 nucleotides 1860-2099 of SEQ ID NO:
271
35313 at 292 nucleotides 6412-6826 of SEQ ID NO:
272
1520 s at 293 SEQ ID NO: 273
40171 at 295 SEQ ID NO: 274
32162 r at 296 nucleotides 420-480 of SEQ ID NO: 275
1369 s at 297 nucleotides 3645-4005 of SEQ ID NO:
276
34490 f at 298 SEQ ID NO: 277
36710 at 300 nucleotides 74-557 of SEQ ID N0:,.27-8
37220 at 301 SEQ ID NO: 279
32003 at 302 nucleotides 1144-1487 of SEQ ID NO:
280
1667 s at 303 nucleotides 1531-1603 of SEQ ID NO:
281
731 f at 304 SEQ ID NO: 282
39448 r at 305 the complement of nucleotides 46-344
- - of SEQ ID NO:
283
40385 at 306 nucleotides 207-742 of SEQ ID NO: 284
37603 at 307 nucleotides 1184-1653 of SEQ I~ NO:
285
41046 s at 308 nucleotides 5551-6046 of SEQ ID NO:
286
37456 at 309 SEQ ID NO: 287
31828 r at 310 nucleotides 1750 to 2274 of SEQ ID NO:
288
27
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Table 4. SEQ ID Nos and Corresponding Entrez Accession Nos
SEQ ID Entrez Accession Reported Source of Entrez
NO No. Sequence
Homo Sapiens mRNA; cDNA
~
1 AL080080 DKFZp564E1962 (from clone
DKFZ 564E1962
2 M62831 Human transcription factor
ETR101
mRNA
3 J03191 ~ Human profilin mRNA
4 AA806768
D49738 H~an cytoskeleton associated
protein
(CG22) mRNA
6 U55980
H~an mRNA for actin binding
protein
7 D44497 57
8 X66436 H.sapiens hsrl mRNA
9 J04794 Human aldehyde reductase mRNA
D13891 Human mRNA for Id-2H
11 ' U18467 H~an pregnancy-specific beta
1-
1 co rotein 7 PSG7 mRNA
12 X69433 H.sapiens mRNA for mitochondrial
isocitrate deh dro enase (NADP
)
13 AW044624
14 AF035316 Homo sapiens clone 23678 mRNA
Homo sapiens l7beta-hydroxysteroid
dehydrogenase type 10/short
chain L-3-
AF035555 hydroxyacyl-CoA dehydrogenase
(HSD 17B 1 O/SCHAD) mRNA;
nuclear
gene for mitochondrial roduct.
16 AF047181 Homo sapiens NADH-ubiquinone
oxidoreductase subunit CI-SGDH
mRNA
H~an mRNA for proteasome activator
18 D45248 hPA28 subunit beta
21 X12451 H~an mRNA for pro-cathepsin
L (major
excreted rotein MEP
22 AI432401
23 W28652
24 M27830 Human 28S ribosomal RNA gene
H~an semaphorin III family
homolog
U38276 mRNA
26 D28137 Human mRNA for BST-2
28
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SEQ ID Entrez Accession Reported Source of Entrez
NO No. Sequence
Homo sapiens mRNA; cDNA
27 AL050021 DI~FZp564D016 (from clone
DKFZ ~64D016)
28 AA883502
29 D50402 Human mRNA for NRAMP1
31 X91809 H.sapiens mRNA for GAIP protein.
32 AF095791 Homo Sapiens TACC2 protein
(TACC2)
mRNA
33 X91788 H.sapiens mRNA for Icln protein
34 U97105 Homo Sapiens N2A3 mRNA
35 J04162 Human leukocyte IgG receptor
(Fc-
gamma-R mRNA
36 L16842 Human ubiquinol cytochrome-c
reductase
core I rotein mRNA
37 M18737 Human Hanukah factor serine
protease
HuHF mRNA
39 L40586 Homo sapiens iduronate-2-sulphatase
(IDS) mRNA
41 D11327 Human mRNA for protein-tyrosine
hos hatase
42 L11329 Homo Sapiens protein tyrosine
hos hatase (PAC-1) mRNA
43 AA808961
44 AI652978
45 AF025529 Homo Sapiens leucocyte immunoglobulin-
like rece tor-6b (LIR-6) mRNA
46 AF061741 Homo Sapiens retinal short-chain
deh dro enaselreductase retSDRl
mRNA
47 U37690 Human RNA polymerase II subunit
(hsRPB 10) mRNA
48 M26683 Human interferon gamma treatment
inducible mRNA
49 Y00630 Human mRNA for Arg-Serpin
lasmino en activator-inhibitor
2, PAI-2
50 U66047 Homo Sapiens clone Z'3-1 placenta
ex ressed mRNA from chromosome
X
51 U00930 Human clone C4E 1.63 (CAC)n/(GTG)n
re eat-containin mRNA
Homo sapiens DNA sequence
from PAC
232K4 on chromosome 6p22.3.
Contains
52 AL021938 the JUMONJI gene for a hypothetical
141.7 kD protein. Contains
ESTs, STSs, a
CA repeat polymorphism and
genomic
marker D6S260'
29
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SEQ ID Entrez Accession Reported Source of Entrez
NO No. Sequence
Human uridine diphosphoglucose
53 LT27460 pyrophosphorylase mRNA
54 AB007870 Homo Sapiens KIAA0410 mRNA
56 AI040181
61 X73066 H.sapiens NM23-H1 mRNA
62 AI679353
64 AJ224901 Homo ~sapiens mRNA for ZNF198
protein.
65 L13977 Human prolylcarboxypeptidase
mRNA
Homo sapiens mRNA; cDNA
66 AL050159 DKFZp586A0522 (from clone
DKFZ 586A0~22)
67 M74002 Human arginine-rich nuclear
protein
mRNA
68 M64595 Human small G protein (Gx)
mRNA
69 D76444 Homo sapiens hkf 1 mRNA
70 D 14041 Homo Sapiens mRNA for H-2K
binding
factor-2
71 X93209 H.sapiens mRNA for NRD1 convertase
72 AF070644 Homo Sapiens clone 24742 mRNA
se uence
73 AB020713 Homo Sapiens mRNA for KIAA0906
rotein
75 D63476 Human mRNA for KIAA0142 gene
76 N53547
77 L15388 Human G protein-coupled receptor
kinase
(GRKS) mRNA
78 X72308 Homo sapiens mRNA for monocyte
chemotactic rotein-3 MCP-3
79 X01703 Human gene for alpha-tubulin
(b alpha 1)
80 Y18004 Homo Sapiens mRNA for SCML2
protein
81 M27492 Human interleukin 1 receptor
mRNA
82 AL008729 Human DNA sequence from PAC
257A7
on chromosome 6 24
83 D83776 Human mRNA for KIAA0191 gene
84 AB011542 Homo Sapiens mRNA for MEGF9
85 X68277 H~Sapiens CL 100 mRNA for
protein
osine hos hatase
88 299716 H~~ DNA sequence from clone
CTA-
250D10 on chromosome 22 Contains
the
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SEQ ID Entrez Accession Reported Source of Entrez
NO No. Sequence
genes for SREBF2 (sterol regulatory
element binding transcription
factor 2),
AGA (alpha-N-acetylgalactosaminidase),
a gene similar to neuronal-specific
septin
3, a pseudogene similar to
ANT2 (adenine
nucleotide translocator 2),
2 mRNAs base
on ESTs, a genomic marker
D22S 1178, a
CA repeat polymorpism, ESTs
and a CpG
island
89 X76648 H.sapiens mRNA for glutaredoxin
90 W28281
93 U20938 H~an lymphocyte dihydropyrimidine
deh dro enase mRNA
94 M63193 Human platelet-derived endothelial
cell
owth factor mltNA
96 X04412 Human mRNA for plasma gelsolin
97 U77643 Homo sapiens I~12 protein
precursor
mIZNA
99 AF000424 Homo Sapiens LST1 mRNA, cLSTl/C
s lice variant
100 M29039 Human transactivator (jun-B)
gene
102 D38251 Homo sapiens mRNA for RPBS
(XAP4)
103 X14787 Human mIZNA for thrombospondin
106 M16591 Human hemopoietic cell protein-tyrosine
kinase HCI~) ene
107 AB015631 Homo Sapiens mRNA for type
II
membrane rotein
108 U51712
109 D86971 Human ml2NA for KIAA0217 gene
110 M55067 Human 47-kD autosomal chronic
anulomatous disease rotein
mltNA
111 AB029036 Homo Sapiens mRNA for KIAA1113
rotein
Homo Sapiens mRNA; cDNA
112 ~ AL050060 DKFZp566H073 (from clone
DKFZ 566H073)
Human plasma membrane Ca2+
pumping
113 J04027 ATPase mRNA
114 X57351 H~an 1-8D gene from interferon-
inducible ene famil
115 M817~0 H.sapiens myeloid cell nuclear
differentiation anti. en mRNA
116 U90546 Human butyrophilin (BTF4)
mRNA
31
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SEQ ID Entrez Accession Reported Source of Entrez
NO No. Sequence
117 AB018319 Homo Sapiens mRNA for I~IAA0776
rotein
118 D82061 Homo Sapiens mRNA for a member
of the
short-chain alcohol deh dro
enase famil
119 AB014528 Homo sapiens mRNA for KIAA0628
rotein
120 M25280 Human lymph node homing receptor
mRNA
121 X76538 ~ H.sapiens Mpvl7 mRNA
123 U13697 H~an interleukin 1-beta converting
enzyme isoform beta (IL1BCE)
mRNA
124 X62055 H.sapiens PTP1C mRNA forprotein-
t osine hos hatase 1 C
125 AF051323 Homo sapiens Src-associated
adaptor
rotein (SAPS) mRNA
126 M36820 Human cytokine (GRO-beta)
mRNA
127 AI201108
128 D 14664 Human mRNA for KIAA0022 gene
131 D14658 Human mRNA for I~IAA0102 gene
132 AA176780
134 U48213 Human D-site binding protein
gene
135 AF012086 Homo Sapiens Ran binding protein
2
RanBP2a1 ha mRNA
136 U37518 Human TNF-related apoptosis
inducing
ligand TRAIL mRNA
137 AB020661 Homo sapiens mRNA for I~IAA0854
rotein
138 J05037 Human serine dehydratase mRNA
139 AB011148 Homo sapiens mRNA for I~IAA0576
rotein
140 X16863 Human Fc-gamma RIII-1 cDNA
for Fc-
amma rece for III-1 (CD 16)
141 X06948 Human mRNA for high affinity
IgE
rece for al ha=subunit (FcERI)
143 X77956 H.sapiens Id1 mRNA
144 AI760801
145 M34175 Human beta adaptin mRNA
146 U68019 Homo Sapiens mad protein homolog
(hMAD-3) mRNA
147 AF006084 Homo sapiens Arp2/3 protein
complex
subunit 41-Arc (ARC41 ) mRNA
149 AL035079 Human DNA sequence from clone
53C18
32
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SEQ ID Entrez Accession Reported Source of Entrez
NO No. Sequence
on chromosome 11p12-13
Homo Sapiens hUNClBb alternatively-
150 AF004563 s liced mRNA
H~an mRNA for uracil-DNA
151 X52486 glycosylase
Human dual-specificity protein
152 U15932 hos hatase mRNA
Human glomerular epithelial
protein 1
153 U20489 GLEPP 1 mRNA
Homo Sapiens mRNA for Src-like
adapter
154 D89077 rotein
Homo Sapiens mRNA for candidate
tumor
155 AJ224819 su ressor involved in B-CLL
156 X97324 H.sapiens mRNA for adipophilin
157 AF002163 Homo sapiens delta-adaptin
mRNA
Homo Sapiens mRNA; cDNA
158 AL050025 DKFZp564D066 (from clone
DKFZ 564D066
Homo sapiens macrophage capping
protei
160 M94345 mRNA
Homo sapiens mRNA for ADP
161 AB016811 ribos lation factor-like rotein
recoverin photoreceptor protein
[human,
162 543855 retina, mRNA]
163 M36821 Human cytokine (GRO-gamma)
mRNA
Homo Sapiens clone 24411 mRNA
164 AF070606
se uence
165 M62840 Human acyloxyacyl hydrolase
mRNA
Homo Sapiens mRNA for putative
166 AJ224442 meth ltransferase
H~an mRNA for macrophage scavenger
167 D13265 rece for t a II
Human HBV associated factor
(XAP4)
168 U67322 mRNA
Human Clq/MBL/SPA receptor
ClqR(p)
169 U94333 mRNA
170 L78440 Homo sapiens STAT4 mRNA
Homo sapiens mRNA; cDNA
171 AL049309 DKFZp564B176 (from clone
DI~FZ 564B176
Human EDN mIZNA for eosinophil
172 X55988 derived neurotoxin
Human DNA sequence from clone
CTA-
173 AL008637 833B7 on chromosome 22 12.3-13.2
33
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SEQ ID Entrez Accession Reported Source of Entrez
NO No. Sequence
Contains the NCF4 gene for
cytosolic
neutrophil factor 4 (40kD),
the 5' part of
the CSF2RB gene for granulocyte-
macrophage low-affinity colony
stimulating factor 2 receptor
beta, ESTs,
STSs and GSSs
174 M82809 Human annexin IV (ANX4) mRNA
176 U72882 Human interferon-induced leucine
zipper
rotein (IFP35) mRNA
177 AF054825 Homo sapiens VAMPS mRNA
178 AF014398 Homo sapiens myo-inositol
mono hos hatase 2 mRNA
179 U26174 Human pre-granzyme 3 mRNA
181 U49392 H~an allograft inflammatory
factor-1
(AIF-1 mRNA
182 D83174 H~~ mRNA for collagen binding
rotein 2
183 L33075 Homo Sapiens ras GTPase-activating-like
rotein I GAP 1 mRNA
184 AB020630 Homo sapiens mRNA for KIAA0823
rotein
185 AI018098
186 222971 H.sapiens mRNA for M130 antigen
extracellular variant
187 U51333 Human hexokinase III (HI~3)
mRNA
188 K00650 Human fos proto-oncogene (c-fos)
189 U49187 Human placenta (Diff48) mRNA
190 L23134 Homo sapiens metase (MET-1)
mRNA
191 X61118 Human TTG-2 mRNA for a cysteine
rich
rotein with LIM motif
192 AB023211 Homo sapiens mRNA for KIAA0994
rotein
Human DNA sequence from clone
283E3
on chromosome 1p36.21-36.33.
Contains
the alternatively spliced
gene for Matrix
Metalloproteinase in the Female
Reproductive tract MIFRl,
-2,
193 AL031282 MMP21J22A, -B and -C, a novel
gene, the
alternatively spliced CDC2L2
gene for
Cell Division Cycle 2-Lilce
2 (PITSLRE,
p58/GTA, Galactosyltransferase
Associated Protein Kinase)
beta l, beta 2-
l, beta 2-2 and alpha 2-4,
a 4bS Ribosomal
Protein S7 seudoaene, art
of the
34
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SEQ ID NO Entrez Accession Reported Source of Entrez
No. Sequence
I~IAA0447 gene, a novel alternatively
spliced gene similar to many
(archae)bacterial, worm and
yeast
hypothetical genes, and the
GNB 1 gene fo
Guanine Nucleotide Binding
Protein (G
protein), Beta polypeptide
1 (Transducin
Beta chain 1). Contains putative
CpG
islands, ESTs, STSs and GSSs
194 X15376 H~an mRNA for GABA-A receptor,
aroma 2 subunit
195 AB007864 Homo sapiens KIAA0404 mRNA
196 U12471 Human thrombospondin-1 gene
Ig alpha 2 mmunoglobulin A
heavy chain
197 571043 allotype 2 {constant region,
germ line
[human, peripheral blood neutrophils,
Genomic
198 M14758 Homo Sapiens P-glycoprotein
(PGY1)
mRNA
199 X84373 H.sapiens mRNA for nuclear
factor
RIP140
200 M34423 Human beta-galactosidase (GLB1)
mRNA
201 AF087036 Homo Sapiens musculin mRNA
202 U95006 Human D9 splice variant A
mRNA
203 AA631972
204 224724 H.sapiens polyA site DNA
205 AF055008 Homo Sapiens clone 24720 epithelin
1 and
2 mRNA
206 D30783 Homo Sapiens mRNA for epiregulin
.
208 AI142565
210 M10098 Human 18S rRNA gene
211 U82303 Homo Sapiens unknown protein
mRNA
212 L25081 Homo Sapiens GTPase (rhoC)
mRNA
214 M13755 Human interferon-induced 17-kDa/16-kDa
rotein mRNA
216 M13142 H~an factor XI (blood coagulation
factor mRNA
217 AI687419
219 AI961743
220 X93086 H.sapiens mRNA for biliverdin
IX alpha
reductase
221 J04765 Human osteopontin mRNA
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SEQ ID Entrez Accession Reported Source of Entrez
NO No. Sequence
222 L37792 Homo Sapiens syntaxin lA mRNA
223 X91817 H.sapiens mRNA for transketolase-like
rotein
224 581914 IEX-1=radiation-inducible
immediate-
earl ene [human, lacenta,
mRNA]
225 X02419 H.sapiens uPA gene
226 X01630 Human mRNA for argininosuccinate
s thetase
227 AJ001481 Homo sapiens mRNA for DUXl
protein
228 U79725 Human A33 antigen precursor
mRNA
229 M14083 Human beta-migrating plasminogen
activator inhibitor I mRNA
230 U03688 Human dioxin-inducible cytochrome
P450
CYP 1 B 1 mRNA
Human lysophospholipase homolog
(HU-
231 U6796 3
KS mRNA
232 AJ223183 Homo sapiens mRNA for DORA
protein
233 AB018549 Homo Sapiens MD-2 mRNA
Human ABL gene, exon lb and
intron lb,
234 U07563 and putative M8604 Met protein
(M8604
Met) ene
235 AI961220
BB 1 malignant cell expression-enhanced
gene/tumor progression-enhanced
gene
236 582470 [human, UM-UC-9 bladder carcinoma
cell
line, mRNA
Homo sapiens mRNA for immunoglobulin
237 Y14737 lambda heavy chain
240 Y09392 H.sapiens mRNA for WSL-LR,
WSL-S 1
and WSL-S2 roteins
Human DNA sequence from clone
RPS-
963K23 on chromosome 20q13.11-13.2
Contains a KRT18 (Keratin
type I,
Cytoskeletal 18 ~(Cytokeratin
18,
CK18,CYK18)) pseudogene, a
gene for a
novel protein, the SPATA2
gene for
241 AL031685 spermatogenesis associated
protein 2
(KIAA0757) and the 3' end
of the gene for
KIAA0939 (novel Sodium/hydrogen
exchanger family member).
Contains
ESTs, STSs, GSSs and four
putative CpG
islands
Homo Sapiens mRNA; cDNA
242 AL049963 DKFZ 564A132 (from clone
36
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SEQ ID Entrez Accession Reported Source of Entrez
NO No. Sequence
DI~FZp5b4A132)
Homo sapiens DNA sequence
from PAC
454M7 on chromosome Xq25-26.3.
243 AL022162 Contains the OCRLl gene for
Lowe
Oculocerebrorenal Syndrome
protein
OCRL-1. Contains ESTs, STSs
and GSSs
244 AF022375 Homo Sapiens vascular endothelial
growth
factor mRNA
H~an ELAV-like neuronal protein-2
245 U29943 Hel-N2 mRNA
Human protein phosphatase
2A alpha
246 M64929 subunit mRNA
Homo Sapiens FYN binding protein
.
247 AF001862 mRNA
Human l.6Kb mRNA for 2-5A
synthetase
248 X04371 induced b interferon
Human mRNA of X-CGD gene involved
249 X04011 in chronic granulomatous disease
located
. on chromosome X
Homo Sapiens mRNA for
250 AB016789 Glutamine:fructose-6-phosphate
amidotransferase
Homo sapiens E1B 19I~/Bcl-2-binding
251 AF002697 protein Nip3 mRNA, nuclear
gene
encodin mitochondrial rotein
252 D21878 Human mRNA for BST-1
253 U50535 Human BRCA2 region, mRNA sequence
CG006
H~an G protein-coupled receptor
V28
254 U20350 mRNA
255 AF045800 Homo Sapiens gremlin mRNA
Homo Sapiens mRNA for
256 D89974 glycosylphosphatidyl inositol-anchored
rotein GPI-80
257 D31764 Human mRNA for KIAA0064 gene
H~an gene for melanoma growth
258 X54489 stimulato activit MGSA
Homo sapiens mRNA for KIAA0655
259 AB014555 rotein
Human retinoblastoma associated
(RB1)
260 M33647 mRNA
261 D38552 Human mRNA for KIAA0073 gene
Human mRNA for calcium dependent
262 X04106 rotease (small subunit)
37
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SEQ ID NO Entrez Accession Reported Source of Entrez
No. Sequence
263 U92818 Homo Sapiens c33.28 unnamed
HERV-H
rotein mRNA
264 AF010316 Homo Sapiens Pigl2 (PIG12)
mRNA
265 X54486 Human gene for Cl-inhibitor
266 D64142 Human mRNA for histone Hlx
267 M15330 Human interleukin 1-beta (IL1B)
mRNA
268 J02931 H~a~ placental tissue factor
(two forms)
mRNA
269 U48807 H~an MAP kinase phosphatase
(MIDI'-2)
mRNA
Homo Sapiens human endogeneous
270 M27826 retrovirus RTVL-H neutral
protease large
subunit mRNA
Homo Sapiens mRNA; cDNA
271 AL049250 DKFZp564D113 (from clone
DKFZ 564D113
272 AB002308 Homo Sapiens mRNA for KIAA0310
rotein
275 AI817548
276 M28130 Human interleukin 8 (IL8)
.gene
278 238026 H.sapiens mRNA for FALL-39
peptide
antibiotic
280 D49357 Human mRNA for S-adenosylmethionine
s thetase
281 J02871 H~an lung cytochrome P450
(IV
subfamil BI rotein
282 M55405 Homo Sapiens mucin (MUC-3)
mRNA
283 W27095
284 U64197 Homo Sapiens chemokine exodus-1
mRNA
285 X52015 H.sapiens mRNA for inter~eukin-1
rece for ante onist
H.sapiens mRNA for protein
encoded by a
286 X95808 candidate gene, DXS6673E,
for mental
retardation
288 AF027516 Homo sapiens trans-golgi network
lyco rotein 51 (TGN) mRNA
[0041] CCI-779 activity genes represented by each qualifier in Table 2 can be
identified based on the HG-U95Av2 gene chip annotation provided by Affymetrix.
Genes
thus identified are illustrated in Table 5. CCI-779 activity genes can also be
determined
based on the corresponding Entrez accession numbers. In addition, CCI-779
activity :genes
38
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can be determined by BLAST searching the corresponding CPSs, or the
unambiguous
segments of the corresponding SEQ ID NOs, against a human genome sequence
database.
Suitable human genome sequence databases for this purpose include, but are not
limited to,
the NCBI human genome database. The NCBI also provides BLAST programs, such as
"blastn," for searching its sequence databases.
Table 5. CCI-779 Activity Genes
CPS CCI-779 Activity GeneSequences Useful For Malting Probes/Primers
for CCI-779 Activity Genes
1 DKFZP564E1962 SE ID NO: 1
2 ETR101 SE ID NO: 2
3 PFN1 SEQ ID NO: 3
4 APOBEC1L SE ID NO: 4
CKAP1 SE ID NO: 5
6 KIAA0220 SE ID NO: 6
7 COROlA SE ID NO: 7
8 GNL1 SE ID NO: 8
9 AKR1A1 SE ID NO: 9
ID2 SE ID NOS: 10, 289, and 353
11 PSG7 SE ID NO: 11
13 IDH2 SEQ ID NO: 12
14 RERl SEQ ID NO: 13
TUBB SE ID NOS: 14 and 290
16 HADH2 SE ID NO: 15
17 NDUFBS SE ID NO: 16
18 APRT SE ID NOS: 17 and 310 Y00486)
19 PSME2 SE ID NOS: 18 and 291
MTCP1 SE ID NOS: 19 and 311 (Z24459
21 NDUFB3 SEQ ID NOS: 20 and 312 (A203354)
23 CTSL SEQ ID NO: 21
24 FGL2 SE ID NOS: 22 and 292
DKFZP564C1940 SE ID NO: 23
26 28SRNA5 Hs AFFX SE ID NO: 24
27 SEMA3F SE ID NO: 25
28 BST2 SEQ ID NO: 26
29 UNK AL050021 SE ID NO: 27
UBE2L6 SE ID NO: 28
31 SLC11A1 SE ID NOS: 29 and 354
32 CDKN1C SE ID NOS: 30 and 313 (U22398
33 GAIP SE ID NO: 31
34 TACC2 SEQ ID NOS: 32 and 355
CLNS1A SE ID NO: 33
36 DPYSL2 SE ID NO: 34
37 FCGR3A SE ID NO: 35
38 U CRCl SE ID NO: 36
39 GZMA SE ID NO: 37
39
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CPS CCI-779 Activity GeneSequences Useful For Making Probes/Primers
for CCI-779 Activity Genes
41 PSMB10 SEQ ID NOS: 38 and 314 (X71874)
42 IDS SE ID NO: 39
43 AHNAK SEQ ID NOS: 40, 315 (M80899), and
356
44 PTPN7 SE ID NOS: 41 and 293
45 DUSP2 SE ID NO: 42
46 PSMB9 SEQ ID NO: 43
47 UNK AI652978 SE ID NO: 44
48 UNK AF025529 . J SE ID NO: 45
49 SDRl ~ SEQ ID NO: 46
50 . POLR2L SE ID NO: 47
51 SCYA2 SE ID NOS: 48 and 294
52 PAI2 SE ID NO: 49
53 UNK U66047 SE ID NO: 50
54 UNK U00930 SE ID NO: 51
55 JMJ SEQ ID NO: 52
56 UGP2 SE ID NOS: 'S3 and 357
57 KIAA0410 SE ID NO: 54
58 NDUFS7 SE ID NOS: 55 and 316 AC005329
59 KIAA0645 SE ID NO: 56
60 GSTP1 SE ID NOS: 57, 295, and 317 (U12472
61 DECRl SE ID NOS: 58 and 318 U78302
62 PLXNC1 SEQ ID NOS: 59 and 319 (AF030339)
63 TUBA2 SE ID NOS: 60 and 320 AF005392
64 NMEl SEQ ID NO: 61
65 UNK AI679353 SE ID NO: 62
66 RNAHP SE ID NOS: 63 and 321 H68340
67 ZNF 198 SE ID NO: 64
68 PROP SE ID NO: 65
70 DKFZP586A0522 SEQ ID NO: 66
71 SFRSl 1 SE ID NO: 67
72 RAC2 SE ID NO: 68
73 ZFP 103 SE ID NO: 69
74 LOC51580 SE ID NOS: 70 and 358
75 NRD1 SEQ ID NOS: 71 and 359
76 UNK AF070644 SEQ ID NO: 72
77 KIAA0906 SE ID NO: 73
78 MT1F SE ID NOS: 74 and 322 M10943)
79 P85SPR SE ID NO: 75
80 UNK N53547 SE ID NO: 76
81 GPRKS SE ID NOS: 77 and 296
83 SCYA7 SE ID NO: 78
84 TUBA3 SE ID NO: 79
85 SCML2 SE ID NO: 80
87 IL1R1 SE ID NO: 81
88 UNK AL008729 SEQ ID NO: 82
89 KIAA0191 SE ID NO: 83
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CPS CCI-779 Activity Genesequences Useful For Making Probes/Primers
for CCI-779 Activity Genes
90 EGFLS SE ID NO: 84
91 DUSP1 SE ID NO: 85
92 FBP1 SEQ ID NOS: 86 and 323.(U21931
93 HRB SEQ ID NOS: 87 and 324 L42025
94 NAGA SEQ ID NO: 88
95 GLRX SE ID NO: 89
96 UNK W28281 SE ID NOS: 90 and 360
97 UNK AL096740 SE ID NOS: 91, 325 AL096740 , and
361
98 TBXAS1 SEQ ID NOS: 92, 326 (D34625), 362,
and 363
99 DPYD SE ID NO: 93
100 ECGF1 SE ID NOS: 94 and 297
101 TIMP1 SE ID NOS: 9~ and 327 D11139
102 GSN SE ID NO: 96
103 SECTMl SEQ ID NO: 97
104 OLRI SE ID NOS: 98 and 328 AF079167
105 D6S49E SEQ ID NOS: 99 and 364
106 JLJNB ~ SE ID NO: 100
107 PFC SE ID NOS: 101 and 329 AF005664
108 POLR2E SE ID NO: 102
109 THBSl SE ID NO: 103
110 HK2 SE ID NOS: 104 and 330 246376
111 INSIG1 SEQ ID NOS: 105, 331 (U96876), 365,
and 366
112 HCK SEQ ID NOS: 106 and 298
113 HP10390 SE ID NO: 107
114 UNK U51712 SE ID NO: 108
115 KIAA0217 SE ID NO: 109
116 NCF1 SE ID NO: 110
117 KIAA1113 SEQ ID NOS: 111 and 367
118 DKFZP566H073 SEQ ID NO: 112
119 ATP2B1 SE ID NOS: 113 and 368
120 IFITM2 SE ID NO: 114
121 MNDA SE ID NO: 115
122 BTN3A2 SE ID NO: 116
123 KIAA0776 SE ID NO: 117
124 D6S2245E SEQ ID NO: 118
125 KIAA0628 SE ID NO: 119
126 SELL SE ID NO: 120
127 MPV 17 SE ID NO: 121
128 FABPS SE ID NOS: 122 and 332 M94856
129 CASP1 SE ID NOS: 123 and 299
130 PTPN6 SE ID NO: 124
131 SKAP-HOM SEQ ID NO: 125
133 GR02 SE ID NO: 126
134 RRAS SE ID NO: 127
135 KIAA0022 SEQ ID NOS: 128 and 369
136 FLII SEQ ID NOS: 129 and 333 {U80184)
41
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CPS CCI-779 Activity GeneSequences Useful For Making Probes/Primers
for CCI-779 Activity Genes
137 PRF1 SEQ ID NOS: 130 and 334 M28393
138 KIAA0102 SEQ ID NO: 131
139 UNK AA176780 SEQ ID NO: 132
140 PYGL SEQ ID NOS: 133 and 335 (AF046798
141 DBP SE ID NO: 134
143 RANBP2L1 SE ID NO: 135
144 TNFSF10 SE ID NO: 136
145 KIAA0854 ~ SE ID NO: 137
146 SDS I SE ID NOS: 138 and 370
147 KIAA0576 SE ID NO: 139
148 FCGR3B SE ID NO: 140
149 FCER1A SE ID NO: 141
150 CD44 SE ID NOS: 142 and 336 (L05424
151 ID1 SE ID NOS: 143 and 300
152 UNK AI760801 SE IDNO: 14
4
153 ADTB2 _
SEQ ID NO: 145
154 MADH3 SE ID NOS: 146 and 301
155 ARPC1B SE ID NO: 147
156 TALDO1 SEQ ID NOS: 148, 337 AF010400 ,
and 371
157 UNK AL035079 SEQ ID NO: 149
158 STXBPl SE ID NO: 150
159 UNG2 SEQ ID NO: 151
160 DUSPS SE ID NO: 152
161 PTPRO SEQ ID NO: 153
162 SLA SE ID NOS: 154 and 302
163 RFP2 SEQ ID NO: 155
164 ADFP SEQ ID NOS: 156 and 372
165 ADTD SE ID NOS: 157 and 373
166 ADTG SEQ ID NO: 158
168 UNK X87344 SE ID NOS: 159 and 338 (X87344
170 CAPG SE ID NO: 160
171 ARL7 SE ID NO: 161
172 RCV 1 SE ID NO: 162
173 GR03 SE ID N0: 163
175 UNK AF070606 SEQ ID NO: 164
176 AOAH SE ID NO: 165
177 UNK AJ224442 SE ID NO: 166
178 MSRl SEQ ID NO: 167
179 XAP4 SE ID NO: 168
180 C 1 R SE ID NO: 169
181 STAT4 SE ID NO: 170
182 UNK AL049309 SEQ ID NO: 171
183 RNASE2 SE ID NO: 172
184 NCF4 SE ID NOS: 173 and 303
185 ANXA4 SE ID NO: 174
186 ME2 SE ID NOS: 175 and 339 M55905
42
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CPS CCI-779 Activity GeneSequences Useful For Making Probes/Primers
for CCI-779 Activity Genes
187 IFI35 SE IDNO: 176
188 VAMPS SE ID N0: 177
189 IMPA2 SEQ ID NO: 178
190 GZMK SE ID NO: 179
191 BGN SE ID NOS: 180 and 340 J04599
192 AIF1 SE ID NO: 181
193 CBP2 SE ID NO: 182
195 I GAPl SE ID NO: 183
196 KIAA0823 SEQ ID NO: 184
197 UNK AI018098 SE ID NOS: 185 and 374
198 CD163 SE ID NO: 186
199 HK3 SE ID NO: 187
200 FOS SEQ ID NO: 188
201 DIFF48 SE ID NO: 189
202 UNK L23134 SE ID NO: 190
203 LM02 SE ID NO: 191
204 PDI2 SE ID NO: 192
205 UNK AL031282 SE ID NO: 193
206 GABRG2 SE . ID NO: 194
207 KIAA0404 SE ID NO: 195
208 UNK U12471 SE ID NO: 196
209 IGHAl SEQ ID NOS: 197, 304, and 305
210 ABCB 1 SE ID NO: 198
211 NRIP1 SE ID NO: 199
213 GLB 1 SEQ ID NO: 200
214 MSC SE ID NO: 201
216 UNK U95006 SE ID NO: 202
_ NK4 SEQ ID NO: 203
217
218 UNK 224724 SEQ ID NO: 204
219 GRN SE ID NO: 205
220 EREG SE ID NO: 206
221 KIAA0382 SE ID NOS: 207 and 341 AB002380
222 RNASE6 SEQ ID NO: 2fl8
223 KIAA0442 SE ID NOS: 209, 342 AB007902 , and
375
225 18SRNA3 Hs AFFX SEQ ID NO: 21.0
226 UNK U82303 SE ID NO: 211
227 ARHC SE ID NO: 212
228 CREM SE ID NOS: 213, 306, and 343 568134
229 ISG15 SE ID NO: 214
230 CCR7 SE ID NOS: 215 and 344 L31584)
231 F11 SE ID NOS: 216 and 376
232 UNK AI687419 SEQ ID NO: 217
233 UNK AC002073 SE ID NOS: 218, 345 (AC002073 ,
and 377
234 STK17A SE I~ NO: 219 .
235 BLVRA SE ID NO: 220
236 SPPl SE ID NOS: 221 and 307
43
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CPS CCI-779 Activity Gene.Sequences Useful For Making Probes/Primers
for CCI-779 Activity Genes
2 STX1A SE ID NO: 222
37
_ TKTL1 SE ID NO: 223_
238
239 IER3 SEQ ID N0: 224
241 PLAU SE ID NO: 225
242 ASS SE ID NO: 226
244 DUX1 SE ID NO: 227
245 GPA33 SEQ ID NO: 228
246 PAI1 ~ SE ID NO: 229
247 CYP1B1 I SE ID NOS: 230 and 308
249 HU-KS SE ID NOS: 231 and 378
250 DORA SE ID NO: 232
253 MD-2 SEQ ID NO: 233
254 UNK U07563 SE ID NO: 234
255 SPINKl SE ID NO: 235
256 UNK 582470 SE ID NO: 236
257 IGHG3 SEQ ID NO: 237
258 UNK AA151971 SE ID NOS: 238, 309, 346 (AA151971),
and 379
259 UNK AA216639 SEQ ID NOS: 239 and 347 AA216639
260 TNFRSF12 SE ID NO: 240
261 UNK AL031685 SE ID NO: 241
262 UNK AL049963 SE ID NO: 242
263 APELIN SEQ ID NO: 243
264 VEGF SE ID NO: 244
265 ELAVL2 SE ID NO: 245
266 PPP2R2A SE ID NO: 246
267 UNK AF001862 SE ID NOS: 247 and 380
268 OASl SE ID NO: 248
269 CYBB SE ID NO: 249
270 GFPT2 SEQ ID NO: 250
271 BNIP3 SE ID NO: 251
272 BST1 SE ID NO: 252
273 UNK U50535 SE ID NO: 253
274 CX3CR1 SE ID NO: 254
275 CKTSF 1 B 1 SE ID NO: 255
276 VNN2 SEQ ID NO: 256
277 KIAA0064 SEQ ID NOS: 257 and 381
278 GRO1 SE ID NO: 258
279 KIAA0655 SE ID NO: 259
280 RB 1 SE ID NO: 260
281 KIAA0073 SE ID NO: 261
282 CAPN4 SE ID NO: 262
283 UNK U92818 SEQ ID NO: 263
284 MGST1L1 SE ID NO: 264
285 C1NH SE ID NO: 265
286 H1FX SE ID NO: 266
287 IL1B SE ID NO: 267
44
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CPS CCI-779 Activity GeneSequences Useful For Making Probes/Primers
CCI-779 Activity Genes
f
o
r
288 F3 _
_
_
SEQ ID NO: 268
289 DUSP4 SEQ ID NO: 269
290 HUMRTVLH3 SEQ ID NO: 270
291 UNK AL049250 SEQ ID NO: 271
292 UNK AB002308 SE ID NO: 272
293 EDNl SE ID NOS: 273 and 348 J05008
295 FRAT2 SE ID NOS: 274 and 349 (AF062739
296 UNK AI817548 SEQ ID NOS: 275 and 382
297 IL8 SEQ ID NO: 276
298 FSCN2 SE ID NOS: 277, 350 AI189621 , and
383
300 CAMP SEQ ID NO: 278
301 FCGRlA SE ID NOS: 279 and 351 M63835
30_2 MAT1A SE ID NOS: 280 and 384
303 CYP4B 1 SE ID NO: 281
304 MUC3 SE ID NO: 282
305 B7 SEQ ID NO: 283
306 SCYA20 SE ID NO: 284
307 IL1RN SE ID NO: 285
_308 ZNF261 SE ID NO: 286
309 LGALS2 SE ID NOS: 287, 352 AL022315), and
385
310 TGN51 ~ SEQ' ID NOS: 288 and 386
~
[0042] In one embodiment, the BLAST search of the NCBI human genome database
is conducted by using CPSs. Genes) that aligns to a given CPS with at least
95% sequence
identity can be identified. In many cases, the identified genes) has at least
96%, 97%, 98%,
99%, or more sequence identity with the CPS. The results of the BLAST search
are
detailed below.
(0043] CPS 1 corresponds to DKFZP564E1962 (TXNDC) which encodes
thioredoxin domain-containing. This gene has LocusID: 81542, and is located on
chromosome 14 with reported cytogenetic location 14q21.3. The gene resides in
.genomic
locus NT 025892 (NCBI Genome Annotation). The gene product is a member of the
thioredoxin family.
[0044] CPS 1 also has 86-90% sequence identity with an intron sequence of
GK003
which encodes GK003 protein. GK003 has LocusID: 57002, and is located on
chromosome
7 with reported cytogenetic location 7p15.2. In addition, fragments of CPS 1
align with a
chromosomal region on chromosome 13 and an intron sequence of OATPRP4 with 87-
95%
sequence identity. The chromosomal region on chromosome 13 is located near
ING1 which
encodes inhibitor of growth family, member 1, and has LocusID: 3621. OATPRP4
encodes
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organic anion transporter polypeptide-related protein 4, and has LocusID:
81796 with
reported cytogenetic location 8q13.1.
[0045] CPS 2 corresponds to ETR101 which encodes immediate early protein. This
gene has LocusID: 9592, and is located on chromosome 19 with reported
cytogenetic
location 19p 13.13. The gene resides in genomic locus NT 031915 (NCBI Genome
Annotation). Expression of immediate early protein can be induced by TPA
stimulation in
promyelocytic leukemia cell line HL-60 and in other leukemia cell lines.
[0046] A fragment of CPS 2 (nucleotide 309 to 492 of CPS 2) shows 98%
sequence identity with an intron sequence of LOC169782. LOC169782 encodes a
protein
similar to transcription factor IIIA (Factor A) (TFIIIA), and has reported
cytogenetic
location 9p24.1.
[0047] CPS 3 corresponds to PFNl which encodes profilin 1. This gene has
LocusID: 5216, and is located on chromosome 17 with reported cytogenetic
location
17p13.3. The gene resides in genomic locus NT 033299 (NCBI Genome Annotation).
Profilin 1 is a ubiquitous actin monomer-binding protein belonging to the
profilin family. It
is thought to regulate actin polymerization in response to extracellular
signals. Deletion of
PFNl gene is associated with Miller-Dieker syndrome.
[0048] Nucleotides 7 to 406 of CPS 3 align with various regions in the human
genome with 86-93% sequence identity. These regions include LOC163511, COAS3,
a
region near LOC149010, a region near LOC200030, an intron sequence of
DKFZp434D177, FLJ20719, LOC199970, and LOC206456. LOC163511 encodes a
protein similar to profilin I, and has reported cytogenetic location 1q23.2.
COAS3 encodes
chromosome 1 amplified sequence 3, and has LocusID: 200025 with reported
cytogenetic
location 1 q12. LOC 149010 encodes a protein similar to hypothetical protein
DI~FZp434D177, and has reported cytogenetic location 1q12. LOC200030 encodes a
protein similar to hypothetical protein DJ328E19.C1.1, and has reported
cytogenetic
location 1 q12. DKFZp434D 177 encodes hypothetical protein DKFZp434D 177, and
has
LocusID: 84224 with reported cytogenetic location 1p36.12. FLJ20719 encodes
hypothetical protein FLJ20719, and has LocusID: 55672 with reported
cytogenetic location
1p31. LOC199970 has reported cytogenetic location lpll.l. LOC206456 encodes a
protein similar to chain P, structure of bovine beta-actin-profilin complex
with actin bound
Atp phosphates solvent accessible. LOC206456 is located on chromosome 6.
46
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[0049] CPS 4 corresponds to APOBEC1L (APOBEC3C) which encodes a protein
similar to APOBEC1 protein. APOBEC1L .gene has LocusID: 27350, and is located
on
chromosome 22 with reported cytogenetic location 22q13.1-q13.2. APOBEC1L gene
product is similar to phorbolin (DJ742C19.2), and may catalyze hydrolytic
deamination of
cytidine nucleotides. The gene product contains a cytidine deaminase zinc-
binding domain.
[0050] CPS 4 also has 91°/~ sequence identity with LOC200316 which
encodes a
protein similar to phorbolin 3 (APOBEC1-like). LOC200316 has LocusID: 200316
with
reported cytogenetic location 22q13.1. In addition, CPS 4 aligns with two
other regions on
chromosome 22 with 89-92% sequence identity.
[0051] CPS 5 corresponds to CKAP 1 which encodes cytoskeleton-associated
protein 1. This gene has LocusID: 1155, and is located on chromosome 19 with
reported
cytogenetic location 19q13.11-q13.12. The gene resides in genomic locus NT
011296
(NCBI Genome Annotation). Cytoskeleton-associated protein 1 associates with
microtubules. It contains a glycine domain which plays a role in association
with
microtubules.
[0052] Affymetrix annotation suggests that CPS 6 corresponds to KIAA0220 which
has LocusID: 23117 and is located at chromosome 16p12.1. Blast search of the
Entrez
human genome sequence database shows that CPS 6 has 99% sequence identity to a
region
on chromosome 16. This region is near LOC2~5565, and resides in genomic locus
NT 035368 (NCBI Genome Annotation).
[0053] In addition, fragments of CPS 6 align with various chromosomal regions
with at least 90% sequence identity: These regions include LOC220~55,
LOC124302, a
chromosomal region near LOC220567, a chromosomal region near LOC254081, and a
chromosomal region near LOC197363. LOC220555 encodes a protein similar to
nuclear
pore complex interacting protein, and has reported cytogenetic location 16p
11.2.
LOC124302 encodes a protein similar to nuclear pore complex interacting
protein, and has
reported cytogenetic location 18p11.1. LOC220567 encodes a protein similar to
apolipoprotein B48 receptor, and is located at chromosome 16q13. LOC254081
encodes a
protein similar to group X secretory phospholipase A2 precursor
(phosphatidylcholine 2-
acylhydrolase GX) (GX sPLA2) (sPLA2-X), and is located on chromosome 16.
LOC197363 encodes a protein similar to ataxin 2 related protein (isoform 1),
and is located
on chromosome 16.
47
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[0054] CPS 7 corresponds to COROlA which encodes coronin, actin binding
protein, lA. This gene has LocusID: 11151, and is located on chromosome 16
with
reported cytogenetic location 16q13. The gene resides in genomic locus NT
033291 (NCBI
Genome Annotation). The gene product (coronin lA) binds to actin, and may be
involved
in mitosis, cell motility, formation of phagocytic vacuoles and phagocytosis.
Coronin lA
has at least five WD domains.
[0055] CPS 8 corresponds to GNL1 which encodes guanine nucleotide binding
protein-like 1. This gene has LocusID: 2794, and ishocated on chromosome 6
with reported
cytogenetic location 6p21.3. The gene resides in genomic locus NT 007592 (NCBI
Genome Annotation). The GNL1 gene, identified in the human major
histocompatibility
complex class I region, shows a high degree of similarity with its mouse
counterpart. The
GNL1 gene is located less than 2 kb centromeric to HLA-E, in the same
transcriptional
orientation. GNL1 is telomeric to HLA-B and HLA-C.
[0056] CPS 9 corresponds to AKRlAl which encodes aldo-keto reductase family 1,
member A1 (aldehyde reductase). This gene has LocusID: 10327, and is located
on
chromosome 1 with reported cytogenetic location 1p33-p32. The gene resides in
genomic
locus NT 032972 (NCBI Genome Annotation). Aldehyde reductase (aldo-keto
reductase
family 1, member Al) reduces carbonyl-containing substrates, and may
metabolize
xenobiotics. It is a NADPH-dependent member of the aldo-keto reductase
superfamily.
[0057] CPS 10 corresponds to ID2 which encodes inhibitor of DNA binding 2,
dominant negative helix-loop-helix protein. This gene has LocusID: 3398, and
is located on
chromosome 2 with reported cytogenetic location 2p25. The gene resides in
genomic locus
NT 005334 (NCBI Genome Annotation). The gene product is a member of the Id
helix-
loop-helix family of proteins, and may negatively regulate cell
differentiation.
[0058] CPS 10 also has 95% sequence identity with an intron sequence of PTPRG.
PTPRG encodes protein tyrosine phosphatase, receptor type, G, and has LocusID:
5793
with reported cytogenetic location 3p21-p14. The protein encoded by PTPRG gene
is a
member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be
signaling
molecules that regulate a variety of cellular processes including cell
.growth, differentiation,
mitotic cycle, and oncogenic transformation. The PTP encoded by PTPRG gene
possesses
an extracellular region, a single transmembrane region, and two tandem
intracytoplasmic
catalytic domains, and thus represents a receptor-type PTP. The extracellular
region of this
PTP contains a carbonic anhydrase-like (CAH) domain, which is also found in
the
48
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extracellular region of PTPRBETAJ~ETA. PTPRG gene is located in a chromosomal
region that is frequently deleted in renal cell carcinoma and lung carcinoma,
and thus is
thought to be a candidate tumor suppressor gene.
[0059] In addition, CPS 10 aligns with a chromosomal region near LOC140282
with
88% sequence identity. ,LOC140282 encodes a protein similar to translationally
controlled
tumor protein (TCTP) (p23) (Histamine-releasing factor) (HRF), and has
reported
cytogenetic location 21 q21.3.
[0060] Affymetrix annotation suggests that CPS 11 corresponds to PSG7 which
encodes pregnancy specific beta-1-glycoprotein 7 and has LocusID: 5676. PSG7
is located
at chromosome 19q13.2.
[0061] Blast search of the Entrez human genome sequence database shows that
CPS
11 aligns with a region 3' to PSG1 with at least 98% sequence identity. PSG1
encodes
pregnancy specific beta-1-glycoprotein, and has LocusID: 5669 with reported
cytogenetic
location 19q13.2. The gene product is a member of the pregnancy-specific
glycoprotein
(PSG) and CEA families.
[0062] Moreover, CPS 11 has 92-95% sequence identity with various regions on
chromosome 19. They include PSG2, PSG9, a region near PSG3, and a region near
PSG7.
PSG2 encodes pregnancy specific beta-1-glycoprotein 2, and has LocusID: 5670
with
reported cytogenetic location 19q13.1-q13.2. PSG9 encodes pregnancy specific
beta-1-
glycoprotein 9, and has LocusID: 5678 with reported cytogenetic location
19q13.2. PSG3
encodes pregnancy specific beta-1-glycoprotein 3, and has LocusID: 5671 with
reported
cytogenetic location 19q13.2. PSG7 encodes pregnancy specific beta-1-
glycoprotein 7, and
has LocusID: 5676 with reported cytogenetic location 19q13.2.
[0063] CPS 13 corresponds to IDH2 which encodes isocitrate dehydrogenase 2
(NADP+), mitochondrial. This gene has LocusID: 3418, and is located on
chromosome 15
with reported cytogenetic location 15q26.1. The gene resides in genomic locus
NT 033276
(NCBI Genome Annotation). Mitochondrial NADP(+)-specific isocitrate
dehydrogenase 2
can decarboxylate isocitrate into alpha-ketoglutarate.
[0064] CPS 14 corresponds to RERl which encodes a protein similar to S.
cerevisiae RERl. This gene has LocusID: 11079, and is located on chromosome 1
with
reported cytogenetic location lpter-q24. The gene resides in genomic locus NT
00430
(NCBI Genome Annotation).
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[0065] CPS 15 corresponds to TUBB which encodes tubulin, beta polypeptide.
This
gene has LocusID: 7280, and is located on chromosome 6 with reported
cytogenetic
location 6p21.3. The gene resides in genomic locus NT 034880 (NCBI Genome
Annotation). Beta-tubulin polymerizes to form microtubules, and is a member of
a family
of structural proteins.
[0066] CPS 16 corresponds to HADH2 which encodes hydroxyacyl-Coenzyme A
dehydrogenase, type II. This gene has LocusID: 3028, and is located on
chromosome X
with reported cytogenetic location Xp11.2. The gent a resides in genomic locus
NT 011799
(NCBI Genome Annotation). The gene product can bind to amyloid-beta peptide.
(0067] CPS 17 corresponds to NDUFBS which encodes NADH dehydrogenase
(ubiquinone) 1 beta subcomplex, 5 (l6kD, SGDH). This gene has LocusID: 4711,
and is
located on chromosome 3 with reported cytogenetic location 3q27.1. The gene
resides in
genomic locus NT 022396 (NCBI Genome Annotation). The gene product is a
subunit of
NADH-ubiquinone oxidoreductase (complex I). It can transport electrons from
NADH to
ubiquinone.
[0068] CPS 17 also shows 77% sequence identity with a chromosomal region near
LOC205833. LOC205833 has reported cytogenetic location 4q34.3.
[0069] CPS 18 corresponds to APRT which encodes adenine
phosphoribosyltransferase. This gene has LocusID: 353, and is located on
chromosome 16
with reported cytogenetic location 16q24. The gene resides in genomic locus NT
010404
(NCBI Genome Annotation). Adenine phosphoribosyltransferase belongs to the
purine/pyrimidine phosphoribosyltransferase family. This enzyme catalyzes the
formation
of AMP and inorganic pyrophosphate from adenine and ~-phosphoribosyl-1-
pyrophosphate
(PRPP). It can also produce adenine as a by-product of the polyamine
biosynthesis
pathway. A homozygous deficiency in this enzyme may cause 2,8-dihydroxyadenine
urolithiasis.
[0070] CPS 19 corresponds to PSME2 which encodes proteasome (prosome,
macropain) activator subunit 2 (PA28 beta). This gene has LocusID: 5721, and
is located
on chromosome 14 with reported cytogenetic location 14q11.2. The gene resides
in
genomia locus NT 025892 (NCBI Genome Annotation).
[0071] CPS 19 also aligns with LOC220462 with 97% sequence identity.
LOC220462 encodes a protein similar to proteasome activator complex subunit 2
(Proteasome activator 28-beta subunit) (PA28beta) .(PA28b) (Activator of
multicatalytic
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protease subunit 2) (11S regulator complex beta subunit) (REG-beta). LOC220462
has
reported cytogenetic location 13q14.11. In addition, CPS 19 has about 90-96%
sequence
identity with LOC257093, LOC 166868, and an intron sequence of LOC152940.
LOC257093 encodes a protein similar to proteasome activator complex subunit 2
(Proteasome activator 28-beta subunit), and is located on chromosome 5. LOC
166868
encodes a protein similar to PA28beta, and has reported cytogenetic location
4p14.
LOC152940 has reported cytogenetic location 4q31.3-q32.1. Furthermore,
fragments of
CPS 17 show 86-97% sequence identity with LOC220220 and LOC206704. LOC220220
encodes a protein similar to PA28beta, and has reported cytogenetic location
1Op11.23.
LOC206704 also encodes a protein similar to PA28beta, and is located on
chromosome
8p21.1.
[0072] CPS 20 corresponds to MTCP1 which encodes mature T-cell proliferation
1.
This gene has LocusID: 4515, and is located on chromosome X with reported
cytogenetic
location Xq28. The gene resides in genomic locus NT 025965 (NCBI Genome
Annotation). The gene product may be involved in the leukemogenic process of
mature T
cell proliferation.
[0073] CPS 21 corresponds to NDUFB3 which encodes NADH dehydrogenase
(ubiquinone) 1 beta subcomplex, 3 (l2kD, B12). This gene has LocusID: 4709,
and is
located on chromosome 2 with reported cytogenetic location 2q31.3. The gene
resides in
genomic locus NT 005370 (NCBI Genome Annotation). The multisubunit
NADH:ubiquinone oxidoreductase (complex I) is an enzyme complex in the
electron
transport chain of mitochondria. NDUFB3 gene product is a subunit of NADH-
ubiquinone
oxidoreductase (complex I), and can transport electrons from NADH to
ubiquinone.
[0074] CPS 21 also has about 96% sequence identity with NDUFB3P4.
NDUFB3P4 encodes NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 3 (l2kD,
B 12) pseudogene 4. It has LocusID: 93995, and is located on chromosome 14.
The gene is
located in an intron of WARS which encodes tryptophanyl-tRNA synthetase and
has
LocusID: 7453 with reported cytogenetic location 14q32.31.
[0075] Moreover, CPS 21 has about 86-91% sequence identity with NDUFB3P3,
and intron sequence of KIAA0893, and an intron sequence of PPP6C. NDUFB3P3
encodes
NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 3 (l2kD, B12) pseudogene 3.
It
has LocusID: 93996, and is located on chromosome 14. KIAA0893 encodes KIAA0893
protein, and has LocusID: 22911 with reported cytogenetic location lp13.2.
PPP6C
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encodes protein phosphatase 6, catalytic subunit, and has LocusID: 5537 with
reported
cytogenetic location 9q34.11.
[0076] CPS 23 corresponds to CTSL which encodes cathepsin L. This gene has
LocusID: 1514, and is located on chromosome 9 with reported cytogenetic
location 9q21-
q22. The gene resides in genomic locus NT 023935 (NCBI Genome Annotation). The
protein encoded by CTSL gene is a lysosomal cysteine proteinase that plays a
role in
intracellular protein catabolism. Its substrates include collagen and elastin,
as well as alpha-
1 protease inhibitor, a major controlling element) of neutrophil elastase
activity. The
encoded protein has been implicated in several pathologic processes, including
myofibril
necrosis in myopathies and in myocardial ischemia, and in the renal tubular
response to
proteinuria. This protein is a member of the peptidase C 1 family. At least
two transcript
variants encoding the same protein have been found for CTSL gene.
[0077] Fragments of CPS 23 have 84-88% sequence identity with LOC118945,
LOC119215, and LOC219343. LOC118945, LOC119215, and LOC219343 encode
proteins similar to cathepsin L precursor (Major excreted protein) (MEP), and
are located at
chromosome 1Oq23.32, 1Oq21.1 and 1Oq23.2, respectively.
[0078] Affymetrix annotation suggests that CPS 24 corresponds to FGL2 which
encodes fibrinogen-like 2 and has LocusID: 10875. FGL2 has the reported
cytogenetic
location at chromosome 7q11.23.
[0079] Blast search of the Entrez human genome database shows that CPS 24
aligns
with the non-protein-coding strand of KIAA1505 with at least 98% sequence
identity.
I~IAA1505 encodes KIAA1505 protein, and has LocusID: 57639 with reported
cytogenetic
location 7p12.3. I~IAA1505 resides in genomic locus NT 007933 (NCBI Genome
Annotation).
[0080] Affymetrix annotation suggests that CPS 25 corresponds to
DKFZP564C 1940 which is also known as LRP 10. LRP 10 encodes low density
lipoprotein
receptor-related protein 10, and has LocusID: 26020. LRP10 is located at
chromosome
l4ql l.l.
[0081] Blast search of the Entrez human genome sequence database shows that
fragments of CPS 26 have 84-98% sequence identity with various regions on
chromosomes
1, 2, 4, 5, 7, 9, 10, 11, 12, 17, 18, X, or Y. For instance, nucleotides 164-
283 and 359-589
have 95% sequence identity with an intron sequence of LOC121292. LOC121292 is
located at chromosome 12q24.31, and resides in genomic locus NT 035241 (NCBI
Genome
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Annotation). Nucleotides 253-323 and 359-589 of CPS 26 align with a region
near
LOC138924 with at least 95% sequence identity. LOC138924 encodes a protein
similar to
peptidyl-Pro cis traps isomerase, and is located at chromosome 9q21.31 and in
genomic
locus NT 008580 (NCBI Genome Annotation). Nucleotides 374-588 of CPS 26 have
93%
sequence identity with a region between DIM1 and FLJ21172. ~DIM1 encodes a
protein
similar to S. pombe diml+, and has LocusID: 10907 with reported cytogenetic
location
18q23. FLJ21172 encodes hypothetical protein FLJ21172, and has LocusID: 79863
with
reported cytogenetic location 18q23. Nucleotides 634-1116 of CPS 26 have 86%
sequence
identity with an intron sequence of MYO 1 D. MYO 1 D encodes myosin ID, and
has
LocusID: 4642 and reported cytogenetic location 17q11-q12.
[0082] CPS 27 corresponds to SEMA3F which encodes 5ema domain,
immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3F.
This gene has
LocusID: 6405, and is located on chromosome 3 with reported cytogenetic
location 3p21.3.
The gene resides in genomic locus NT 006014 (NCBI Genome Annotation). The
semaphorins are a family of proteins that are involved in signaling. A typical
family
member has a secretion signal, a 500-amino acid sema domain, and 16 conserved
cysteine
residues. Sequence comparisons have grouped the secreted semaphorins into 3
general
classes. Members of the semaphorin III family, including human semaphorin III,
chicken
collapsin, and mouse semaphorins A, D, and E, have a basic domain at the C
terminus.
SEMA3F gene product is a secreted member of the semaphorin III family.
[0083] CPS 28 corresponds to BST2 which encodes bone marrow stromal cell
antigen 2. This gene has LocusID: 684, and' is located on chromosome 19 with
reported
cytogenetic location 19p 13.2. The gene resides in genomic locus NT O 11295
(NCBI
Genome Annotation). Bone marrow stromal cells are involved in the growth and
development of B-cells. Bone marrow stromal cell antigen 2 may play a role in
pre-B-cell
growth and in rheumatoid arthritis.
[0084] Blast search of the Entrez human genome sequence database shows that
CPS
29 overlaps or includes a chromosomal region between SLC7A1 and I~IAA0774.
SLC7A1
encodes solute carrier family 7 (cationic amino acid transpouter, y+ system),
member 1.
SLC7A1 has LocusID: 6541, and is located on chromosome 13 with reported
cytogenetic
location 13q12-q14. KIAA0774 encodes KIAA0774 protein, and has LocusID: 23281.
KIAA0774 is located on chromosome 13 with reported cytogenetic location
13q12.2. Both
SLC7A1 and I~IAA0774 have genomic locus NT 009799 (NCBI Genome Annotation).
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CPS 29 is located 3' to the protein-coding regions of both genes. CPS 2~9
matches with the
protein-coding strand of SLC7A1. SLC7A1 gene product can has strong similarity
to
murine Rec-1 (Atrcl), and can transport arginine, lysine and ornithine across
the plasma
membrane.
[0085] CPS 30 corresponds to UBE2L6 which encodes ubiquitin-conjugating
enzyme E2L 6. This gene has LocusID: 9246, and is located on chromosome 11
with
reported cytogenetic location l lql2. The gene resides in genomic locus
NT_033903 (NCBI
Genome Annotation). The gene product is a mem ler of the ubiquitin-conjugating
enzyme
family, and can ubiquitinate cellular proteins and mark them for degradation.
The gene
product can also bind to Hect domains of E3 proteins.
[0086] CPS 31 corresponds to SLC11A1 which encodes solute carrier family 11
(proton-coupled divalent metal ion transporters), member 1. This .gene has
LocusID: 6556,
and is located on chromosome 2 with reported cytogenetic location 2q35. The
gene resides
in genomic locus NT 005403 (NCBI Genome Annotation). The gene product is
similar to
murine Bcg (Nrampl), and may control antimicrobial activity ofmacrophages.
[0087] CPS 32 corresponds to CDI~N1C which encodes cyclin-dependent kinase
inhibitor 1C (p57, I~ip2). This gene has LocusID: 1028, and is located on
chromosome 11
with reported cytogenetic location 11p15.5. The gene resides in genomic locus
NT 009368
(NCBI Genome Annotation). Cyclin-dependent kinase inhibitor 1 C is a tight-
binding
inhibitor of several G1 cyclin/Cdk complexes and a negative regulator of cell
proliferation.
Mutations of CDKN1C are implicated in sporadic cancers and Beckwith-Wiedemann
syndrome, suggesting that CDI~N1C may be a tumor suppressor candidate.
[0088] CPS 32 also has 98% sequence identity with a chromosomal region near
LOC256784. LOC256784 encodes a protein similar to cyclin-dependent kinase
inhibitor
1 C (Cyclin-dependent kinase inhibitor P57) (P57KIP2), and is located on
chromosome 11
with genomic locus NT 009368 (NCBI Genome Annotation).
[0089] CPS 33 corresponds to GAIP (RGS19) which encodes regulator of G-protein
signaling 19. This gene has LocusID: 10287, and is located on chromosome 20
with
reported cytogenetic location 20q13.3. The gene resides in genomic locus NT
011333
(NCBI Genome Annotation). G proteins mediate a number of cellular processes.
The
protein encoded by this gene belongs to the RGS (regulators of G-protein
signaling) family
and can interact with G protein, GAI3. G-protein signaling 19 is a guanosine
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triphosphatase-activating protein that may function to down-regulate Galpha
i/Galpha q-
linked signaling.
[0090] CPS 34 corresponds to TACC2 which encodes transforming, acidic coiled-
coil containing protein 2. This gene has LocusID: 10579, and is located on
chromosome 10
with reported cytogenetic location 1Oq26. The gene resides in genomic locus NT
030764
(NCBI Genome Annotation). Transforming acidic coiled-coil proteins are a
conserved
family of centrosome- and microtubule-interacting proteins that are implicated
in cancer.
The member encoded by TACC2 gene concentrates at centrosomes throughout the
cell
cycle, and it is a candidate breast tumor suppressor and biomarker for tumor
progression.
[0091] CPS 3~ corresponds to CLNS1A which encodes chloride channel,
nucleotide-sensitive, 1 A. This gene has LocusID: 1207, and is located on
chromosome 11
with' reported cytogenetic location 11q13.5-q14. The gene resides in .genomic
locus
NT 033927 (NCBI Genome Annotation). The gene product is associated with a
swelling-
induced chloride channel, and may be involved in aqueous humor formation in
the eye
[0092] CPS 35 also has 88% sequence identity with an intron sequence of TDRKH.
TDRI~H encodes tudor and KH domain-containing protein, and has LocusID: 11022.
It is
located at chromosome 1q21. In addition, nucleotides 66-459 of CPS 35 have 89%
sequence identity with a region near LOC221349. LOC221349 encodes a protein
similar to
chloride conductance regulatory protein ICIn (I(Cln)) (Chloride channel,
nucleotide
sensitive lA) (Chloride ion current inducer protein) (C1CI) (Reticulocyte
PICln), and has
reported cytogenetic location 6p11.2. Nucleotides 1-66 of CPS 35 aligns with
LOC152922
with 98% sequence identity. LOC152922 encodes a protein similar to chloride
conductance
regulatory protein ICIn (I(Cln)) (Chloride channel, nucleotide sensitive lA)
(Chloride ion
current inducer protein) (C1CI) (Reticulocyte PICIn), and is located at
chromosome 4q32.3.
[0093] CPS 36 corresponds to DPYSL2 which encodes dihydropyrimidinase-like 2.
This gene has LocusID: 1808, and is located on chromosome 8 with reported
cytogenetic
location 8p22-p21. The gene resides in genomic locus NT 023666 (NCBI Genome
Annotation). The gene product is a member of the dihydropyrimidinase family.
[0094] CPS 37 corresponds to FCGR3A which encodes Fc fragment of IgG, low
affinity IIIa, receptor for (CD 16). This gene has LocusID: 2214, and is
located on
chromosome 1 with reported cytogenetic location l q23. The gene resides in
genomic locus
NT 004668 (NCBI Genome Annotation). The gene product is type III Fc gamma
receptor,
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and can associate with zeta chain of the T-cell receptor complex (CD3Z). The
gene product
is a member of the immunoglobulin superfamily
[0095] CPS 38 corresponds to UQCRCl which encodes ubiquinol-cytochrome c
reductase core protein I. This gene has LocusID: 7384, and is located on
chromosome 3
with reported cytogenetic location 3p21.3. The gene resides in genomic locus
NT 005990
(NCBI Genome Annotation). The gene product, core I protein, is a subunit of
the
ubiquinol-cytochrome c oxidoreductase in the mitoc~ ondrial respiratory chain.
[0096] CPS 39 corresponds to GZMA which encodes granzyme A (granzyme 1,
cytotoxic T-lymphocyte-associated serine esterase 3). This gene has LocusID:
3001, and is
located on chromosome 5 with reported cytogenetic location Sql 1-q12. The gene
resides in
genomic locus NT 006431 (NCBI Genome Annotation). Cytolytic T lymphocytes
(CTL)
and natural killer (NIA) cells share the ability to recognize, bind, and lyse
specific target
cells. They are thought to protect their host by lysing cells bearing on their
surface
"nonself ' antigens, usually peptides or proteins resulting from infection by
intracellular
pathogens. GZMA gene product is a T cell- and natural killer cell-specific
serine protease
that may function as a common component necessary for lysis of target cells by
cytotoxic T
lymphocytes and natural killer cells.
[0097] CPS 41 corresponds to PSMB 10 which encodes proteasome ~(prosome,
macropain) subunit, beta type, 10. This gene has LocusID: 5699, and is located
on
chromosome 16 with reported cytogenetic location 16q22.1. The gene resides in
genomic
locus NT 010478 (NCBI Genome Annotation). The gene can replace beta subunit
PSMB7
when cells are stimulated by interferon g.
[0098] CPS 42 corresponds to IDS which encodes iduronate 2-sulfatase (Hunter
syndrome). This gene has LocusID: 3423, and is located on chromosome X with
reported
cytogenetic location Xq28. The gene resides in genomic locus NT 019686 (NCBI
Genome
Annotation). Iduronate-2-sulfatase is involved in the lysosomal degradation of
heparan
sulfate and dermatan sulfate. Mutations in this X-chromosome gene that result
in enzymatic
deficiency may lead to the sex-linked Mucopolysaccharidosis Type II, also
known as
Hunter Syndrome. Iduronate-2-sulfatase has a sequence homology with human
arylsulfatases A, B, and C, and human glucosamine-6-sulfatase. A splice
variant of this
gene has been described.
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[0099) Affymetrix annotation suggests that CPS 43corresponds to AHNAI~ which
encodes AHNAI~ nucleoprotein (desmoyokin) and has LocusID: 195. The gene is
located
at chromosome 11 q12-q13.
[0100] Blast search of the Entrez human genome sequence database indicates
that
CPS 43 aligns with a region 3' to LOC221087 with 100% sequence identity.
LOC221087
is hypothetical gene supported by M80899. The gene is located on chromosome l
1q13.1,
and resides in genomic locus NT 033241 (NCBI Genome Annotation).
[0101) CPS 44 corresponds to PTPN7 which encodes protein tyrosine phosphatase,
non-receptor type 7. This gene has LocusID: 5778, and is located on chromosome
1 with
reported cytogenetic location 1 q32.1. The gene resides in genomic locus NT
034408
(NCBI Genome Annotation). The gene product is a member of the protein tyrosine
phosphatase (PTP) family. PTPs are known to be signaling molecules that
regulate a
variety of cellular processes including cell growth, differentiation, mitotic
cycle, and
oncogenic transformation. PTPN7 gene is expressed in a variety of
hematopoietic cells, and
is an early response gene in lymphokine stimulated cells The noncatalytic N-
terminus of
PTPN7 gene product can interact with MAP kinases and suppress the MAP kinase
activities. The gene product is also shown to be involved in the regulation of
T cell antigen
receptor (TCR) signaling, which is thought to function through
dephosphorylating the
molecules related to MAP kinase pathway. At least three alternatively spliced
transcript
variants of this gene, which encode at least two distinct isoforms, have been
reported.
[0102] CPS 45 corresponds to DUSP2 which encodes dual specificity phosphatase
2. This gene has LocusID: 1844, and is located on chromosome 2 with reported
cytogenetic
location 2q11. The gene resides in genomic locus NT 026970 (NCBI Genome
Annotation). The protein encoded by DUSP2 is a member of the dual specificity
protein
phosphatase subfamily. These phosphatases can inactivate their target kinases
by
dephosphorylating both the phosphoserine/threonine and phosphotyrosine
residues. They
negatively regulate members of the mitogen-activated protein (MAP) kinase
superfamily
(MAPK/ERI~, SAPI~/JNI~, p38), which are associated with cellular proliferation
and
differentiation. Different members of the family of dual specificity
phosphatases show
distinct substrate specificities for various MAP kinases, different tissue
distribution and
subcellular localization, and different modes of inducibility of their
expression by
extracellular stimuli. DUSP2 gene product can inactivate ERKl and ERK2, is
expressed in
hematopoietic tissues, and is localized in the nucleus.
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[0103] Affymetrix annotation suggests that CPS 46 corresponds to PSMB9 which
encodes proteasome (prosome, macropain) subunit, beta type, 9 (large
multifunctional
protease 2). PSMB9 has LocusID: 5698, and is located at chromosome 6p21.3.
[0104] Blast search of the Entrez human genome sequence database indicates
that
CPS 46 shows 100% sequence identity with three regions near PSMBB. These
regions are
within genomic locus NT 007592 (NCBI Genome Annotation). PSMBB encodes
proteasome (prosome, macropain) subunit, beta type, 8 (large multifunctional
protease 7).
It has LocusID: 5696 and reported cytogenetic location 6p21.3.
[0105] Blast search of the Entrez human genome sequence database shows that
CPS
47 overlaps or includes an intron sequence of HAN11. HAN11 encodes WD-repeat
protein,
and has LocusID: 10238 with reported cytogenetic location 17q21.33. HAN11
resides in
genomic locus NT 035428 (NCBI Genome Annotation). HAN11 gene product has WD-
repeats, and is similar to plant and 1.
[0106] Blast search of the Entrez human genome sequence database also shows
that
CPS 48 overlaps or includes LILRB 1. LILRB 1 encodes leukocyte immunoglobulin-
like
receptor, subfamily B (with TM and ITIM domains), member 1. LILRB 1 has
LocusID:
10859, and is located on chromosome 19 with reported cytogenetic location
19q13.4.
LILRB 1 resides in genomic locus NT 011225 (NCBI Genome Annotation). The gene
product (leukocyte immunoglobulin-like receptor B1) contains immunoreceptor
tyrosine-
based inhibitory motifs, and can bind to cellular and viral MHC class I
antigens.
[0107] CPS 48 also aligns with LILRB2 with 91% sequence identity. LILRB2
encodes leukocyte immunoglobulin-like receptor, subfamily B (with TM and ITIM
domains), member 2. The gene has LocusID: 10288 and reported cytogenetic
location
19q13.4.
(0108] CPS 49 corresponds to SDRl which encodes short-chain
dehydrogenase/reductase 1. This gene has LocusID: 9249, and is located on
chromosome 1
with reported cytogenetic location 1p36.1. The gene resides in genomic locus
NT 022041
(NCBI Genome Annotation). Short-chain dehydrogenase/reductase 1 can reduce all-
trans-
retinal during bleached visual pigment regeneration.
[0109] Affymetrix annotation suggests that CPS 50 corresponds to POLR2L which
encodes polymerase (RNA) II (DNA directed) polypeptide L, 7.6kDa. POLR2L has
LocusID: 5441, and is located at chromosome 11p15.
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[0110] CPS 51 corresponds to SCYA2 which encodes small inducible cytokine A2
(monocyte chemotactic protein 1). This gene has LocusID: 6347, and is located
on
chromosome 17 with reported cytogenetic location 17q11.2-q2l.l. The -gene
resides in
genomic locus NT 010799 (NCBI Genome Annotation). Cytokine A 2 is a
chemotactic
factor for monocytes.
[0111] CPS 52 corresponds to PAI2 (SERP1NB2) which encodes serine (or
cysteine) proteinase inhibitor, Glade B (ovalbumin), member 2. This :gene has
LocusID:
5055, and is located on chromosome 18 with reported cytogenetic location
18q21.3. The
gene resides in genomic locus NT 033907 (NCBI Genome Annotation). The gene
product
is also known as plasminogen activator inhibitor II, and may function as a
serine protease
inhibitor. It is considered a member of the serpin family of serine protease
inhibitors.
[0112] Blast search of the Entrez human genome sequence database shows that
CPS
53 overlaps or includes LOC158972. LOC1~8972 has reported cytogenetic location
Xq28,
and is located in genomic locus NT 026504 (NCBI Genome Annotation).
[0113] CPS 53 also aligns with a chromosomal region near LOC93052 with 93%
sequence identity. LOC93052 has reported cytogenetic location Xq28.
[0114] Blast search of the Entrez human genome sequence database shows that
CPS
54 overlaps or includes KIAA1564. I~IAA1564 encodes KIAA1564 protein, and has
LocusID: 57680 with reported cytogenetic location l4ql 1.1. KIAA1564 resides
in genomic
locus NT 025892 (NCBI Genome Annotation). CPS 54 matches with the non-protein-
coding strand of KIAA1564.
[0115] Affymetrix annotation indicates that CPS 55 corresponds to JMJ.
Nucleotides 1997 to 198161 of AL021938 (SEQ ID N0:52) have 99% sequence
identity
with JMJ. JMJ encodes jumonji homolog (mouse), and has LocusID: 3720. The
.gene is
located on chromosome 6 with reported cytogenetic location 6p24-p23 and
genomic locus
NT 007592 (NCBI Genome Annotation). JMJ is an ortholog of the mouse jumonji
gene,
which encodes a nuclear protein involved in mouse embryogenesis, including
neural tube
formation. Overexpression of mouse jumonji negatively regulates cell
proliferation. The
jumonji proteins contain a DNA-binding domain, called an AT-rich interaction
domain
(ARID), and share regions of similarity with human retinoblastoma-binding
protein-2 and
the human SMCX protein. Nucleotides 1997 to 198161 of AL021938 match with the
non-
protein-coding strand of JMJ.
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(0116] Nucleotides 1 to 66 of CPS SS have 100% 'sequence identity with a
chromosomal region in genomic locus NT 010463 (NCBI Genome Annotation). This
chromosomal region is located 3' to LOC222499 which has reported cytogenetic
location
16q21.
[0117] CPS 56 corresponds to UGP2 which encodes UDP-glucose
pyrophosphorylase 2. This gene has LocusID: 7360, and is located on chromosome
2 with
reported cytogenetic location 2p14-p13. The gene resides in genomic locus NT
005375
(NCBI Genome Annotation). The enzyme enc, ded by UGP2 is an intermediary in
mammalian carbohydrate interconversions. It can transfer a glucose moiety from
glucose-
1-phosphate to MgUTP and form UDP-glucose and MgPPi.
[0118] Nucleotides 155 to 433 of CPS .56 have 96% sequence identity with
LOC253415. LOC253415 encodes a protein similar to UDP-glucose
pyrophosphorylase 2
(UTP-glucose-1-phosphate uridyltransferase) (UDP-glucose diphosphorylase)
(UGPase 2).
LOC253415 is located on chromosome 2.
[0119] CPS 57 corresponds to KIAA0410. This gene has LocusID: 9818, and is
located on chromosome 13 with reported cytogenetic location 13q12.12. The gene
resides
in genomic locus NT 009799 (NCBI Genome Annotation).
[0120] CPS 58 corresponds to NDUFS7 which encodes NADH dehydrogenase
(ubiquinone) Fe-S protein 7 (20kD) (NADH-coenzyme Q reductase). This gene has
LocusID: 4727, and is located on chromosome 19 with reported cytogenetic
location 19p13.
The gene resides in genomic locus NT 011268 (NCBI Genome Annotation).
[0121] CPS 59 corresponds to KIAA0645. This gene has LocusID: 9681, and is
located on chromosome 22 with reported cytogenetic location 22q12.3. The gene
resides in
genomic locus NT Ol 1520 (NCBI Genome Annotation).
[0122] CPS 60 corresponds to GSTP1 which encodes glutathione S-transferase pi.
This gene has LocusID: 2950, and is located on chromosome 11 with reported
cytogenetic
location 11q13. The gene resides in genomic locus NT 033241 (NCBI Genome
Annotation). Glutathione S-transferases (GSTs) are a family of enzymes that
play a role in
detoxification by catalyzing the conjugation of many hydrophobic and
electrophilic
compounds with reduced glutathione. The soluble GSTs are categorized into 4
main
classes: alpha, mu, pi, and theta. The glutathione S-transferase pi gene
.(GSTP1) is a
polymorphic gene encoding active, functionally different GSTP 1 variant
proteins that are
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thought to function in xenobiotic metabolism and play a role in susceptibility
to cancer, and
other diseases.
[0123] Nucleotides 180 to 558 have 86% sequence identity with a chromosomal
region near DGKA. DGK encodes diacylglycerol kinase, alpha .(80kD), and is
located at
chromosome 12q13.3 with LocusID: 1606.
[0124] CPS 61 corresponds to DECRl which encodes 2,4-dienoyl CoA reductase 1,
mitochondrial. This gene has LocusID: 1666, and is located on chromosome 8
with
reported cytogenetic location 8q21.3. The gene resides in genomic locus NT
034898
(NCBI Genome Annotation). The gene product is an accessory enzyme which
participates
in the beta-oxidation and metabolism of unsaturated fatty enoyl-CoA esters.
[0125] CPS 62 corresponds to PLXNC 1 which encodes plexin C 1. This gene has
LocusID: 10154, and is located on chromosome 12 with reported cytogenetic
location
12q23.3. The gene resides in genomic locus NT 009575 (NCBI Genome Annotation).
Plexin C 1 can function as a receptor for virally-encoded semphorin. It is a
member of the
plexin family.
[0126] CPS 63 corresponds to TUBA2 which encodes tubulin, alpha 2. This gene
has LocusID: 7278, and is located on chromosome 13 with reported cytogenetic
location
13q11. The gene resides in genomic locus NT 009799 .(NCBI Genome Annotation).
Microtubules of the eukaryotic cytoskeleton perform essential and diverse
functions and are
composed of a heterodimer of alpha and beta tubulin. The genes encoding .these
microtubule constituents are part of the tubulin superfamily, which is
composed of six
distinct families. Genes from the alpha, beta and gamma tubulin families are
found in all
eukaryotes. The alpha and beta tubulins represent the major components of
microtubules,
while gamma tubulin plays a critical role in the nucleation of microtubule
assembly. There
are multiple alpha and beta tubulin genes and they are conserved among and
between
species. TUBA2 gene is an alpha tubulin gene that encodes a protein similar to
the moue
testis-specific Tuba3 and Tuba? gene products. TUBA2 gene is located in the
13q11
region, which is associated with the genetic diseases Clouston hidrotic
ectodermal dysplasia
and Kabuki syndrome. Alternative splicing has been observed for this gene and
at least two
variants have been identified.
(0127] CPS 63 has 95-96% sequence identity with H2-ALPHA and LOC112714.
H2-ALPHA encodes alpha-tubulin isotype H2-alpha, and has LocusID: 113457 with
61
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reported cytogenetic location 2q22.1. LOC112714 encodes a protein similar to
alpha
tubulin, and has LocusID: 112714 with reported cytogenetic location 2q14.2.
[0128] In addition, CPS 63 shows 85-90% sequence identity with a chromosomal
region near MGC 16703. MGC 16703 encodes alpha tubulin-like, and is located at
chromosome 22q11.21 with LocusID: 113691. Fragments of CPS have 83-91%
sequence
identity with regions on chromosomes 1 and 22.
[0129] CPS 64 corresponds to NMEl whic i encodes non-metastatic cells 1,
protein
(NM23A) expressed in. This gene has LocusID: 4830, and is located on
chromosome 17
with reported cytogenetic location 17q21.3. The gene resides in genomic locus
NT 010783
(NCBI Genome Annotation). NME1 was reported to have reduced mRNA transcript
levels
in highly metastatic cells. NMEI encodes the "A" isoform of nucleoside
diphosphate
kinase (NDK). NDK exists as a hexamer composed of the "A" (encoded by NMEl)
and
"B" (encoded by NME2) isoforms. Mutations in NMEl have been identified in
aggressive
neuroblastomas. NME1 gene product may have a role in the transcriptional
regulation of c-
myc expression.
[0130] Blast search of the Entrez human genome sequence database shows that
CPS
65 overlaps or includes a chromosomal region between SLC1 lAl and NLI-IF. Both
.genes
are located on chromosome 2 with reported cytogenetic location 2q35 and
genomic locus
NT 005403 (NCBI Genome Annotation). SLC11A1 encodes solute carrier family 11
(proton-coupled divalent metal ion transporters), member 1, and has LocusID:
6556.
SLC11A1 gene product is similar to marine Bcg (Nrampl), and may control
antimicrobial
activity of macrophages. NLI-IF encodes nuclear LIM interactor-interacting
factor, and has
LocusID: 58190. NLI-IF gene product is similar to a region of S. cerevisiae
plasma
membrane phosphatase Psr2p. CPS 65 is located 3' to the protein-coding
sequence of
SLC11A1 and 5' to the protein-coding sequence ofNLl-IF.
[0131] Affymetrix annotation suggests that CPS 66 corresponds to RNAHP which
encodes RNA helicase-related protein and has LocusID: 11325. The gene has
reported
cytogenetic location at chromosome 17q22.
[0132] Blast search of the Entrez human genome sequence database shows that
CPS
66 aligns with a chromosomal region at chromosome 16q13 with at least 95%
sequence
identity. This region resides in genomic locus NT 010498 (NCBI Genome
Annotation),
and is located near MT1 G. MT1 G encodes metallothionein 1 G, and has LocusID:
4495.
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[0133] In addition, CPS 66 has 83-92% sequence identity with various regions
on
chromosomes l, 4, 9, 16 and 20. These regions include MT1H, MT2P1, LOC255917,
LOC127544, LOC149450, a region near MGC10731, and a region near MMP24. MT1H
encodes metallothionein 1H, and has LocusID: 4496 with reported cytogenetic
location
16q13. MT2P 1 encodes metallothionein 2 pseudogene 1 (processed), and is
located at
chromosome 4p11-q21 (LocusID: 4503). MGC10731 has LocusID: 79363; and is
located
at chromosome 1p36.13. LOC255917 encodes a protein similar to Metallothionein-
IE (MT-
1 E), and is located on chromosome 9. LOC 127544 encodes a protein similar to
dJ1174N9.1 (novel protein with IBR domain), and is located at chromosome
1p34.3.
LOC149450 has reported cytogenetic location 1q42.3. MMP24 encodes matrix
metalloproteinase 24 (membrane-inserted), and is located at chromosome 20q11.2
with
LocusID: 10893.
[0134] CPS 67 corresponds to ZNF198 which encodes zinc finger protein 198.
This
gene has LocusID: 7750, and is located on chromosome 13 with reported
cytogenetic
location 13q11-q12. . The gene resides in genomic locus NT 009799 (NCBI Genome
Annotation). Zinc-finger protein 198 contains zinc fingers.
[0135] Nucleotides 185-221 of CPS 67 have 100% sequence identity with an
intron
sequence of LOC205936. LOC205936 is located at chromosome 4p16.2, and resides
in
genomic locus NT 006051 (NCBI Genome Annotation).
[0136] CPS 68 corresponds to PROP which encodes prolylcarboxypeptidase
(angiotensinase C). This gene has LocusID: 5547, and is located on chromosome
11 with
reported cytogenetic location l 1q14. The gene resides in genomic locus NT
033927 (NCBI
Genome Annotation). Prolylcarboxypeptidase (angiotensinase C) is a serine
carboxypeptidase and can remove residues linked to proline.
[0137] CPS 70 corresponds to DKFZP586A0522 which encodes DKFZP586A0522
protein. This gene has LocusID: 25840, and is located on chromosome 12 with
reported
cytogenetic location 12q11. The gene resides in .genomic locus NT 009782 (NCBI
Genome Annotation). The gene product include a region with low sequence
similarity to a
region of S. cerevisiae CoqSp. DKFZP586A0522 overlaps with LOC196~29 which is
encodes a protein similar to DKFZP586A0522 protein.
[0138] CPS 71 corresponds to SFRS 11 which encodes splicing factor,
arginine/serine-rich 11. This gene has LocusID: 9295, and is located on
chromosome 1
with reported cytogenetic location 1p21-p34. The gene resides in genomic locus
~63
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NT 004464 (NCBI Genome Annotation). The gene product contains arginine/serine-
rich
domain and an RRM domain, and may have a role in pre-mRNA splicing.
[0139] Nucleotides 1 to 234 of CPS 71 have 89% sequence identity with an
intron
sequence of PEPP2. PEPP2 encodes phosphoinositol 3-phosphate-binding protein-
2, and
has LocusID: 54477 with reported cytogenetic location 12p12.
[0140] CPS 72 corresponds to RAC2 which encodes ras-related C3 botulinum toxin
substrate 2 (rho family, small GTP binding protein, Rac2). This gene has
LocusID: X880,
and is located on chromosome 22 with reported cfytogenetic location 22q13.1.
The gene
resides in genomic locus NT 011520 (NCBI Genome Annotation). The protein
encoded by
RAC2 is a GTPase which belongs to the RAS superfamily of small GTP-binding
proteins.
Members of this superfamily appear to regulate a diverse array of cellular
events, including
the control of cell growth, cytoskeletal reorganization, and the activation of
protein kinases.
The RAC2 gene product may be a target for ADP ribosylation by the C3 subunit
of
botulinum toxin.
[0141] Nucleotides 400 to 487 of CPS 72 have 95% sequence identity with
STI~17A. STK17A encodes serine/threonine kinase 17a (apoptosis-inducing), and
has
LocusID: 9263 with reported cytogenetic location 7p12-p14.
[0142] CPS 73 corresponds to ZFP103 which encodes zinc finger protein 103
homolog (mouse). This gene has LocusID: 7844, and is located on chromosome 2
with
reported cytogenetic location 2p11.2. The .gene resides in genomic locus NT
015805 NCBI
Genome Annotation). The gene product contains a zinc-finger domain, and may be
associated with membranous protein sorting.
[0143] CPS 74 corresponds to LOC51580 which encodes H-2I~ binding factor-2.
This gene has LocusID: 51580, and is located on chromosome 9. The gene resides
in
genomic locus NT 006316 (NCBI Genome Annotation). The gene product is a member
of
the recombination signal-sequence binding protein family. It is a
transcription factor that
binds to the NFkB site of MHC class I genes.
[0144] CPS 75 corresponds to NRD1 which encodes nardilysin (N-arginine dibasic
convertase). This gene has LocusID: 4898, and is located on chromosome 1 with
reported
cytogenetic location 1p32.2-p32.1. The gene resides in genomic locus NT 004424
(NCBI
Genome Annotation). N-arginine dibasic convertase (NRD convertase) is a zinc-
dependent
endopeptidase. It is a member of the insulinase family.
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[0145] Blast search of the Entrez human genome sequence database shows that
CPS
76 overlaps or includes the 3' untranslated region of FLJ20154. FLJ20154
encodes
hypothetical protein FLJ20154, and is located at chromosome 1Oq24.32 with
LocusID:
54838. FLJ20154 resides in genomic locus NT 030059 (NCBI Genome Annotation).
[0146] CPS 76 also has 85-88% sequence identity with an intron sequence of
I~IAA0103, a chromosome 13 region near LOC160822, and a chromosome 7 region
near
BAP29. I~IAA0103 has LocusID: 9694 and reported cytogenetic location 8q23.1.
LOC160822 encodes a protein similar to hypothetical protein FLJ124~7, and is
located at
chromosome 13q31.1. BAP29 encodes B-cell receptor-associated protein BAP29,
and is
located at chromosome 7q22.2 with LocusID: 55973. Moreover, frabarnents of CPS
76 align
with various other regions on chromosome 1, 6, 15 and 19 with 89-90% sequence
identity.
[0147] Affymetrix annotation suggests that CPS 77 corresponds to KIAA0906,
also
known as NUP210 which encodes nucleoporin 210. The gene has LocusID: 23225,
and is
located at chromosome 3p25.1.
[0148] , Blast search of the Entrez human genome sequence database shows that
CPS
77 aligns with FLJ22389 with at least 99% sequence identity. FLJ22389 has
LocusID:
79985, and is located on chromosome 3 with reported cytogenetic location
3p25.1. The
gene resides in genomic locus NT 005927 (NCBI Genome Annotation).
[0149] Affymetrix annotation suggests that CPS 78 corresponds to MT1F which
encodes metallothionein 1F (functional) and has LocusID: 4494. The gene is
located at
16q13.
[0150] Blast search of the Entrez human genome sequence database shows that
CPS
78 has 100% sequence identity with a chromosomal region located 3' to the
protein-coding
sequence of MT1G. This chromosomal region, as well as MT1G, are within genomic
locus
NT 010498 (NCBI Genome Annotation) on chromosome 16. MT1G encodes
metallothionein 1G, and has LocusID: 4495 with reported cytogenetic location
16q13.
[0151] Nucleotides 1 to 67 of CPS 78 have 90-9~% sequence identity to various
regions in genomic locus NT 010498. These regions include MT2A, LOC221228,
MT1G
and MT1L. MT2A encodes metallothionein 2A, and has LocusID: 4502 with reported
cytogenetic location 16q13. LOC221228 is a hypothetical gene supported by
AF495759.
MT1G encodes metallothionein 1G. MT1L encodes metallothionein 1L, and has
LocusID:
4500 with reported cytogenetic location 16q13.
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[0152] In addition, CPS 78, and certain fragments thereof, have 89-93%
sequence
identity with MT2P1, LOC127544, LOC255917, a chromosomal region near MMP24, a
chromosomal region near MGC10731, and a chromosomal region near LOC149450.
MT2P1 encodes metallothionein 2 pseudogene 1 (processed), and has LocusID:
4503 with
reported cytogenetic location 4p11-q21. LOC127544 encodes a protein similar to
dJ1174N9.1 (novel protein with IBR domain), and is located at chromosome
1p34.3.
LOC255917 encodes a protein similar to metallothionein-IE (MT-lE), and is
located on
chromosome 9. MMP24 encodes matrix metalloproteinase 24 (membrane-inserted),
and is
located at chromosome 20q11.2 with LocusID: 10893. MGC10731 encodes
hypothetical
protein MGC10731, and has LocusID: 79363 with reported cytogenetic location
1p36.13.
LOC 149450 is located at chromosome 1 q42.3.
[0153] CPS 79 corresponds to P85SPR (ARHGEF7) which encodes Rho guanine
nucleotide exchange factor (GEF) 7. This gene has LocusID: 8874, and is
located on
chromosome 13 with reported cytogenetic location 13q34. The gene resides in
genomic
locus NT 009952 (NCBI Genome Annotation). Rho GTPases are involved in numerous
cellular processes that are initiated by extracellular stimuli that work
through G protein
coupled receptors. The protein encoded by P85SPR belongs to a family of
cytoplasmic
proteins that activate the Ras-like family of Rho proteins by exchanging bound
GDP for
GTP. The encoded protein may form a complex with G proteins and stimulate Rho-
dependent signals. The protein can induce membrane ruffling. The gene product
is also
involved in Pak recruitment to Cdc42- and Racl-driven focal complexes.
Multiple
alternatively spliced transcript variants encoding different isoforms have
been described for
this gene.
[0154] CPS 80 corresponds to UNK N53547 (MGC5~08) which encodes
hypothetical protein MGC5508. This gene has LocusID: 79073, and is located on
chromosome 11 with reported cytogenetic location l 1q13.1. The gene resides in
.genomic
locus NT 033903 (NCBI Genome Annotation).
[0155] CPS 81 corresponds to GPRKS which encodes G protein-coupled receptor
kinase 5. This gene has LocusID: 2869, and is located on chromosome 10 with
reported
cytogenetic location 1Oq24-qter. The gene resides in genomic locus NT 008902
.(NCBI
Genome Annotation). G protein-coupled receptor kinases (GRKs) play a role in
phosphorylating and regulating the activity of a variety of G protein-coupled
receptors. G
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protein-coupled receptor kinase 5 can phosphorylate agonist-stimulated G
protein-coupled
receptors.
(0156] CPS 83 corresponds to SCYA7 which encodes small inducible cytokine A7
(monocyte chemotactic protein 3). This gene has LocusID: 6354, and is located
on
chromosome 17 with reported cytogenetic location 17q11.2-q12. The .gene
resides in
genomic locus NT 010799 (NCBI Genome Annotation). Monocyte chemotactic protein
3
is a secreted chemokine which attracts macrophages during inflammation and
metastasis. It
is a member of the C-C subfamily of chemokines which are characterized by
having two
adjacent cysteine residues. The protein is an in vivo substrate of matrix
metalloproteinase
2, an enzyme which degrades components of the extracellular matrix. SCYA7 gene
is part
of a cluster of C-C chemokine family members on chromosome 17q.
[0157] CPS 84 corresponds to TUBAS which encodes tubulin, alpha 3. This gene
has LocusID: 7846, and is located on chromosome 12 with reported cytogenetic
location
12q12-12q14.3. The gene resides in genomic locus NT 009526 (NCBI Genome
Annotation). There are multiple alpha and beta tubulin genes, which are
conserved among
species. TUBAS encodes alpha tubulin and is similar to mouse and rat Tubal
gene.
Northern blotting studies have shown the gene expression in morphologically
differentiated
neurologic cells. TUBAS is one of three alpha-tubulin genes in a cluster on
chromosome
12q.
[0158] CPS 84 also has 97% sequence identity with a chromosomal region located
3' to L~C134262. LOC134262 encodes a protein similar to alphaTub84B gene
product.
The gene is located at Spl l, and resides in genomic locus NT 023098.
[0159] CPS 85 corresponds to SCML2 which encodes sex comb on midleg-like 2
(Drosophila). This gene has LocusID: 10389, and is located on chromosome X
with
reported cytogenetic location Xp22. The gene resides in genomic locus NT
011586 (NCBI
Genome Annotation). The gene product is similar to Drosophila Scm.
[0160] CPS 85 also aligns with SCMLl with 94% sequence identity. SCML1
encodes sex comb on midleg-like 1 (Drosophila). The gene has LocusID: 6322,
and is
located on chromosome X with reported cytogenetic location Xp22.2-p22.1. The
gene
resides in genomic locus NT 011586.
[0161] CPS 87 corresponds to ILIRl which encodes interleukin 1 receptor, type
I.
This gene has LocusID: 3554, and is located on chromosome 2 with reported
cytogenetic
location 2q12. The gene resides in genomic locus NT 022171 (NCBI Genome
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Annotation). Type I interleukin-1 receptor contains immmunoglobulin domains,
and can
bind to all three forms of interleukin-1 (IL1A, IL1B, and IL1RN).
[0162] CPS 88 corresponds to UNK AL008729 (LOC221692) which encodes a
protein similar to KIAA1733 protein. This gene is located on chromosome 6 with
reported
cytogenetic location 6p22.3. The gene resides in genomic locus NT 007592 (NCBI
Genome Annotation). LOC221692 is located within LOC51256 which has LocusID:
51256. CPS 88 matches with the non-protein-coding strand of LOC51256.
[0163] CPS 89 corresponds to KIAA0191 which encodes KIAA0191 protein. This
gene has LocusID: 23318, and is located on chromosome 1 with reported
cytogenetic
location 1p32.3. The gene resides in genomic locus NT 004424 (NCBI Genome
Annotation).
[0164] CPS 90 corresponds to EGFLS which encodes EGF-like-domain, multiple 5.
This gene has LocusID: 1955, and is located on chromosome 9 with reported
cytogenetic
location 9q32-q33.3. The gene resides in genomic locus NT 017568 (NCBI Genome
Annotation).
[0165] CPS 91 corresponds to DUSPl which encodes dual specificity phosphatase
1. This gene has LocusID: 1843, and is located on chromosome 5 with reported
cytogenetic
location Sq34. The gene resides in genomic locus NT 023132 (NCBI Genome
Annotation). The expression of DUSP 1 gene can be induced in human skin
fibroblasts by
oxidative/heat stress and growth factors. The bacterially expressed and
purified DUSPl
protein has intrinsic phosphatase activity, and can inactivate mitogen-
activated protein
(MAP) kinase in vitro by the concomitant dephosphorylation of both its
phosphothreonine
and phosphotyrosine residues. DUSPl protein can also suppress the activation
of MAP
kinase by oncogenic ras in extracts of Xenopus oocytes. Thus, DUSP1 may play a
role in
the human cellular response to environmental stress as well as in the negative
regulation of
cellular proliferation.
[0166] CPS 92 corresponds to FBP1 which encodes fructose-1,6-bisphosphatase 1.
This gene has LocusID: 2203, and is located on chromosome 9 with reported
cytogenetic
location 9q22.3. The gene resides in genomic locus NT 008476 (NCBI Genome
Annotation). Fructose-1,6-bisphosphatase 1 is a gluconeogenesis regulatory
enzyme. It can
catalyze the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate
and inorganic
phosphate. Fructose-1,6-diphosphatase deficiency is associated with
hypoglycemia and
metabolic acidosis.
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[0167] CPS 93 corresponds to HRB which encodes HIV-1 Rev binding protein.
This gene has LocusID: 3267, and is located on chromosome 2 with reported
cytogenetic
location 2q36. The gene resides in genomic locus NT 005403 (NCBI Genome
Annotation). HIV-1 Rev binding protein can interact with the activation
domains of the
HIV-1 Rev protein, and may be related to nucleoporins, a class of proteins
that mediate
nucleocytoplasmic transport. HIV-1 Rev binding protein binds to the Rev
activation
domain when Rev is assembled onto its RNA target and can significantly enhance
Rev
activity when over-expressed. The HRB gene can Xpressed as a major 2.8-kb and
a minor
4.6-kb mRNA.
[0168] CPS 94 corresponds to NAGA which encodes N-acetylgalactosaminidase,
alpha-. This gene has LocusID: 4668, and is located on chromosome 22 with
reported
cytogenetic location 22q13-qter. The gene resides in genomic locus NT 011520
(NCBI
Genome Annotation). The lysosomal enzyme alpha-N-acetylgalactosaminidase can
cleave
alpha-N-acetylgalactosaminyl moieties from glycoconjugates. Mutations in NAGA
have
been implicated as the cause of Schindler disease types I and II .(type II
also known as
I~anzaki disease).
[0169] CPS 95 corresponds to GLRX which encodes glutaredoxin
(thioltransferase).
This gene has LocusID: 2745, and is located on chromosome 5 with reported
cytogenetic
location Sql4. The gene resides in genomic locus NT 023148 (NCBI Genome ,
Annotation). Glutaredoxin can function as a glutathione-dependent hydrogen
donor for
ribonucleotide reductase.
[0170] Fragments of CPS 95 also align with AF3582~9, a chromosomal region near
GABRA6 and a chromosomal region near GLRXP with 86-90% sequence identity.
AF358259 encodes glutaredoxin pseudogene 2, and has LocusID: 171418 with
reported
cytogenetic location 14q32.13-q32.2. GABRA6 encodes gamma-aminobutyric acid
(GABA) A receptor, alpha 6. It has LocusID: 2559, and is located at chromosome
Sq34.
GLRXP encodes glutaredoxin (thioltransferase) pseudogene, and is located at
chromosome
20q11.2 with LocusID: 170522. In addition, nucleotides 1 to 29 of CPS 95 has
100%
sequence identity with LOC257079. LOC2~7079 encodes a protein similar to
glutaredoxin
(Thioltransferase) (TTase), and is located on chromosome 5.
[0171] CPS 96 corresponds to IJNK W28281 (GABARAPL1) which encodes
GABA(A) receptor-associated protein like 1. This gene has LocusID: 23710, and
is located
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on chromosome 12 with reported cyto-genetic location 12p13.1. The gene resides
in
genomic locus NT 035207 (NCBI Genome Annotation).
[0172] SEQ ID NO: 360, which can be used as a probe sequence for detecting the
expression level of UNK W28281, also aligns with GABARAPL3 with about 95%
sequence identity. GABAR.APL3 encodes GABA(A) receptors associated protein
like 3. It
has LocusID: 23766, and is located on chromosome 15 with reported cytogenetic
location
15q25.1.
[0173] CPS 97 corresponds to UNK AL096740 (UBE3B) which encodes ubiquitin
protein ligase. This gene has LocusID: 89910, and is located on chromosome 12
with
reported cytogenetic location 12q24.11. The gene resides in genomic locus NT
009770
(NCBI Genome Annotation).
[0174] CPS 98 corresponds to TBXAS1 which encodes thromboxane A synthase 1
(platelet, cytochrome P450, subfamily V). This gene has LocusID: 6916, and is
located on
chromosome 7 with reported cytogenetic location 7q34-q35. The gene resides in
genomic
locus NT 007914 (NCBI Genome Annotation). The gene product is a member of the
cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are
monooxygenases which catalyze many reactions involved in drug metabolism and
synthesis
of cholesterol, steroids and other lipids. TBXAS 1 gene product is considered
a member of
the cytochrome P450 superfamily on the basis of sequence similarity rather
than functional
similarity. It is an endoplasmic reticulum membrane protein, and can catalyze
the
conversion of prostglandin Ii2 to thromboxane A2, a potent vasoconstrictor and
inducer of
platelet aggregation. TBXAS 1 gene product may play a role in several
pathophysiological
processes including hemostasis, cardiovascular disease; and stroke. The gene
expresses at
least two transcript variants.
[0175] CPS 99 corresponds to DPYD which encodes dihydropyrimidine
dehydrogenase. This gene has LocusID: 1 X06, and is located on chromosome 1
with
reported cytogenetic location 1p22. The gene resides in genomic locus NT
034389 (NCBI
Genome Annotation). Dihydropyrimidine dehydrogenase is a pyrimidine catabolic
enzyme
which is involved in the initial and rate-limiting step in the pathway of
uracil and thymidine
catabolism and also in the pathway leading to the formation of beta-alanine.
The DPYD
gene is a large gene of approximately 150 kb consisting of at least 23 exons
encoding a
protein of approximately 111-kDa. Genetic deficiency of DPYD enzyme results in
an error
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in pyrimidine metabolism associated with thymine-uraciluria and an increased
risk of
toxicity in cancer patients receiving 5-flourouracil chemotherapy.
[0176] Affymetrix annotation suggests that CPS 100 corresponds to ECGF1 which
encodes endothelial cell growth factor 1 (platelet-derived). Nucleotides 4 to
120 of M63193
(SEQ ID NO: 94) align with ECGFl. This gene has LocusID: 1890, and is located
on
chromosome 22 with reported cytogenetic location 22q13.33. The gene resides in
genomic
locus NT_011526 (NCBI Genome Annotation).
[0177] CPS 100 aligns with SC02 with a't least 98% sequence identity. SC02
encodes SCO cytochrome oxidase deficient homolog 2 (yeast). It has LocusID:
9997, and
is located on chromosome 22 with reported cytogenetic location 22q13.33. The
gene
resides in genomic locus NT 011526. Mammalian cytochrome c oxidase (COX)
catalyzes
the transfer of reducing equivalents from cytochrome c to molecular oxygen and
pumps
protons across the inner mitochondria) membrane. In yeast, two related COX
assembly
genes, yeast SCO1 and SC02 (synthesis of cytochrome c oxidase), enable
subunits 1 and 2
to be incorporated into the holoprotein. SC02 is the human homolog of the
yeast SC02
gene.
[0178] Affymetrix annotation suggests that CPS 101 corresponds to TIMP1 which
encodes tissue inhibitor of metalloproteinase 1 (erythroid potentiating
activity, collagenase
inhibitor). The gene has LocusID: 7076, and is located at chromosome Xp 11.3-p
11.23.
[0179] Blast search of the Entrez human genome sequence database shows that
CPS
101 aligns with an intron sequence of SYN1 with at least 97% sequence
identity. SYN1
encodes synapsin I, and has LocusID: 6853 with reported cytogenetic location
Xp11.23.
The gene resides in genomic locus NT 011568. CPS 101 matches with the non-
protein-
coding strand of SYN1.
[0180] CPS 102 corresponds to GSN which encodes gelsolin (amyloidosis, Finnish
type). This gene has LocusID: 2934, and is located on chromosome 9 with
reported
cytogenetic location 9q33. The gene resides in genomic locus NT 017568 (NCBI
Genome
Annotation). Gelsolin is a calcium-dependent protein which may function to
sever and cap
actin filaments.
[0181] CPS 103 corresponds to SECTM1 which encodes secreted and
transmembrane 1. This gene has LocusID: 6398, and is located on chromosome 17
with
reported cytogenetic location 17q25. The gene resides in genomic locus NT
025911 (NCBI
Genome Annotation). The gene product is a transmembrane and secreted protein
with
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characteristics of a type la transmembrane protein. It is found in a
perinuclear Golgi-like
pattern and thought to be involved in hematopoietic or immune system
processes. The gene
product may have a role in hematopoiesis or immune processes.
[0182] CPS 104 corresponds to OLRl which encodes oxidised low density
lipoprotein (lectin-like) receptor 1. This gene has LocusID: 4973, and is
located on
chromosome 12 with reported cytogenetic location 12p13.2-p12.3. The gene
resides in
genomic locus NT 035207 (NCBI Genome Annotation). Lectin-like oxidized low
density
lipoprotein receptor is a member of the C-type lectin receptor family, and may
be involved
in degradation of oxidized LDL by vascular endothelial cells.
[0183] CPS 105 corresponds to D6S49E (LST1) which encodes leukocyte specific
transcript 1. This gene has LocusID: 7940, and is located on chromosome 6 with
reported
cytogenetic location 6p21.3. The gene resides in genomic locus NT 007592 (NCBI
Genome Annotation). The gene product is expressed in leukocytes and induced by
IFN-
gamma. It possibly functions in the immune response of monocytes and T cells.
[0184] CPS 106 corresponds to JIJNB which encodes jun B proto-oncogene. This
gene has LocusID: 3726, and is located on chromosome 19 with reported
cytogenetic
location 19p 13.2. The gene resides in genomic locus NT 011176 (NCBI Genome
Annotation). The gene product may participate in AP-1 transcriptional
activation.
[0185] CPS 107 corresponds to PFC which encodes properdin P factor,
complement. This gene has LocusID: 5199, and is located on chromosome X with
reported
cytogenetic location Xpl 1.3-pl 1.23. The gene resides in genomic locus NT Ol
1'568 (NCBI
Genome Annotation). The gene product contains a related type-I repeat
sequence, and may
play a role in complement-mediated clearance.
[0186] CPS 108 corresponds to POLR2E which encodes polymerase {RNA) II
(DNA directed) polypeptide E (25kD). This gene has LocusID: 5434, and is
located on
chromosome 19 with reported cytogenetic location 19p13.3. The gene resides in
genomic
locus NT 011277 (NCBI Genome Annotation). This gene encodes a subunit of RNA
polyrrierase II, the polymerase responsible for synthesizing messenger RNA in
eukaryotes.
The encoded subunit is shared by the other two DNA-directed RNA polymerases
and is
present in two-fold molar excess over the other polymerase subunits. An
interaction
between this subunit and a hepatitis virus transactivating protein has been
demonstrated,
suggesting that interaction between transcriptional activators and the
polymerase can occur
through this subunit. A pseudogene is located on chromosome 11.
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[0187] CPS 109 corresponds to THBSl which encodes thrombospondin 1. This
gene has LocusID: 7057, and is located on chromosome 15 with reported
cytogenetic
location 15q15. The gene resides in genomic locus NT 030828 (NCBI Genome
Annotation). Thrombospondin-1 is a member of a family of adhesive molecules.
It has a
role in blood clotting and in angiogenesis.
[0188] CPS 110 corresponds to HK2 which encodes hexokinase 2. This gene has
LocusID: 3099, and is located on chromosome 2 vYith reported cytogenetic
location 2p13.
The gene resides in genomic locus NT 022184 (NCBI Genome Annotation).
Hexokinases
phosphorylate glucose to produce glucose-6-phosphate, thus committing glucose
to the
glycolytic pathway. HK2 gene encodes hexokinase 2, the predominant form found
in
skeletal muscle. The gene product localizes to the outer membrane of
mitochondria.
Expression of this gene is insulin-responsive, and studies in rat suggest that
it is involved in
the increased rate of glycolysis seen in rapidly growing cancer cells.
[0189] CPS 110 also aligns with a chromosomal region near LOC139132 with about
95% sequence identity. Both the chromosomal region and LOC139132 reside in
genomic
locus NT 011597. LOC139132 encodes a protein similar to WW domain binding
protein
11 (SH3 domain-binding protein SNP70) (Npw38-binding protein NpwBP), and is
located
at Xq13.2.
[0190] Affymetrix annotation suggests that CPS 111 corresponds to INSIG1 which
encodes insulin induced gene 1. The gene has LocusID: 3638 and is located at
chromosome
7q36.
[0191] Blast search of the Entrez human =genome sequence database shows that
CPS
111 has about 80-85% sequence identity with a chromosomal region near
LOC131742.
This chromosomal region and LOC131742 reside in genomic locus NT 022554.
LOC 131742 has reported cytogenetic location 3p 12.1-p 11.2.
[0192] CPS 112 corresponds to HCK which encodes hemopoietic cell kinase. This
gene has LocusID: 3055, and is located on chromosome 20 with reported
cytogenetic
location 20q11-q12. The gene resides in genomic locus NT 028392 (NCBI Genome
Annotation). The gene product can function as a non-receptor protein tyrosine
kinase.
[0193] Affymetrix annotation suggests that CPS 113 corresponds to HP10390,
alos
known as TMEM4 which encodes transmembrane protein 4. The .gene has LocusLD: i
0330,
and is located at chromosome 12q15.
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[0194] Blast search of the Entrez human .genome sequence database shows that
CPS
113 aligns with two regions with 100% sequence identity. The first region is
located in an
intron of TIMELESS. The second region is located 5' to the polypeptide-coding
sequence
of TIMELESS. TIMELESS encodes timeless homolog (Drosophila). It has LocusID:
8914, and is located on chromosome 12 with reported cytogenetic location 12q12-
q13. The
gene resides in genomic locus NT 009458 (NCBI Genome Annotation). The gene
product
may be involved in circadian oscillation autoregulation.
[0195] CPS 114 corresponds to UNK U51712 (LAGY) which encodes lung cancer-
associated Y protein. This gene has LocusID: 84525, and is located on
chromosome 4 with
reported cytogenetic location 4q11-q12. The gene resides in genomic locus NT
022853
(NCBI Genome Annotation). Multiple alternatively spliced transcript variants
have been
described for this gene.
[0196] CPS 115 corresponds to which encodes KIAA0217 which encodes
KIAA0217 protein. This gene has LocusID: 23185, and is located on chromosome
10 with
reported cytogenetic location 1 Op 15.3. The gene resides in .genomic locus NT
024115
(NCBI Genome Annotation).
[0197] CPS 116 corresponds to NCF1 which encodes neutrophil cytosolic factor 1
(47kD, chronic granulomatous disease, autosomal 1). This gene has LocusID:
4687, and is
located on chromosome 7 with reported cytogenetic location 7q11.23. The gene
resides in
genomic locus NT 034886 (NCBI Genome Annotation). NCFl gene product can
produce a
burst of superoxide which is delivered to the lumen of the neutrophil
phagosome.
Mutations in NCF1, as well as in other NADPH oxidase subunits, can result in
chronic
granulomatous disease.
[0198] CPS 116 also aligns with LOC220830 and LOC256379 with 95-99%
sequence identity. Both genes reside in genomic locus NT 007758 on chromosome
7.
Both genes encode proteins similar to neutrophil cytosolic factor 1 (47kD,
chronic
granulomatous disease, autosomal 1).
[0199] CPS 117 corresponds to KIAA1113 (TRIM33) which encodes tripartite
motif containing 33. This gene has LocusID: 51592, and is located on
chromosome 1 with
reported cytogenetic location 1p13.1. The gene resides in genomic locus NT
019273
(NCBI Genome Annotation). The protein encoded by this gene is thought to be a
transcriptional corepressor. The protein is a member of the tripartite motif
family. The
tripartite motif includes three zinc-binding domains, a RING, a B-box type 1
and a B-box
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type 2, and a coiled-coil region. At least three alternatively spliced
transcript variants for
this gene, have been described.
[0200] CPS 118 corresponds to DKFZP566H073 which encodes DKFZP566H073
protein. This gene has LocusID: 26001, and is located on chromosome 17 with
reported
cytogenetic location 17p13.3. The gene resides in genomic .locus NT 033299
(NCBI
Genome Annotation). The gene product contains a C3HC4 type (RING) zinc finger,
and
can mediate protein-protein interactions.
(0201] CPS 119 corresponds to ATP2iB 1 which encodes ATPase, Ca++
transporting, plasma membrane 1. This gene has LocusID: 490, and is located on
chromosome 12 with reported cytogenetic location 12q21-q23. The gene resides
in
genomic locus NT 009729 (NCBI Genome Annotation).
[0202] Nucleotides 305 to 338 of CPS 119 align with an intron sequence of
FLJ14075 with 100% sequence identity. FLJ14075 encodes hypothetical protein
FLJ14075,
and has LocusID: 79954 with reported cytogenetic location 2p25.1.
[0203] CPS 120 corresponds to IFITM2 which encodes interferon induced
transmembrane protein 2 (1-8D). This gene has LocusID: 1081, and is located on
chromosome 11 with reported cytogenetic location 11p1~.5. The gene resides in
genomic
locus NT 009407 (NCBI Genome Annotation). The expression of this gene can be
induced
by interferon.
[0204] CPS 121 corresponds to MNDA which encodes myeloid cell nuclear
differentiation antigen. This gene has LocusID: 4332 , and is located on
chromosome 1
with reported cytogenetic location 1 q22. The gene resides in genomic locus NT
004982
(NCBI Genome Annotation). The myeloid cell nuclear differentiation antigen -
can be
detected in nuclei of cells of the granulocyte-monocyte lineage. A 200-amino
acid region of
the protein is similar to a region in the proteins encoded by a family of
interferon-inducible
mouse genes, designated Ifi-201, Ifi-202, and Ifi-203. The MNDA mRNA, which
contains
an interferon-stimulated response element in the 5-prime untranslated region,
can be
upregulated in human monocytes exposed to interferon alpha. MNDA is located
within
2,200 kb of FCERlA, APCS, CRP, and SPTA1. In its pattern of expression or
regulation,
MNDA resembles IFI16, suggesting that these genes participate in blood cell-
specific
responses to interferons.
[0205] CPS 122 corresponds to BTN3A2 which encodes butyrophilin, subfamily 3,
member A2. This gene has LocusID: 11118, and is located on chromosome 6 with
reported
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cytogenetic location 6p22.1. The gene resides in genomic locus NT 007592 (NCBI
Genome Annotation).
[0206] Nucleotides 213 to 250 of CPS 122 align with BTN3A3 and BTN3A1 with
94% and 97% sequence identity, respectively. BTN3A3 encodes butyrophilin,
subfamily 3,
member A3, and has LocusID: 10384. BTN3A1 encodes butyrophilin, subfamily 3,
member A1, and has LocusID: 11119. Both genes are located at chromosome
6p22.1.
[0207] CPS 123 corresponds to KIAA0776 which encodes I~IAA0776 protein. This
gene has LocusID: 23376, and is located on chromosome 6 with reported
cytogenetic
location 6q16.3. The gene resides in genomic locus NT 019424 (NCBI Genome
Annotation).
[0208] CPS 124 corresponds to D6S2245E (HSD17B8) which encodes
hydroxysteroid (17-beta) dehydrogenase 8. This gene has LocusID: 7923, and is
located on
chromosome 6 with reported cytogenetic location 6p21.3. The gene resides in
genomic
locus NT 007592 (NCBI Genome Annotation). The protein encoded by this gene is
similar
to mouse I~e6 and is a member of the short-chain dehydrogenase superfarriily.
An
alternatively spliced transcript of this gene has been detected.
[0209] CPS 125 corresponds to KIAA0628. This gene has LocusID: 9831, and is
located on chromosome 8 with reported cytogenetic location 8q24.3. The gene
resides in
genomic locus NT 023684 (NCBI Genome Annotation). CPS 125 is in the 3' UTR of
the
gene.
[0210] CPS 126 corresponds to SELL which encodes selectin L (lymphocyte
adhesion molecule 1). This gene has LocusID: 6402, and is located on
chromosome 1 with
reported cytogenetic location 1 q23-q25. The gene resides in genomic locus NT
fl34405
(NCBI Genome Annotation). Selectin L is a cell surface component that is a
member of a
family of adhesion/homing receptors which are involved in leukocyte-
endothelial cell
interactions. Selectin L is composed of multiple domains including one domain
homologous to lectins, one to epidermal growth factor, and two to the
consensus repeat
units found in C3/C4 binding proteins. The protein can attach lymphocytes to
lymph node
high endothelial venules.
[0211] CPS 127 corresponds to MPV17 which encodes MpVl7 transgene, murine
homolog, glomerulosclerosis. This gene has LocusID: 4358, and is located on
chromosome
2 with reported cytogenetic location 2p23-p21. The gene resides in genomic
locus
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NT 005204 (NCBI Genome Annotation). The gene product is similar to murine
Mpvl7. It
is a predicted membrane protein and may be associated with nephrotic syndrome.
[0212] CPS 128 corresponds to FABPS which encodes fatty acid binding protein 5
(psoriasis-associated). This gene has LocusID: 2171, and is located on
chromosome 8 with
reported cytogenetic location 8q21.13. The gene resides in genomic locus NT
007972
(NCBI Genome Annotation). The gene product can be found in epidermal cells,
and was
identified as being upregulated in psoriasis tissue. Fatty acid binding
proteins (FABPs) are
a family of small, conserved, cytoplasmic proteins that bind long-chain fatty
acids and other
hydrophobic ligands. It is thought that FABPs roles include fatty acid uptake,
transport, and
metabolism.
[0213] Nucleotides 1 to 260 of CPS 128 have 100% sequence identity with an
intron
sequence of STX3A. STX3A encodes syntaxin 3A, and has LocusID: 6809 with
reported
cytogenetic location 11q12.3. STX3A resides in genomic locus NT 033903. The
alignment between CPS 128 and STX3A is in the non-protein-coding of the gene.
Nucleotides 1 to 260. of CPS 128, or fragments thereof, also align to various
regions on
chromosomes 7, 13 and 15 with 95-97% sequence identity. In addition,
nucleotides 1-260
of CPS 128, or fragments thereof, align to various region on chromosomes 2, 4,
13, 15 and
22 with sequence identity 88-93%.
[0214] CPS 129 corresponds to CASP1 which encodes caspase 1, apoptosis-related
cysteine protease (interleukin 1, beta, convertase). This gene has LocusID:
834, and is
located on chromosome 11 with reported cytogenetic location 11 q23. The gene
resides in
genomic locus NT 009151 (NCBI Genome Annotation). The gene product is a member
of
the cysteine-aspartic acid protease (caspase) family. Sequential activation of
caspases plays
a central role in the execution-phase of cell apoptosis. Caspases exist as
inactive
proenzymes which undergo proteolytic processing at conserved aspartic residues
to produce
2 subunits, large and small, that dimerize to form the active enzyme. The
CASP1 ,gene
product can proteolytically cleave and activate the inactive precursor of
interlukin-1, a
cytokine involved in the processes such as inflammation, septic shock, and
wound healing.
CASPl gene has been shown to induce cell apoptosis and may function in various
developmental stages. It may have a role in the pathogenesis of Huntington
disease.
Alternative splicing of this gene results in at least five transcript variants
encoding distinct
isoforms:
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(0215] Nucleotides 1 to 487 of CPS 129, or fragments thereof, aligns with
various
chromosome 11 regions with sequence identity 86-95%. These regions include
LOC120332 and LOC160131, both of which have reported cytogenetic location
11q22.3
and encode proteins similar to caspase l, isoform beta precursor {interleukin
1-beta
convertase) (interleukin 1-B converting enzyme) (IL1B-convertase).
[0216] CPS 130 corresponds to PTPN6 which encodes protein tyrosine
phosphatase,
non-receptor type 6. This gene has LocusID: ~777,I and is located on
chromosome 12 with
reported cytogenetic location 12p13. The gene resides in genomic locus NT
035206 (NCBI
Genome Annotation). The protein encoded by this gene is a member of the
protein tyrosine
phosphatase (PTP) family. PTPs are known to be signaling molecules that
regulate a
variety of cellular processes including cell growth, differentiation, mitotic
cycle, and
oncogenic transformation. N-terminal part of PTPN6 gene product contains two
tandem Src
homolog (SH2) domains, which act as protein phospho-tyrosine binding domains
and
mediate the interaction of the gene product with its substrates. PTPN6 gene
product can be
expressed in hematopoietic cells, and may function as a regulator of multiple
signaling
pathways in hematopoietic cells. The gene product has been shown to interact
with, and
dephosphorylate a wide spectrum of phospho-proteins involved in hematopoietic
cell
signaling. At least three alternatively spliced variants of this gene, which
encode distinct
isoforms, have been reported.
[0217] CPS 130 also aligns with a chromosomal region near REA with at least
98%
sequence identity. REA encodes repressor of estrogen receptor activity. It has
LocusID:
11331 and reported cytogenetic location 12p13.
[0218] CPS 131 corresponds to SKAP-HOM (SCAP2) which encodes src family
associated phosphoprotein 2. This gene has LocusID: 8935, and is located on
chromosome
7 with reported cytogenetic location 7p21-p15. The gene resides in genomic
locus
NT 007819 (NCBI Genome Annotation). The protein encoded by this gene belongs
to the
src family kinases. The encoded protein is similar to the src family
associated
phosphoprotein 1 and may function as an adaptor protein. The encoded protein
has coiled-
coil and SH3 domains, and is thought to play a role in the src signaling
pathway in various
cells. In a mouse study the SCAP2 gene is implicated in the processes of
myeloid
differentiation and growth arrest.
[0219] CPS 133 corresponds to GR02 which encodes GR02 oncogene. This gene
has LocusID: 2920, and is located on chromosome 4 with reported cytogenetic
locatiDn
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4q21. The gene resides in genomic locus NT 006216 (NCBI Genome Annotation).
GRO2
is similar to GRO1. The gene product is a chemotactic agent for
polymorphonuclear
leukocytes.
[0220] CPS 133 also aligns with GROl with 85% sequence identity. GRO1
encodes GRO1 oncogene (melanoma growth stimulating activity, alpha), and has
LocusID:
2919 with reported cytogenetic location 4q21. The gene resides in genomic
locus
NT 006216.
[0221] CPS 134 corresponds to RRAS which encodes related RAS viral (r-ras)
oncogene homolog. This gene has LocusID: 6237, and is located on chromosome 19
with
reported cytogenetic location 19q13.3-qter. The gene resides in genomic locus
NT 011109
(NCBI Genome Annotation). , The gene product is a member of the ras family of
GTP
binding proteins.
[0222] CPS 135 corresponds to I~IAA0022 which encodes KIAA0022 gene product.
This gene has LocusID: 9936, and is located on chromosome 2 with reported
cytogenetic
location 2q24.2. The gene resides in genomic locus NT 0051 S 1 (NCBI Genome
Annotation).
[0223] CPS 136 corresponds to FLII which encodes flightless I homolog
(Drosophila). This gene has LocusID: 2314, and is located on chromosome 17
with
reported cytogenetic location 17p11.2. The gene resides in genomic locus NT
030843
(NCBI Genome Annotation). The gene product is a homolog of Drosophila
flightless I. It
has a gelsolin-like actin-binding domain and a leucine-rich interaction
domain.
[0224] CPS 137 corresponds to PRF1 which encodes perform 1 (pore forming
protein). This gene has LocusID: 5551, and is located on chromosome 10 with
reported
cytogenetic location 1Oq22. The gene resides in genomic locus NT 024037 (NCBI
Genome Annotation). Perform is a cytolytic, channel-forming protein which
plays a role in
clearing virally infected host cells and tumor cells.
[0225] CPS 138 corresponds to KIAA0102 which encodes KIAA0102 gene product.
This gene has LocusID: 9789, and is located on chromosome 11 with .reported
cytogenetic
location 11q13.3. The gene resides in genomic locus NT 033927 (NCBI Genome
Annotation).
[0226] CPS 138 also aligns with a chromosomal region near PTAFR with 99%
sequence identity. PTAFR encodes platelet-activating factor receptor, and has
LocusID:
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5724 and reported cytogenetic location 1p35-p34.3. It resides in genomic locus
NT 028053. Platelet-activating factor receptor is a G protein-coupled
receptor.
[0227] In addition, CPS 138 has 86-94% sequence identity with various regions
in
chromosomes 5, 10, 11 and 15. For instance, CPS 138 aligns with a chromosome
15 region
with 94% sequence identity. The chromosome 15 region includes LOC255320 which
encodes a protein similar to microsomal signal peptidase 25 kDa subunit (SPase
2~ kDa
subunit) (SPC25).
[0228] CPS 139 corresponds to UNK AA176780 (HSA249128) which encodes
DIPB protein. This gene has LocusID: 54765, and is located on chromosome 11
with
reported cytogenetic location 11p11.2. The gene resides in genomic locus NT
009237
(NCBI Genome Annotation). The gene product is member of the B-box zinc finger
family,
and contains a region of low similarity to a region of marine Mid2. CPS 139
aligns with the
region 3' to the protein-coding strand of UNK AA176780.
[0229] CPS 140 corresponds to PYGL which encodes phosphorylase, glycogen;
liver (Hers disease, glycogen storage disease type VI). This gene has LocusID:
X836, and is
located on chromosome 14 with reported cytogenetic location 14q21-q22. The
gene resides
in genomic locus NT 025892 (NCBI Geriome Annotation).
[0230] CPS 141 corresponds to DBP which encodes D site of albumin promoter
(albumin D-box) binding protein. This gene has LocusID: 1628, and is located
on
chromosome 19 with reported cytogenetic location 19q13.3. The gene resides in
genomic
locus NT 011109 (NCBI Genome Annotation). Albumin D-site-binding protein is a
transcription factor which may play a role in the diurnal regulation of liver-
specific genes.
It is a member of the PAR (proline and acidic amino acid-rich) b/ZIP family.
[0231] CPS 143 corresponds to RANBP2L1 which encodes RAN binding protein 2-
like 1. This gene has LocusID: 84220, and is located on chromosome 2 with
reported
cytogenetic location 2q12.3. The gene resides in genomic locus NT 022135 (NCBI
Genome Annotation). RAN is a small GTP-binding protein of the RAS superfamily
that is
associated with the nuclear membrane and is thought to control a variety of
cellular
functions through its interactions with other proteins. RANBP2L1 gene shares
sequence
similarity with RANBP2, a large RAN-binding protein localized at the
cytoplasmic side of
the nuclear pore complex. It is believed that this RANBP2 gene family member
arose from
a duplication event 3 Mb distal to RANBP2. Alternative splicing has been
observed for this
locus and two variants are described. Additional splicing is suggested.
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(0232] CPS 143 also aligns with LOC220692 with 100% sequence identity.
LOC220692 encodes protein similar to RAN-binding protein 2-like 1, isoform 1
(sperm
membrane protein BS-63). The gene is located at chromosome 2q12.3. and resides
in
genomic locus NT 022135 (NCBI Genome Annotation).
[0233] In addition, CPS 143 has 94-96% sequence identity with KIAA0336, a
chromosomal region near LOC256197, and an intron of LOC150821. KIAA0336
encodes
KIAA0336 gene product, and has LocusID: 9648 and reported cytogenetic location
2q12.2.
LOC256197 encodes a protein similar to ribosomal protein L22, and is located
on
chromosome 2. LOC150821 encodes a protein similar to KIAA0336 gene product,
and is
located at chromosome 2p11.1.
[0234] CPS 144 corresponds to TNFSF10 which encodes tumor necrosis factor
(ligand) superfamily, member 10. This gene has LocusID: 8743, and is located
on
chromosome 3 with reported cytogenetic location 3q26. The gene resides in
genomic locus
NT 025667 (NCBI Genome Annotation). Tumor necrosis factor (TNF) family
cytokines
function as mediators.of immune regulation and the inflammatory response.
TNFSF10 gene
product is a Type II glycoprotein of the tumor necrosis factor ligand
superfamily, and can
mediate cell death.
[0235] CPS 145 corresponds to KIAA0854 which encodes KIAA0854 protein. This
gene has LocusID: 22882, and is located on chromosome 8 with reported
cytogenetic
location 8q24.13. The gene resides in genomic locus NT 023663 (NCBI Genome
Annotation).
[0236] CPS 146 corresponds to SDS which encodes serine dehydratase. This gene
has LocusID: 10993, and is located on chromosome 12 with reported cytogenetic
location
12q24.12. The gene resides in genomic locus NT 009601 (NCBI Genome
Annotation).
Serine dehydratase catalyzes the PLP-dependent alpha,beta-elimination of L-
serine to
pyruvate and ammonia. It is one of three enzymes that are regarded as
metabolic exits of
the serine-glycine pool. Serine dehydratase can be found in the liver.
[0237] CPS 147 corresponds to KIAA0576 (COASTER) which encodes coactivator
for steroid receptors. This gene has LocusID: 26036, and is located on
chromosome 6 with
reported cytogenetic location 6p11.1. The gene resides in genomic locus NT
007592
(NCBI Genome Annotation).
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[0238] Affymetrix annotation suggests that CPS 148 corresponds to FCGR3B which
encodes Fc fragment of IgG, low affinity IIib, receptor for (CD16). The gene
has LocusID:
2215, and is located at chromosome 1 q23.
[0239] Blast search of the Entrez human genome sequence database shows that
CPS
148 aligns with FCGR3A with at least 97% sequence identity. FCGR3A encodes Fc
fragment of IgG, low affinity IIIa, receptor for (CD16). The gene has LocusID:
2214, and
is located on chromosome 1 with reported cytogenetic location 1 q23. The gene
resides in
genomic locus NT 004668 (NCBI Genome Annotation). The gene product is a Type
III Fc
gamma receptor and a member of the immunoglobulin superfamily. It can
associate with
zeta chain of the T-cell receptor complex (CD3Z).
[0240] CPS 149 corresponds to FCERlA which encodes Fc fragment of LgE, high
affinity I, receptor for; alpha polypeptide. The gene product is the alpha
subunit of the high
affinity IgE receptor, and may be involved in triggering allergic responses.
This gene has
LocusID: 2205, and is located on chromosome 1 with reported cytogenetic
location 1 q23.
The gene resides in genomic locus NT 004982 (NCBI Genome Annotation). The IgE
receptorcontains 3 subunits: alpha, beta (MIM 147138 ), and gamma (MIM 147139
). The
alpha subunit can be glycosylated.
[0241] CPS 150 corresponds to CD44 which encodes CD44 antigen (homing
function and Indian blood group system). This gene has LocusID: 960, and is
located on
chromosome 11 with reported cytogenetic location 11p13. The gene resides in
genomic
locus NT 009237 (NCBI Genome Annotation).
[0242] CPS 151 corresponds to ID1 which encodes inhibitor of DNA binding l,
dominant negative helix-loop-helix protein. This gene has LocusID: 3397, and
is located on
chromosome 20 with reported cytogenetic location 20q11. The gene resides in
.genomic
locus NT 028392 (NCBI Genome Annotation). The gene product is a member of the
Id
helix-loop-helix family of proteins, and may negatively regulate cell
differentiation.
[0243] Blast search of the Entrez human genome sequence database shows that
CPS
152 overlaps KIAA0963. CPS 152 aligns with the non-protein-coding strand of
KIAA0963. I~IAA0963 encodes I~IAA0963 protein, and has LocusID: 22904 with
reported
cytogenetic location 19p 13.3. KIAA0963 resides in genomic locus NT 011277
(NCBI
Genome Annotation).
[0244] CPS 153 corresponds to ADTB2 (AP2B1) which encodes adaptor-related
protein complex 2, beta 1 subunit. This gene has LocusID: 163, and is located
on
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chromosome 17 with reported cytogenetic location 17q11.2-q12. The gene resides
in
genomic locus NT 010799 (NCBI Genome Annotation). The beta adaptin subunit is
part of
the clathrin coat assembly complex which links clathrin to receptors in coated
pits and
vesicles. These vesicles are involved in endocytosis and Golgi processing. The
beta 1
subunit is one of the assembly proteins which binds to clathrin and initiates
coat formation.
[0245] CPS 154 corresponds to MADH3 which encodes MAD, mothers against
decapentaplegic homolog 3 (Drosophila). This gene has LocusID: 4088, and is
located on
chromosome 15 with reported cytogenetic location 15q21-q22. The gene resides
in
genomic locus NT 010265 (NCBI Genome Annotation). The gene product is similar
to
murine Madh3. It is a member of the Smad family of proteins, and may affect
transcription
in response to TGF-beta signaling pathways.
[0246] CPS 155 corresponds to ARPC1B which encodes actin related protein 2l3
complex, subunit 1 B (41 kD). This gene has LocusID: 10095; and is located on
chromosome 7 with reported cytogenetic location 7q11.21. The gene resides in
genomic
locus NT 007933 (NCBI Genome Annotation). The gene product is involved in
assembly
of the actin cytoskeleton, and may have a role in protrusion of lamellipodia.
[0247] CPS 155 also aligns with two chromosome 12 regions with 99-100%
sequence identity. These two regions reside in genomic locus NT 035283 (NCBI
Genome
Annotation). The first region is located near LOC 196489 which encodes a
protein similar
to FLJ00209 protein. The second region is located near LOC144584 which encodes
a
protein similar to vacuolar protein sorting 35 (yeast); maternal-embryonic 3.
Both
LOC196489 and LOC144584 have reported cytogenetic location 12q13.12.
[0248] Affymetrix annotation suggests that CPS 156 corresponds to TALDO1
which encodes transaldolase 1 and has LocusID: 6888. The gene is located at
chromosome
11p15.5-p15.4.
[0249] CPS 157 corresponds to UNK AL035079 (CAT) which encodes catalase.
This gene has LocusID: 847, and is located on chromosome 11 with reported
cytogenetic
location llpl3. The gene resides in genomic locus NT 009237 (NCBI Genome
Annotation). Catalase is a tetrameric hemoprotein that can detoxify hydrogen
peroxide.
[0250] CPS 158 corresponds to STXBP1 which encodes syntaxin binding protein 1.
This gene has LocusID: 6812, and is located on chromosome 9 with reported
cytogenetic
location 9q34.1. The gene resides in genomic locus NT 029366 (NCBI Genome
Annotation).
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[0251] CPS 159 corresponds to UNG2 which encodes uracil-I~NA glycosylase 2.
This gene has LocusID: 10309, and is located on chromosome 5 with reported
cytogenetic
location Sp15.2-p13.1. The gene resides in genomic locus NT 006431 (NCBI
Genome
Annotation). Uracil-DNA glycosylase 2 possesses uracil-DNA glycosylase
activity.
[0252] CPS 160 corresponds to DUSPS which encodes dual specificity phosphatase
5. This gene has LocusID: 1847, and is located on chromosome 10 with reported
cytogenetic location 1Oq25. The gene resides in genomic locus NT 030059 (NCBI
Genome Annotation). The protein encoded by DUSPS gene is a member of the dual
specificity protein phosphatase subfamily. These phosphatases can inactivate
their target
kinases by dephosphorylating both the phosphoserine/threonine and
phosphotyrosine
residues. They can negatively regulate members of the mitogen-activated
protein (MAP)
kinase superfamily (MAPK/ERK, SAPI~/JNK, p38), which are associated with
cellular
proliferation and differentiation. Different members of the family of dual
specificity
phosphatases show distinct substrate specificities for various MAP kinases,
different tissue
distribution and subcellular localization, and different modes of inducibility
of their
expression by extracellular stimuli. DUSPS gene product can inactivate ERI~l,
and is
expressed in a variety of tissues including pancreas and brain.
[0253] CPS 161 corresponds to PTPRO which encodes protein tyrosine
phosphatase, receptor type, O. This gene has LocusID: 5800, and is located on
chromosome 12 with reported cytogenetic location 12p13.3-p13.2. The gene
resides in
genomic locus NT 009714 (NCBI Genome Annotation). The gene product is~ an
integral
membrane protein containing a transmembrane domain and an intracellular
catalytic domain
with a characteristic signature motif. Several alternatively spliced
transcript variants, some
of which encode different isoforms of the protein, have been described. The
gene product
also contains fibronectin type III-like repeats and putative glycosylation
sites in the
extracellular domain.
[0254] Affymetrix annotation suggests that CPS 162 corresponds to SLA which
encodes Src-like-adaptor and has LocusID: 6503. The gene has reported
cytogenetic
location at chromosome 8q24.
[0255] Blast search of the Entrez human genome sequence database shows that
CPS
162 aligns with an intron sequence of TG with at least 99% sequence identity.
TG encodes
thyroglobulin, and has LocusID: ,7038 with reported cytogenetic location
8q24.2-q24.3.
The gene resides in genomic locus NT 008150 (NCBI Genome Annotation). CPS 162
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matches with the non-protein-coding strand of TG. Thyroglobulin is a precursor
of thyroid
hormones.
[0256] CPS 163 corresponds to RFP2 which encodes ret finger protein 2. This
gene
has LocusID: 10206, and is located on chromosome 13 with reported cytogenetic
location
13q14. The gene resides in genomic locus NT 033922 (NCBI Genome Annotation).
The
protein encoded by RFP2 gene is a member of the tripartite motif (TRIM)
family. The
TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-
box type
2, and a coiled-coil region. The RFP2 gene product localizes to cytoplasmic
bodies near the
nucleus. The gene is located on chromosome 13 within the minimal deletion
region for B-
cell chronic lymphocytic leukemia. Alternative splicing of this gene has been
described.
[0257] Nucleotides 3 to 255 of CPS 163 have 83% sequence identity with a
chromosomal region near LOC162162. LOC162162 encodes a protein similar to
spinocerebellar ataxia type 1, and has reported cytogenetic location 16q23.1.
[0258] CPS 164 corresponds to ADFP which encodes adipose differentiation-
related
protein (adipophilin).. This gene has LocusID: 123, and is located on
chromosome 9 with
reported cytogenetic location 9p21.2. The gene resides in genomic locus NT
023974
(NCBI Genome Annotation). Adipocyte differentiation-related protein is
associated with
the globule surface membrane material. The protein is a major constituent of
the globule
surface. Increase in mRNA levels is one of the earliest indications of
adipocyte
differentiation. The product is also a component of milk lipid globules.
[0259] CPS 164 aligns with a chromosome 1 region near LOC254424 with 94%
sequence identity. LOC254424 encodes a protein similar to adipophilin (adipose
differentiation-related protein) (ADRP).
[0260] CPS 165 corresponds to ADTD (AP3D1) which encodes adaptor-related
protein complex 3, delta 1 subunit. This gene has LocusID: 8943, and is
located on
chromosome 19 with reported cytogenetic location 19p 13.3. The gene resides in
genomic
locus NT 011268 (NCBI Genome Annotation). Delta-adaptin is a component of the
AP-3
complex which is involved in intracellular transport.
[0261] Affymetrix annotation suggests that CPS 166 corresponds to ADTG which
is
also known as AP1G1. The gene encodes adaptor-related protein complex 1, gamma
1
subunit. The gene has LocusID: 164, and is located at chromosome 16q23.
[0262] Blast search of the Entrez human genome sequence database shows that
CPS
166 aligns to LOC255980 with at least 99% sequence identity. LOC255980 encodes
a
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protein similar to hypothetical protein FLJ20151, and is located on chromosome
15.
LOC255980 resides in genomic locus NT 010265. It overlaps FLJ20151 which has
LocusID: 54837 and reported cytogenetic location 15q21.3.
[0263] CPS 168 corresponds to LTNK X87344 (PSMBB) which encodes proteasome
(prosome, macropain) subunit, beta type, 8 (large multifunctional protease 7).
This gene
has LocusID: 5696, and is located on chromosome 6 with reported cytogenetic
location
6p21.3. The gene resides in genomic locus NT 001592 (NCBI Genome Annotation).
Beta
subunit 8 of the proteasome (prosome macropain) can replace beta subunit PSMBS
when
cells are stimulated by interferon gamma, thereby altering proteasome
specificity.
[0264] CPS 170 corresponds to CAPG which encodes capping protein (actin
filament), gelsolin-like. This gene has LocusID: 822, and is located on
chromosome 2 with
reported cytogenetic location 2cen-q24. The gene resides in genomic locus NT
015805
(NCBI Genome Annotation). The gene product is a macrophage capping protein. It
can
reversibly block the barbed ends. The gene product is a member of the
gelsolin/villin
protein family.
[0265] CPS 171 corresponds to ARL7 which encodes ADP-ribosylation factor-like
7. This gene has LocusID: 10123, and is located on chromosome 2 with reported
cytogenetic location 2q37.2. The gene resides in genomic locus NT 005414 (NCBI
Genome Annotation). ADP-ribosylation factor-like 7 (ARL7) is a member of the
ADP-
ribosylation factor family of GTP-binding proteins. ARL7 is similar to ARL4
and ARL6,
and each has a nuclear localization signal and a high guanine nucleotide
exchange rate.
[0266] CPS 172 corresponds to RCV1 which encodes recoverin. This gene has
LocusID: 5957, and is located on chromosome 17 with reported cytogenetic
location
17p 13.1. The gene resides in genomic locus NT 010718 (NCBI Genome
Annotation).
Recoverin is a calcium-binding protein which can activate guanylate cyclase
activity.
[0267] CPS 173 corresponds to GR03 which encodes GR03 oncogene. This gene
has LocusID: 2921, and is located on chromosome 4 with reported cytogenetic
location
4q21. The gene resides in genomic locus NT 006216 (NCBI Genome Annotation).
GR03
is similar to human GRO1, and may encode a mitogenic factor.
(0268] CPS 175 corresponds to UNK AF070606 (ATP2B1) which encodes
ATPase, Ca++ transporting, plasma membrane 1. This gene has LocusID: 490, and
is
located on chromosome 12 with reported cytogenetic location 12q21-q23. The
gene resides
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in genomic locus NT 009729 (NCBI Genome Annotation). CPS 175 aligns with the
3'
UTR of the protein-coding strand of the gene.
[0269] CPS 176 corresponds to AOAH which encodes acyloxyacyl hydrolase
(neutrophil). This gene has LocusID: 313, and is located on chromosome 7 with
reported
cytogenetic location 7p 14-p 12. The gene resides in genomic locus NT 007819
(NCBI
Genome Annotation). Acyloxyacyl hydrolase is a 2-subunit lipase which can
hydrolyze the
secondary (acyloxyacyl-linked) fatty acyl chains from the lipid A region of
bacterial
endotoxins. Acyloxyacyl hydrolase may modulate host inflammatory responses to
gram-
negative bacterial invasion. The 2 subunits are encoded by a single mRNA.
[0270] CPS 177 corresponds to UNK AJ224442 (WBSCR22) which encodes
Williams Beuren syndrome chromosome region 22. This gene has LocusID: 114049,
and is
located on chromosome 7. The gene resides in genomic locus NT 007758 (NCBI
Genome
Annotation).
[0271] CPS 178 corresponds to MSRl which encodes macrophage scavenger
receptor 1. This gene has LocusID: 4481, and is located on chromosome 8 with
reported
cytogenetic location 8p22. The gene resides in genomic locus NT 015280 (NCBI
Genome
Annotation). This gene encodes the class A macrophage scavenger receptors,
which
include at least three different types (1, 2, 3) generated by alternative
splicing of this gene.
These receptors or isoforms are macrophage-specific trimeric integral membrane
glycoproteins and have been implicated in many macrophage-associated
physiological and
pathological processes including atherosclerosis, Alzheimer's disease, and
host defense.
The isoforms type 1 and type 2 are functional receptors and are able to
mediate the
endocytosis of modified low density lipoproteins (LDLs). The isoform type 3
may have an
altered intracellular processing and can be trapped within the endoplasmic
reticulum. The
isoform type 3 can inhibit the function of isoforms type 1 and type 2 when co-
expressed,
indicating a dominant negative effect and suggesting a mechanism for
regulation of
scavenger receptor activity in macrophages.
[0272] CPS 179 corresponds to XAP4 (C20orf18) which encodes chromosome 20
open reading frame 18. This gene has LocusID: 10616, and is located on
chromosome 20
with reported cytogenetic location 20p13. The gene resides in ~genomic locus
NT 011387
(NCBI Genome Annotation). The gene contains at least 12 exons. Several
alternatively
spliced transcript variants have been described. The gene product is similar
to mouse
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UIP28/UbcM4 interacting protein at the amino acid level, and contains a C3HC4
type
(RING) zinc finger. It may interact with PKC and mediate protein-protein
interactions.
[0273] CPS 180 corresponds to ClQRl which encodes complement component 1, q
subcomponent, receptor 1. This gene has LocusID: 22918, and is located on
chromosome
20 with reported cytogenetic location 20p 11.21. The gene resides in .genomic
locus
NT 011387 (NCBI Genome Annotation). The gene product is a type I membrane
protein
and can act as a receptor for complement protein Clq, mannose-binding lectin,
and
pulmonary surfactant protein A. The gene product is a functional receptor
involved in
ligand-mediated enhancement of phagocytosis.
[0274] CPS 181 corresponds to STAT4 which encodes signal transducer and
activator of transcription 4. This gene has LocusID: 6775, and is located on
chromosome 2
with reported cytogenetic location 2q32.2-q32.3. The gene resides in genomic
locus
NT 022197 (NCBI Genome Annotation). The gene product is a member of the STAT
family of transcription factors. In response to cytokines and growth factors,
STAT family
members may be phosphorylated by the receptor associated kinases, and then
form homo-
or heterodimers that translocate to the cell nucleus where they act as
transcription activators.
STAT4 gene product may be involved in mediating responses to IL12 in
lymphocytes and
regulating the differentiation of T helper cells.
[0275] CPS 182 corresponds to UNK AL049309 (SFRS12) which encodes splicing
factor, arginine/serine-rich 12. This gene has LocusID: 140890, and is located
on
chromosome 5 with reported cytogenetic location Sq12.3. The gene resides in
genomic
locus NT 006431 (NCBI Genome Annotation).
[0276] CPS 183 corresponds to RNASE2 which encodes ribonuclease, RNase A
family, 2 (liver, eosinophil-derived neurotoxin). This gene has LocusID: 6036,
and is
located on chromosome 14 with reported cytogenetic location 14q24-q31. The
gene resides
in genomic locus NT 025892 (NCBI Genome Annotation). The gene product is a
member
of ribonuclease superfamily, and has neurotoxic and ribonuclease activities.
[0277] CPS 183 also aligns with LOC122661 and RNASE3 with about 86-93%
sequence identity. LOC122661 encodes a protein similar to nonsecretory
ribonuclease
precursor (Ribonuclease US) (Eosinophil-derived neurotoxin) (RNase UpI-2)
(Ribonuclease
2) (RNase 2). It is located at chromosome 14q11.1, and resides in genomic
locus
NT 025892. RNASE3 encodes ribonuclease, RNase A family, 3 (eosinophil cationic
protein). RNASE3 has LocusID: 6037 and reported cytogenetic location 14q24-
q31. It also
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resides in genomic locus NT 025892. RNASE3 gene product is a member of the
ribonuclease superfamily, and has both neurotoxic and ribonuclease activities.
[0278] CPS 184 corresponds to NCF4 which encodes neutrophil cytosolic factor 4
(40kD). This gene has LocusID: 4689, and is located on chromosome 22 with
reported
cytogenetic location 22q13.1. The gene resides in genomic locus NT 011520
(NCBI
Genome Annotation). The protein encoded by this gene is a cytosolic element of
nicotinamide adenine dinucleotide phosphate-oxidase. Upon neutrophil
stimulation, the
encoded protein and other cytosolic elements are se It to the cell membrane
from the cytosol
to form a complex which produces phagocytic oxygen radicals. Two motifs found
in this
protein, an SH3 domain and a PC motif, are significant to protein-protein
interactions.
Through interaction with the SH3 domain, NCF4 gene product is responsible for
the
downregulation of NADPH-oxidase. Alternative splicing has been observed in
this .gene.
CPS 184 aligns to the 3' UTR of the gene.
[0279] CPS 185 corresponds to ANXA4 which encodes annexin A4. This .gene has
LocusID: 307, and is located on chromosome 2 with reported cytogenetic
location 2p13.
The gene resides in genomic locus NT 022184 (NCBI Genome Annotation). Annexin
A4
belongs to the annexin family of calcium-dependent phospholipid binding
proteins. Several
members of the annexin family have been implicated in membrane-related events
along
exocytotic and endocytotic pathways. Annexin A4 may interact with ATP, have in
vitro
anticoagulant activity, and inhibit phospholipase A2 activity. Annexin A4 can
be detected
in epithelial cells.
[0280] CPS 186 corresponds to ME2 which encodes malic enzyme 2, NAD(+)-
dependent, mitochondrial. This gene has LocusID: 4200, and is located on
chromosome 18
with reported cytogenetic location 18q21. The gene resides in genomic locus NT
033905
(NCBI Genome Annotation). The gene product is a homotetrameric protein which
can
catalyze the oxidative decarboxylation of malate to pyruvate.
[0281] CPS 183 also has 91% sequence identity with a chromosome 9 region near
LOC169570. LOC169570 has reported cytogenetic location 9p13.1.
[0282] CPS 187 corresponds to IFI35 which encodes interferon-induced protein
35.
This gene has LocusID: 3430, and is located on chromosome 17 with reported
cytogenetic
location 17q21. The gene resides in genomic locus NT 035490 (NCBI Genome
Annotation). Interferon-induced protein 35 associates with B-ATF transcription
factor on
interferon treatment. It contains a leucine-zipper motif.
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[0283] CPS 188 corresponds to VAMPS which encodes vesicle-associated
membrane protein 5 (myobrevin). This gene has LocusID: 10791, and is located
on
chromosome 2 with reported cytogenetic location 2p 11.2. The gene resides in
genomic
locus NT 015805 (NCBI Genome Annotation). The gene .product is a member of the
synaptobrevin/VAMP family of proteins.
[0284] CPS 188 also has 87% sequence identity with an intron sequence of NSF.
NSF encodes N-ethylmaleimide-sensitive factor. It has LocusID: 4905 and
reported
cytogenetic location 17q21.
[0285] CPS 189 corresponds to IMPA2 which encodes inositol(myo)-1(or 4)-
monophosphatase 2. This gene has LocusID: 3613, and is located on chromosome
18 with
reported cytogenetic location 18p11.2. The .gene resides in genomic locus NT
010859
(NCBI Genome Annotation).
[0286] CPS 190 corresponds to GZMK which encodes granzyme K (serine protease,
granzyme 3; tryptase II). This gene has LocusID: 3003, and is located on
chromosome 5
with reported cytogenetic location Sqll-q12. The gene resides in -genorriic
locus
NT 006431 (NCBI Genome Annotation). This gene product is a member of a group
of
related serine proteases from the cytoplasmic granules of cytotoxic
lymphocytes. Cytolytic
T lymphocytes (CTL) and natural killer (NK) cells can recognize, bind, and
lyse specific
target cells. They are thought to protect their host by lysing cells bearing
on their surface
"nonsel~' antigens, usually peptides or proteins resulting from infection by
intracellular
pathogens..
[0287] CPS 191 corresponds to BGN which encodes biglycan. This gene has
LocusID: 633, and is located on chromosome X with reported cytogenetic
location ~q28.
The gene resides in genomic locus NT 025965 (NCBI Genome Annotation). The
protein
encoded by this gene is a small cellular or pericellular matrix proteoglycan
that is related in
structure to two other small proteoglycans, decorin and fibromodulin. The
encoded protein
and decorin are thought to be the result of a gene duplication. Decorin
contains one
attached glycosaminoglycan chain, while biglycan probably contains two chains.
Biglycan
is thought to function in connective tissue metabolism by binding to collagen
fibrils and
transfering growth factor-beta. It may promote neuronal survival. This gene is
a candidate
gene for the Happle syndrome.
[0288] CPS 192 corresponds to AIF1 which encodes allograft inflammatory factor
1. This gene has LocusID: 199, and is located on chromosome 6 with reported
cytogenetic
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location .6p21.3. The gene resides in genomic locus NT 007592 {NCBI Genome
Annotation). This gene is induced by cytokines and interferon. Its protein
product is
thought to be involved in negative regulation of growth of vascular smooth
muscle cells,
which contributes to the anti-inflammatory response to vessel wall trauma. The
gene
expresses at least three transcripts.
[0289] CPS 193 corresponds to CBP2 (SERPINH2) which encodes serine (or
cysteine) proteinase inhibitor, Glade H (heat shock protein 47), member 2.
This gene has
LocusID: 872, and is located on chromosome ~ 1 with reported cytogenetic
location
11q13.5. The gene resides in genomic locus NT 033927 (NCBI Genome Annotation).
The
gene product is also known as Colligin-2, which is a collagen-binding protein
that acts as a
heat shock protein.
[0290] CPS 193 also has 92% sequence identity with a chromosome 9 region near
pshsp47. Pshsp47 encodes serine (or cysteine) proteinase inhibitor, Glade H
(heat shock
protein 47), member 2 pseudogene. It has LocusID: 158172 and reported
cytogenetic
location 9p11.2.
[0291] Affymetrix annotation suggests that CPS 195 corresponds to IQGAP1 which
encodes IQ motif containing GTPase activating protein 1. The gene has LocusID:
8826
with reported cytogenetic location 15q26.1.
[0292] Blast search of the Entrez human genome sequence database shows that
nucleotides 395 to 5984 of L33075 align with IQGAP1 with 98% sequence
identity.
IQGAPl encodes IQ motif containing GTPase activating protein 1. The gene has
LocusID:
8826, and is located on chromosome 15 with reported cytogenetic location
15q26.1. The
gene resides in genomic locus NT 033276. The gene product contains a GTPase
activating
domain and multiple calmodulin binding domains, and can bind to actin
cytoskeleton and
inhibit GTPase activity of ras family of GTP binding proteins Cdc42Hs and rac.
[0293] CPS 196 corresponds to KIAA0823 (PPP1R16B) which encodes protein
phosphatase 1, regulatory (inhibitor) subunit 168. This gene has LocusID:
26051, and is
located on chromosome 20 with reported cytogenetic location 20q11.23. The gene
resides
in genomic locus NT Ol 1362 (NCBI Genome Annotation).
[0294] CPS 197 corresponds to UNIT AI018098 (MGC15523) which encodes
hypothetical protein MGC15523. This gene has LocusID: 124565, and is located
on
chromosome 17 with reported cytogenetic location 17q25.3. The gene resides in
genomic
locus NT 010661 (NCBI Genome Annotation).
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[0295] Affymetrix annotation suggests that CPS 198 corresponds to CD163.
CD163 encodes CD163 antigen, and has LocusID: 9332. The gene is located at
chromosome 12p 13.3.
[0296] CPS 199 corresponds to HK3 which encodes hexokinase 3 (white cell).
This
gene has LocusID: 3101, and is located on chromosome 5 with reported
cytogenetic
location Sq35.2. The gene resides in genomic locus NT 023132 (NCBI Genome
Annotation). Hexokinases phosphorylate glucose to produce glucose-6-phosphate,
thus
committing glucose to the glycolytic pathway. HK3 gene encodes hexokinase 3
which is
similar to hexokinases 1 and 2. Hexokinase 3 can be inhibited by its product
glucose-6-
phosphate.
[0297] CPS 200 corresponds to FOS which encodes v-fos FBJ murine osteosarcoma
viral oncogene homolog. This gene has LocusID: 2353, and is located on
chromosome 14
with reported cytogenetic location 14q24.3. The gene resides in genomic locus
NT 026437
(NCBI Genome Annotation). The Fos gene family has 4 members: FOS, FOSB, FOSL1,
and FOSL2. These genes encode leucine zipper proteins that can dimerize with
proteins of
the JUN family, thereby forming the transcription factor complex AP-1. As
such, the FOS
proteins have been implicated as regulators of cell proliferation,
differentiation, and
transformation. In some cases, expression of the FOS gene has also been
associated with
apoptotic cell death. FOS gene product may also be involved in alteration of
DNA
methylation.
[0298] CPS 201 corresponds to DIFF48 (C6orf32) which encodes chromosome 6
open reading frame 32. This gene has LocusID: 9750, and is located on
chromosome 6 with
reported cytogenetic location 6p22.3-p21.32. The gene resides in genomic locus
NT 007592 (NCBI Genome Annotation). The protein encoded by DIFF48 can
stimulate
the formation of a non-mitotic multinucleate syncytium from proliferative
cytotrophoblasts
during trophoblast differentiation. An alternatively spliced transcript
variant of this .gene
has been described.
[0299] CPS 202 corresponds to UNK L23134 (GZMM) which encodes granzyme
M (lymphocyte met-ase 1). This gene has LocusID: 3004, and is located on
chromosome
19 with reported cytogenetic location 19p13.3. The gene resides in genomic
locus
NT 011227 (NCBI Genome Annotation). Human natural killer {NK) cells and
activated
lymphocytes express and store a distinct subset of neutral serine proteases
together with
proteoglycans and other immune effector molecules in large cytoplasmic
granules. These
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serine proteases are collectively termed granzymes and include at least four
distinct gene
products: granzyme A, granzyme B, granzyme H, and Met-ase which is also known
as
granzyme M.
(0300] CPS 203 corresponds to LM02 which encodes LIM domain only 2
(rhombotin-like 1). This gene has LocusID: 4005, and is located on chromosome
11 with
reported cytogenetic location l lpl3. The gene resides in genomic locus NT
009237 (NCBI
Genome Annotation). LM02 encodes a cysteine-rich, two LIM-domain protein that
is
involved in yolk sac erythropoiesis. The LMO2 protein has a role in
hematopoietic
development. The LMO2 transcription start site is located approximately 25 kb
downstream from the l 1p13 T-cell translocation cluster (11p13 ttc), where a
number T-cell
acute lymphoblastic leukemia-specific translocations occur. The LMO2 protein
is a
member of the rhombotin family.
[0301] CPS 204 corresponds to PDI2 (PADI2) which encodes peptidyl arginine
deiminase, type II. This gene has LocusID: 11240, and is located on chromosome
1 with
reported cytogenetic location 1p35.2-p35.1. The gene resides in genomic locus
NT 034376
(NCBI Genome Annotation). The gene product is similar to rat skeletal muscle
peptidyl
arginine deiminase, type II. It may convert arginine residues within proteins
to citrulline
residues.
[0302] CPS 205 corresponds to UNK AL031282 (FLJ13052) which encodes NAD
kinase. This gene has LocusID: 65220, and is located on chromosome 1 with
reported
cytogenetic location 1p36.33-p36.21. The gene resides in genomic locus NT
00430
(NCBI Genome Annotation).
[0303] CPS 205 also aligns with a chromosomal region near MMP23B with at least
98% sequence identity. MMP23B encodes matrix metalloproteinase 23B, and has
LocusID:
8510 and reported cytogenetic location 1p36.3. The gene resides in genomic
locus
NT 004350. CPS 205 aligns with the non-protein-coding strand of MMP23B.
[0304] CPS 206 corresponds to GABRG2 which encodes gamma-aminobutyric acid
(GABA) A receptor, gamma 2. This gene has LocusID: 2566, and is located on
chromosome 5 with reported cytogenetic location Sq3l.l-q33.1. The gene resides
in
genomic locus NT 030698 (NCBI Genome Annotation). The gamma-aminobutyric acid
(GABA) A receptor, gamma 2 is found as an inhibitory neurotransmitter receptor
in the
brain.
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[0305] CPS 207 corresponds to KIAA0404 which encodes KIAA0404 protein. This
gene has LocusID: 23130, and is located on chromosome 11 with reported
cytogenetic
location 11q13.1. The gene resides in genomic locus NT 033241 (NCBI Genome
Annotation).
[0306] CPS 208 corresponds to UNK U12471 (THBS1) which encodes
thrombospondin 1. This gene has LocusID: 7057, and is located on chromosome 15
with
reported cytogenetic location 15q15. The gene resides in genomic locus NT
030828 (NCBI
Genome Annotation). Thrombospondin-1 has a roe in blood clotting and in
angiogenesis.
It is a member of a family of adhesive molecules.
[0307] Affymetrix annotation suggests that CPS 209 corresponds to IGHA1 which
encodes immunoglobulin heavy constant alpha 1. The gene has LocusID: 3493 and
reported cytogenetic location 14q32.33.
[0308] CPS 210 corresponds to ABCB1 which encodes ATP-binding cassette, sub-
family B (MDR/TAP), member 1~. This gene has LocusID: 5243, and is located on
chromosome 7 with reported cytogenetic location 7q21.1. The gene resides in
genomic
locus NT 007933 (NCBI Genome Annotation): The membrane-associated protein
encoded
by this gene is a member of the superfamily of ATP-binding cassette (ABC)
transporters.
ABC proteins transport various molecules across extra- and infra-cellular
membranes. ABC
genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD,
OABP,
GCN20, White). This protein encoded by ABCB1 gene is a member of the MDR/TAP
subfamily. Members of the MDR/TAP subfamily are involved in multidrug
resistance. The
ABCB gene product is an ATP-dependent drug efflux pump for xenobiotic
compounds with
broad substrate specificity. It is responsible for decreased drug accumulation
in multidrug-
resistant cells and often mediates the development of resistance to anticancer
drugs. It can
also function as a transporter in the blood-brain barrier. The ABCB gene
product is also
known as P glycoprotein 1.
[0309] CPS 211 corresponds to NRIP1 which encodes nuclear receptor interacting
protein 1. This gene has LocusID: 8204, and is located on chromosome 21 with
reported
cytogenetic location 21 ql 1.2. The gene resides in genomic locus NT O11 S 12
~(NCBI
Genome Annotation). Nuclear receptor interacting protein 1 is a nuclear
protein that can
interact with the hormone-dependent activation domain AF2 of nuclear
receptors. Also
known as RIP140, this protein modulates transcriptional activity of the
estrogen receptor.
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[0310] CPS 213 corresponds to GLB 1 which encodes galactosidase, beta 1. This
gene has LocusID: 2720, and is located on chromosome 3 with reported
cytogenetic
location 3p21.33. The gene resides in genomic locus NT 005580 (NCBI Genome
Annotation). The gene product can catalyze cleavage of the terminal galactose.
[0311] CPS 214 corresponds to MSC which encodes musculin (activated B-cell
factor-1). This gene has LocusID: 9242, and is located on chromosome 8 with
reported
cytogenetic location 8q21. The gene resides in genomic locus NT 034895 (NCBI
Genome
Annotation). The gene product contains a bHLH motif; a putative nuclear
localization
signal, a glycine-rich region, and a stretch of acidic residues. The gene
product is capable
of binding an E-box element either as a homodimer or as a heterodimer with E2A
in vitro,
and forms heterodimers with E2A proteins in vivo. It also contains a
transcriptional
repression domain and is capable of inhibiting the transactivation capability
of E47, an E2A
protein, in mammalian cells. MSC is thought to be a downstream target of the B-
cell
receptor signal transduction pathway.
(0312] CPS 216 corresponds to UNK U95006 (MGC14480) which encodes
hypothetical protein MGC14480. This gene has LocusID: 201254, and is located
on
chromosome 17 with reported cytogenetic location 17q25.3. The gene resides in
genomic
locus NT 035479 (NCBI Genome Annotation).
[0313] Nucleotides 400 to 561 of CPS 216 also have 84% sequence identity with
an
intron sequence of EG1. EG1 encodes endothelial-derived gene 1, and has
LocusID: 80306
and reported cytogenetic location 4p 16.
[0314] CPS 217 corresponds to NK4 which encodes natural killer cell transcript
4.
This gene has LocusID: 9235, and is located on chromosome 16 with reported
cytogenetic
location 16p13.3. The gene resides in genomic locus NT 010552 (NCBI Genome
Annotation). The gene product may play a role in cell adhesion. It contains an
RGD motif.
(0315] CPS 217 also has 96% sequence identity with LOC124213 which encodes a
protein similar to natural killer cell transcript 4. LOC 124213 is located at
chromosome
16p13.11, and also resides in genomic locus NT 010552.
[0316] CPS 218 corresponds to UNK 224724 (FLJ20986) which encodes
hypothetical protein FLJ20986. This gene has LocusID: 79572, and is located on
chromosome 3 with reported cytogenetic location 3q29. The .gene resides in
genomic locus
NT 005535 (NCBI Genome Annotation). The alignment between CPS 218 and
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UNK Z~4724 is within an intron of GPS which encodes glycoprotein V (platelet)
and has
LocusID: 2814.
[0317] CPS 219 corresponds to GRN which encodes branulin. This gene has
LocusID: 2896, and is located on chromosome 17 with reported cytogenetic
location
17q21.32. The gene resides in genomic locus NT 010755 (NCBI Genome
Annotation).
Granulin is a putative growth factor. It is cysteine rich and contains
multiple granulin
repeats.
[0318] CPS 220 corresponds to EREG which encodes epiregulin. This gene has
LocusID: 2069, and is located on chromosome 4 with reported cytogenetic
location 4q13.3.
The gene resides in genomic locus NT 006216 (NCBI Genome Annotation).
Epiregulin is
a member of the epidermal growth factor family. Epiregulin can function as a
ligand of
EGFR (epidermal growth factor receptor), as well as a ligand of most members
of the
ERBB (v-erb-b2 oncogene homology family of tyrosine-kinase receptors.
Epiregulin may
promote cell proliferation.
[0319] CPS 221 corresponds to KIAA0382 (ARHGEF12) which encodes Rho
guanine nucleotide exchange factor (GEF) 12. This gene has LocusID: 23365, and
is
located on chromosome 11 with reported cytogenetic location 11 q23.3. The gene
resides in
genomic locus NT 033899 (NCBI Genome Annotation). Rho GTPases play a role in
numerous cellular processes that are initiated by extracellular stimuli that
work through G
protein coupled receptors. Rho guanine nucleotide exchange factor (GEF) 12 may
form a
complex with G proteins and stimulate Rho-dependent signals. This protein is
observed to
form myeloid/lymphoid fusion partner in acute myeloid leukemia.
[0320] CPS 222 corresponds to RNASE6 which encodes ribonuclease, RNase A
family, k6. This gene has LocusID: 6039, and is located on chromosome 14 with
reported
cytogenetic location 14q11.1. The gene resides in genomic locus NT 025892
(NCBI
Genome Annotation). Ribonuclease k6 may function in host defense. It is a
member of
eosinophil-derived neurotoxin ribonuclease A superfamily.
[0321] CPS 223 corresponds to KIAA0442 which encodes autism-related protein 1.
This gene has LocusID: 26053, and is located on chromosome 7 with reported
cytogenetic
location 7p13. The gene resides in genomic locus NT 007758 (NCBI Genome
Annotation).
[0322] Blast search of the Entrez human genome sequence database shows that
nucleotides 35 to 1907of CPS 225 align with various chromosomal regions with
89-90%
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sequence identity. These regions include LOC255718, LOC140070, and a
chromosome 2
region between GPR39 and LOC255521. LOC255718 is located on chromosome 2 and
has
genomic locus NT 034486 (NCBI Genome Annotation). LOC140070 encodes a protein
similar to Protein CDC27Hs (Cell division cycle protein 27 homology (H-NUC).
It is
located on chromosome Yq11.1 and has genomic locus NT 011878. GPR39 and
LOC255521 reside in genomic locus NT 034487. GPR39 encodes G protein-coupled
receptor 39, and has LocusID: 2863 and reported cytogenetic location 2q21-q22.
[0323] Nucleotides 1317 to 1481 of CPS 225 have 98% sequence identity with a
chromosome 12 region near LOC256746. LOC256746 encodes phosphodiesterase 3A,
cGMP-inhibited. Nucleotides 1381 to 1418 and 1461 to 1502 have 100% sequence
identity
with an intron sequence of LOC126500. LOC126500 encodes a protein similar io
hypothetical zinc forger protein KIAA1473. It is located on chromosome
19p13.11, and
resides in genomic locus NT 033317. Other fragments of CPS 225 have 84-93%
sequence
identity with regions on chromosomes 7, 11, 14, 18 and 21.
[0324] Blast search of the Entrez human genome sequence database shows that
CPS
226 aligns to a region located in an intron of ATPBA. CPS 226 aligns with the
non-protein-
coding strand of ATP8A2. ATP8A2 encodes ATPase, aminophospholipid transporter-
like,
Class I, type 8A, member 2. ATP8A2 gene has LocusID: 51761, and is located on
chromosome 13 with reported cytogenetic location 13q12-13. ATP8A2 resides in
genomic
locus NT 009799 (NCBI Genome Annotation). ATP8A2 gene product may be a tumor
suppressor. Loss of its function can convert cells to tumorigenic phenotype.
[0325] CPS 227 corresponds to ARHC which encodes ras homolog gene family,
member C. This gene has LocusID: 389, and is located on chromosome 1 with
reported
cytogenetic location 1p21-p13. The gene resides in genomic locus NT 019273
(NCBI
Genome Annotation). The gene product can regulate reorganization of the actin
cytoskeleton. CPS 227 aligns with the 3' UTR region of ARHC. The alignment is
also 3'
to MOV10 which encodes MovlO, Moloney leukemia virus 10, homolog (mouse).
MOV10
has LocusID: 4343 and reported cytogenetic location 1p12. It resides in
genomic locus
NT 019273.
[0326] CPS 228 corresponds to CREM which encodes cAMP responsive element
modulator. This gene has LocusID: 1390, and is located on chromosome 10 with
reported
cytogenetic -location lOpl2.l-p11.1. The gene resides in genomic locus NT
033896-(NCBI
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Genome Annotation). Cyclic AMP-responsive element modulator is a regulator of
the
transcription of cAMP-inducible genes.
[0327] CPS 229 corresponds to ISG15 which encodes interferon-stimulated
protein,
15 kDa. This gene has LocusID: 9636, and is located on chromosome 1 with
reported
cytogenetic location 1p36.33. The gene resides in genomic locus NT 004350
(NCBI
Genome Annotation). The expression of ISG15 can be induced by interferon.
[0328] CPS 230 corresponds to CCR7 ich encodes chemokine (C-C motif)
receptor 7. This gene has LocusID: 1236, and is located on chromosome 17 with
reported
cytogenetic location 17q12-q21.2 . The gene resides in genomic locus NT 024901
(NCBI
Genome Annotation). The gene product is a G protein-coupled receptor, and can
bind to
CC chemokine ELC and mediate intracellular calcium flux.
[0329] CPS 231 corresponds to F11 which encodes coagulation factor XI (plasma
thromboplastin antecedent). This gene has LocusID: 2160, and is located on
chromosome 4
with reported cytogenetic location 4q35. The gene resides in genomic locus NT
022792
(NCBI Genome Annotation). Alternative splicing of the gene results in at least
two
transcripts. One transcript encodes the circulating plasma factor XI and an
alternate
transcript lacking exon 5 encodes the platelet factor XI. The plasma factor XI
is present in
plasma as a zymogen. The platelet factor XI is localized to platelets and
megakaryocytes,
and may play a role both in the maintenance of normal hemostasis and as a
substitute for
plasma factor XI.
[0330] Blast search of the Entrez human genome sequence database shows that
CPS
232 aligns with a chromosome 4 region near LOC166760. This chromosome 14
region
resides in genomic locus NT 006344 (NCBI Genome Annotation). LOC 166760 has
reported cytogenetic location 4p 15.32.
[0331] CPS 233 corresponds to UNK AC002073 (MGC17330) which encodes
hypothetical protein MGC17330. This gene has LocusID: 113791, and is located
on
chromosome 22 with reported cytogenetic location 22q11.2-q22. The gene resides
in
genomic locus NT 011520 (NCBI Genome Annotation).
[0332] CPS 234 corresponds to STK17A which encodes serine~threonine kinase 17a
(apoptosis-inducing). This gene has LocusID: 9263, and is located on
chromosome 7 with
reported cytogenetic location 7p12-p14. The gene resides in genomic locus NT
007819
(NCBI Genome Annotation). The alignment of CPS 234 and STK17A resides in an
intron
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of FLJ10803. FLJ10803 encodes hypothetical protein FLJ10803, and has LocusID:
55744
and reported cytogenetic location 7p15.1.
[0333] CPS 235 corresponds to BLVRA which encodes biliverdin reductase A.
This gene has LocusID: 644, and is located on chromosome 7 with reported
cytogenetic
location 7p14-cen. The gene resides in genomic locus NT 007819 (NCBI Genome
Annotation).
[0334] CPS 236 corresponds to SPPl which encodes secreted phosphoprotein 1
(osteopontin, bone sialoprotein I, early T-lymphocyte activation 1 ). This
gene has LocusID:
6696, and is located on chromosome 4 with reported cytogenetic location 4q21-
q25. The
gene resides in genomic locus NT 006204 (NCBI Genome Annotation). The gene
product
is a bone and blood vessel extracellular matrix protein involved in
calcification and
atherosclerosis.
[0335] CPS 237 corresponds to STXlA which encodes syntaxin lA (brain). This
gene has LocusID: 6804, and is located on chromosome 7 with reported
cytogenetic
location 7q11.23. The gene resides in genomic locus NT 007758 (NCBI Genome
Annotation). Syntaxin lA (brain) may be involved in intracellular transport
and
neurotransmitter release.
[0336] CPS 238 corresponds to TKTL1 which encodes transketolase-like 1. This
gene has LocusID: 8277, and is located on chromosome X with reported
cytogenetic
location Xq28. The gene resides in genomic locus NT 025965 (NCBI Genome
Annotation). Transketolase-like 1 is a thiamine pyrophosphate-dependent enzyme
of
pentose phosphate pathway.
[0337] CPS 239 corresponds to IER3 which encodes immediate early response 3.
This gene has LocusID: 8870, and is located on chromosome 6 with reported
cytogenetic
location 6p21.3. The gene resides in genomic locus NT 007592 (NCBI Genome
Annotation). This gene functions in the protection of cells from Fas or tumor
necrosis
factor type alpha-induced apoptosis. Alternative splicing of this gene results
in at least two
transcript variants.
[0338] CPS 241 corresponds to PLAU which encodes plasminogen activator,
urokinase. This gene has LocusID: 5328, and is located on chromosome 10 with
reported
cytogenetic location 1Oq24. The gene resides in genomic locus NT 033890 (NCBI
Genome Annotation). Urokinase plasminogen activator is a serine protease that
cleaves
plasminogen to form plasmin.
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[0339] CPS 242 corresponds to ASS which encodes argininosuccinate synthetase.
This gene has LocusID: 445, and is located on chromosome 9 with reported
cytogenetic
location 9q34.1. The gene resides in genomic locus NT 008338 (NCBI Genome
Annotation). The protein encoded by this gene catalyzes the penultimate step
of the
arginine biosynthetic pathway. There are approximately 10 to 14 copies of this
gene
including the pseudogenes scattered across the human genome, among which the
one
located on chromosome 9 appears to be the only functional gene for
argininosuccinate
synthetase. Mutations in the chromosome 9 copy of ASS cause citrullinemia. At
least two
alternatively spliced transcript variants of this gene have been reported.
[0340] CPS 242 also has 87-94% sequence identity with various regions on
chromosome 2, 4, 5, 6, 7, 9, 11, 12 and X. , These regions include LOC167449,
LOC222906, ASSP2, ASSP3, ASSP4, ASSPS, LOC158452, LOC253843, LOC120341,
LOC167519, and an intron of intron of LOC90957. LOC167449 encodes a protein
similar
to argininosuccinate synthetase and resides in genomic locus NT 006431 with
reported
cytogenetic location 5q11.2. LOC222906 encodes a protein similar to
argininosuccinate
synthetase, and resides in genomic locus NT 007819 with reported cytogenetic
location
7p21.3. ASSP2 (LocusID: 447) encodes argininosuccinate synthetase pseudogene
2, and
resides in genomic locus NT 007592 with reported cytogenetic location 6p22.1.
ASSP3
(LocusID: 448) encodes argininosuccinate synthetase pseudogene 3, and resides
in genomic
locus NT 033256 with reported cytogenetic location 9q11-q22. ASSP4 (LocusID:
449)
encodes argininosuccinate synthetase pseudogene 4, and resides in genomic
locus
NT 025302 with reported cytogenetic location Xpter-p22. ASSPS (LocusID: 450)
encodes
argininosuccinate synthetase pseudogene 5, and resides in genomic locus NT
028405 with
reported cytogenetic location Xq22-q26. LOC 158452 encodes a protein similar
to
argininosuccinate synthetase, and resides in genomic locus NT 023935 with
reported
cytogenetic location 9q21.31. LOC253843 encodes a protein similar to
argininosuccinate
synthetase, and resides in genomic locus NT 006258 on chromosome 4. LOC120341
encodes a protein similar to argininosuccinate synthetase, and resides in
genomic locus
NT 009151 with reported cytogenetic location 11 q23. l . LOC 167519 encodes a
protein
similar to argininosuccinate synthetase, and resides in genomic locus NT
034778 with
reported cytogenetic location 5q31.3. LOC90957 (LocusID: 90957) encodes DEAR-
box
RNA/DNA helicase AAM73547, and resides in genomic locus NT 005367 with
reported
cytogenetic location 2p22.3.
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[0341] AffymetriX annotation suggests that CPS 244 corresponds to DiJXl which
encodes double homeobox, 1. The gene has LocusID: 26584.
[0342] Blast search of the Entrez human genome sequence database shows that
nucleotides 1 to 689 of AJ001481 (SEQ ID NO: 227) align with two chromosome 4
regions
with 85-88% sequence identity. The first region is located 3' to LOC131308.
LOC131308
encodes a protein similar to FSIiD Region Gene 2 protein. It has reported
cytogenetic
location 3p14.1 and resides in genomic locus NT 022665. The second region is
located
near TRAP95. TR.AP95 encodes thyroid hormone receptor-associated protein, 9'S-
kD
subunit. TRAP95 has LocusID: 10025 and reported cytogenetic looation 19p13.3.
It
resides in genomic locus NT 011277. TRAP95 gene product is a subunit of TRAP
thyroid
hormone receptor-associated protein complex, and functions as a coactivator
for nuclear
receptors.
[0343] CPS 245 corresponds to GPA33 which encodes glycoprotein A33
(transmembrane). This gene has LocusID: 10223, and is located on chromosome 1
with
reported cytogenetic .location 1 q23.2. The gene resides in genomic locus NT
004668
(NCBI Genome Annotation). The glycoprotein encoded by this gene is a cell
surface
antigen that is expressed in human colon cancers. The sequence of the
extracellular region
of the encoded protein contains 2 domains characteristic of the CD2 'subgroup
of the
immunoglobulin (Ig) superfamily. The encoded protein may play a role in cell
adhesion.
[0344] CPS 246 corresponds to PAI1 (SERPINE1) which encodes serine (or
cysteine) proteinase inhibitor, Glade E (nexin, plasminogen activator
inhibitor type 1 ),
member 1. This gene has LocusID: 5054, and is located on chromosome 7 with
reported
cytogenetic location 7q21.3-q22. The gene resides in genomic locus NT 007933
(NCBI
Genome Annotation). The gene product may regulate fibrinolysis. It is a member
of the
serpin family of serine protease inhibitors.
[0345] CPS 247 corresponds to CYP 1 B 1 which encodes cytochrome P450,
subfamily I (dioxin-inducible), polypeptide 1 (glaucoma 3, primary infantile).
This gene
has LocusID: 1545, and is located on chromosome 2 with reported cytogenetic
location
2p21. The gene resides in genomic locus NT 005367 (NCBI Genome Annotation).
This
gene product is a member of the cytochrome P4'S0 superfamily of enzymes. The
cytochrome P450 proteins are monooxygenases which catalyze many reactions
involved in
drug metabolism and synthesis of cholesterol, steroids and other lipids. The
enzyme
encoded by CYP 1 B 1 gene localizes to the endoplasmic reticulum and
metabolizes
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procarcinogens such as polycyclic aromatic hydrocarbons and l7beta-estradiol.
Mutations
in this gene have been associated with primary congenital glaucoma.
[0346] CPS 249 corresponds to HU-KS (MGLL) which encodes monoglyceride
lipase. This gene has LocusID: 11343, and is located on chromosome 3 with
reported
cytogenetic location 3q21.3. The gene resides in genomic locus NT 005588 (NCBI
Genome Annotation). The gene product may function in regulating levels of
lysophospholipids.
[0347] Affymetrix annotation suggests that CPS 250 corresponds to DORA. DORA
is also known as IGSF6 which encodes immunoglobulin superfarnily, member 6.
The gene
has LocusID: 10261, and is located at chromosome 16p12-p13.
[0348] Blast search of the Entrez human genome sequence database shows that
CPS
250 has at least 97% sequence identity with an intron sequence of DREV 1. DREV
1
encodes CGI-81 protein. DREV 1 has LocusID: 51108, and is located on
chromosome 16
with reported cytogenetic location 16p13-p12. The gene resides in genomic
locus
NT 010441 (NCBI Genome Annotation).
[0349] CPS 253 corresponds to MD-2 which encodes MD-2 protein. This gene has
LocusID: 23643, and is located on chromosome 8 with reported cytogenetic
location
8q13.2. The gene resides in genomic locus NT 008209 (NCBI Genome Annotation).
The
MD-2 protein appears to associate with toll-like receptor 4 on the cell
surface and confer
responsiveness to lipopolysaccyaride (LPS), thus providing a link between the
receptor and
LPS signaling.
[0350] CPS 254 corresponds to UNK U07563 (RRP4) which encodes homolog of
yeast RRP4 (ribosomal RNA processing 4), 3'-5'-exoribonuclease. This gene has
LocusID:
23404, and is located on chromosome 9 with reported cytogenetic location 9q34.
The .gene
resides in genomic locus NT 008338 (NCBI Genome Annotation). The gene product,
also
known as ribosomal RNA processing 4, is similar to S. cerevisiae RRP4 which is
a
component of both the nuclear and cytoplasmic forms of the ribosomal RNA
processing 3'-
5' exosome complex. UNK U07563 or RRP4 gene product may function in ribosomal
RNA processing.
[0351] Affymetrix annotation suggests that CPS 255 corresponds to SPINKl which
encodes serine protease inhibitor, Kazal type 1. The gene has LocusID: 6690
and reported
cytogenetic location Sq32.
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(0352] Blast search of the Entrez human genome sequence database shows that
CPS
255 has at least 97% sequence identity with a chromosome 5 region between
LOC256135
and KIAA0555. Both LOC256135 and KIAA0555 reside in genomic locus NT 006859
(NCBI Genome Annotation). LOC256135 encodes a protein similar to N-formyl
peptide
receptor. KTAA0555 encodes KIAA0555 gene product, and has LocusID: 9832 and
reported cytogenetic location Sq32.
[0353] CPS 256 corresponds to UNK 582470 (also known as BB1 or LENG4)
which encodes leukocyte receptor cluster (LRC) member 4. This gene has
LocusID: 79143,
and is located on chromosome 19 with reported cytogenetic location 19q13.4.
The gene
resides in genomic locus NT 011148 (NCBI Genome Annotation).
[0354] Affymetrix annotation suggests that CPS 257 corresponds to IGHG3. The
gene encodes immunoglobulin heavy constant gamma 3 ~G3m marker), and has
LocusID:
3502. The gene is located at chromosome 14q32.33.
[0355] Blast search of the Entrez human genome sequence database shows that
CPS
257 has at least 96% sequence identity with a chromosome 14 region near
LOC122595.
LOC122595 has reported cytogenetic location 14q32.33 and resides in genomic
locus
NT 010168 (NCBI Genome Annotation).
[0356] CPS 260 corresponds to TNFRSF12 which encodes tumor necrosis factor
receptor superfamily, member 12 (translocating chain-association membrane
protein). This
gene has LocusID: 8718, and is located on chromosome 1 with reported
cytogenetic
location 1p36.2. The gene resides in genomic locus NT 028054 (NCBI Genome
Annotation). The gene product contains a cytoplasmic death domain and
transmembrane
domains. It can induce apoptosis and activates NF-kappaB.
[0357] CPS 261 corresponds to LTNK AL031685 (KIAA0939) which encodes
KIAA0939 protein. This gene has LocusID: 2331 ~, and is located on chromosome
20 with
reported cytogenetic location 20q13.13. The gene resides in genomic locus NT
011362
(NCBI Genome Annotation).
[0358] CPS 262 corresponds to LTNK AL049963 (LOC64116) which encodes a
protein up-regulated by BCG-CWS. This gene has LocusID: 64116, and is located
on
chromosome 4 with reported cytogenetic location 4q22-q24. The gene resides in
genomic
locus NT 006383 (NCBI Genome Annotation).
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[0359] Affymetrix annotation suggests that CPS 263 corresponds to APELIN which
encodes apelin, a peptide ligand for APJ receptor. The gene has LocusID: 8862,
and is
located at chromosome Xq25-26.3.
[0360] Blast search of the Entrez human genome sequence database shows that
CPS
263 aligns with OCRL with at least 97% sequence identity. OCRL refers to
oculocerebrorenal syndrome of Lowe. This gene has LocusID: 4952, and is
located on
chromosome X with reported cytogenetic location Xq25-q26.1. The gene resides
in
genomic locus NT 011786 (NCBI Genome Annotation). Mutations in this gene are
linked
to the disease oculocerebrorenal syndrome of Lowe. The encoded protein is a
phospatidylinositol polyphosphate 5-phosphatase that can be found in golgi
cisternae.
[0361] CPS 264 corresponds to VEGF which encodes vascular endothelial growth
factor. This gene has LocusID: 7422, and is located on chromosome 6 with
reported
cytogenetic location 6p12. The gene resides in genomic locus NT 007592 (NCBI
Genome
Annotation). Vascular endothelial growth factor can induce endothelial cell
proliferation
and vascular permeability.
[0362] CPS 265 corresponds to ELAVL2 which encodes ELAV (embryonic lethal,
abnormal vision, Drosophila)-like 2 (Hu antigen B). This gene has LocusID:
1993, and is
located on chromosome 9 with reported cytogenetic location 9p21. The .gene
resides in
genomic locus NT 023974 (NCBI Genome Annotation). The gene product can bind to
.3'-
untranslated regions of mRNA.
[0363] CPS 266 corresponds to PPP2R2A which encodes protein phosphatase 2
(formerly 2A), regulatory subunit B (PR 52), alpha isoform. This -gene has
LocusID: 5520,
and is located on chromosome 8 with reported cytogenetic location 8p21.1. The
gene
resides in genomic locus NT 023666 (NCBI Genome Annotation).
[0364] Nucleotides 163 to 505 of CPS 266 have 96% sequence identity with an
intron sequence of TSC22. TSC22 encodes transforming growth factor beta-
stimulated
protein TSC-22. It has LocusID: 8848, and resides in genomic locus NT 033922
with
reported cytogenetic location 13q14. CPS 266 aligns with the non-protein-
coding strand of
the gene.
[0365] CPS 267 corresponds to UNK AF001862 (FYB) which encodes FYN
binding protein (FYB-120/130). This gene has LocusID: 2533, and is located on
chromosome 5 with reported cytogenetic location Sp 13.1. The gene resides in
genomic
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locus NT 023195 (NCBI Genome Annotation). FYN-binding protein can modulate
interleukin 2 production.
[0366] CPS 268 corresponds to OAS1 which encodes 2',5'-oligoadenylate
synthetase 1 (40-46 kD). This gene has LocusID: 4938, and is located on
chromosome 12
with reported cytogenetic location 12q24.1. The gene resides in ,genomic locus
NT 009770
(NCBI Genome Annotation). This gene product is a member of the 2', 5'
oligoadenylate
synthase family. It can be induced by interferon, and catalyze the 2', 5'
oligomers of
adenosine in order to bind and activate RNase L. This .gene family plays a
significant role
in the inhibition of cellular protein synthesis and viral infection
resistance. Alternative
splicing of OAS 1 gene produces at least two isoforms.
[0367] CPS 269 corresponds to CYBB which encodes cytochrome b-24'5, beta
polypeptide (chronic granulomatous disease). This gene has LocusID: 1536, and
is located
on chromosome X with reported cytogenetic location Xp21.1. The gene resides in
genomic
locus NT 011657 (NCBI Genome Annotation). Cytochrome b (-245) is composed of
cytochrome b alpha (CYBA) and beta (CYBB) chain. It has been proposed as a
primary
component of the microbicidal oxidase system of phagocytes. CYBB deficiency is
one of
five described biochemical defects associated with chronic granulomatous
disease (CGD).
In this disorder, there is decreased activity of phagocyte NADPH oxidase.
Neutrophils are
able to phagocytize bacteria but cannot kill them in the phagocytic vacuoles.
The cause of
the killing defect may be an inability to increase the cell's respiration and
consequent failure
to deliver activated oxygen into the phagocytic vacuole.
[0368] CPS 270 corresponds to GFPT2 which encodes glutamine-fructose-6-
phosphate transaminase 2. This gene has LocusID: 9945, and is located on
chromosome 5
with reported cytogenetic location Sq34-q35. The gene resides in genomic locus
NT 006519 (NCBI Genome Annotation). The encoded protein is an enzyme of the
hexosamine biosynthetic pathway.
[0369] Affymetrix annotation suggests that CPS 271 corresponds to BNIP3 which
encodes BCL2/adenovirus E1B l9kDa interacting protein 3. The gene has LocusID:
664,
and is located at chromosome 14q11.2-q12.
[0370] Blast search of the Entrez human .genome sequence database shows that
CPS
271 has 100% sequence identity with an intron sequence of LOC159348. LOC159348
is
located at chromosome 1Oq26.3 and has genomic locus NT 024040 (NCBI 'Genome
Annotation). Nucleotides 1 to 451 of CPS 270 have 97% sequence identity with a
region 3'
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to the protein-coding sequence of LOC254590. LOC254590 resides in genomic
locus
NT 025892 on chromosome 14. In addition, nucleotides 4 to 450 align to a
chromosome
15 region near CAPN3 with 81 % sequence identity. CAPN3 encodes calpain 3,
(p94), and
has LocusID: 825 and reported cytogenetic location 15q15.1-q21.1. CAPN3
resides in
genomic locus NT 030828.
[0371] CPS 272 corresponds to BST1 which encodes bone marrow stromal cell
antigen 1. This gene has LocusID: 683, and is located on chromosome 4 with
reported
cytogenetic location 4p 15. The gene resides in genomic locus NT 006344 (NCBI
Genome
Annotation). Bone marrow stromal cell antigen 1 is a stromal cell line-derived
glycosylphosphatidylinositol-anchored molecule that facilitates pre-B-cell
growth. BSTl
expression can be enhanced in bone marrow stromal cell lines derived from
patients with
rheumatoid arthritis. The polyclonal B-cell abnormalities in rheumatoid
arthritis may be, at
least in part, attributed to BST1 over-expression in the stromal cell
population.
[0372] CPS 273 corresponds to UNK U50535 (CG005) which encodes hypothetical
protein from BCRA2 .region. This gene has LocusID: 10443, and is located on
chromosome
13 with reported cytogenetic location 13q12-q13. The gene resides in genomic
locus
NT 009984 (NCBI Genome Annotation). The gene product has a region of low
similarity
to a region of rat 2',3'-cyclic nucleotide 3'-phosphodiesterase
[0373] CPS 274 corresponds to CX3CR1 which encodes chemokine (CX3C)
receptor 1. This gene has LocusID: 1524, and is located on chromosome 3 with
reported
cytogenetic location 3p21.3. The gene resides in genomic locus NT 005498 (NCBI
Genome Annotation). CX3C chemokine receptor is a G protein-coupled receptor.
It can
mediate leukocyte migration and adhesion, bind the CX3C chemokine fractalkine
and signal
through a pertussis toxin sensitive G-protein.
[0374] CPS 275 corresponds to CKTSF1B1 which encodes cysteine knot
superfamily 1, BMP antagonist 1. This gene has LocusID: 26585, and is located
on
chromosome 15 with reported cytogenetic location 15q13-q15. The gene resides
in
genomic locus NT 024680 (NCBI Genome Annotation). The gene product is a
homolog of
Xenopus laevis Gremlin which is a secreted protein that blocks signaling of
bone
morphogenetic protein (BMP) by preventing access to the BMP receptor.
[0375] CPS 276 corresponds to VNN2 which encodes vanin 2. This gene has
LocusID: 8875, and is located on chromosome 6 with reported cytogenetic
location 6q23-
q24. The gene resides in genomic locus NT 025741 (NCBI Genome Annotation).
This
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gene product is a member of the Vanin family of proteins which share sequence
similarity
with each other, and also with biotinidase. The family includes secreted and
membrane-
associated proteins, a few of which have been reported to participate in
hematopoietic cell
trafficking. Members of this family possess pantetheinase activity, and may
play a role in
oxidative-stress response. Vanin 2 is a GPI-anchored cell surface molecule
that plays a role
in transendothelial migration of neutrophils. VNN2 gene lies in close
proximity to, and in
same transcriptional orientation as two other vanin genes on chromosome 6q23-
q24. Two
transcript variants encoding different isoforms have neen described for this
gene.
[0376] CPS 277 corresponds to KIAA0064 (SNX17) which encodes sorting nexin
17. This gene has LocusID: 9784, and is located on chromosome 2 with reported
cytogenetic location 2p23-p22. The gene resides in genomic locus NT 005204
(NCBI
Genome Annotation).
[0377] CPS 278 corresponds to GRO1 which encodes GRO1 oncogene (melanoma
growth stimulating activity, alpha). This gene has LocusID: 2919, and is
located on
chromosome 4 with reported cytogenetic location 4q21. The gene resides in
genomic locus
NT 006216 (NCBI Genome Annotation). The gene product has melanoma growth
stimulating activity. It may be a mitogenic factor involved in inflammatory
processes.
[0378] CPS 278 has 88% sequence identity with GR02 which encodes GR02
oncogene. GRO2 has LocusID: 2920, and resides in genomic locus NT 00621,6 with
reported cytogenetic location 4q21.
[0379] CPS 279 corresponds to KIAA0655 (HIP12) which encodes huntingtin
interacting protein 12. This gene has LocusID: 9026, and is located on
chromosome 12
with reported cytogenetic location 12q24. The gene resides in genomic locus NT
009464
(NCBI Genome Annotation).
(0380] Nucleotides 13 to 332 of CPS 279 aligns to an intron of DNAH11 with
100%
sequence identity. DNAH11 encodes dynein, axonemal, heavy polypeptide 11. It
has
LocusID: 8701, and
[0381] resides in genomic locus NT 007819 with reported cytogenetic location
7p21. CPS
279 aligns with the non-protein-coding strand of DNAH11.
(0382] CPS 280 corresponds to RB 1 which encodes retinoblastoma 1 (including
osteosarcoma). This gene has LocusID: 5925, and is located on chromosome 13
with
reported cytogenetic location 13q14.2. The gene resides in genomic locus NT
033922
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(NCBI Genome Annotation). Retinoblastoma protein 1 is a nuclear phosphoprotein
with
DNA binding activity. It can interact with histone deacetylase to repress
transcription.
[0383] CPS 281 corresponds to I~IAA0073 which encodes I~IAA0073 protein. This
gene has LocusID: 23398, and is located on chromosome 5 with reported
cytflgenetic
location 5q12.3. The gene resides in genomic locus NT 006431 (NCBI Genome
Annotation).
[0384] CPS 282 corresponds to CAPN4 (CAPNS1) which encodes calpain, small
subunit 1. This gene has LocusID: 826, and is located on chromosome 19 with
reported
cytogenetic location 19q13.13. The gene resides in genomic locus NT 011296
(NCBI
Genome Annotation). Calpains are a ubiquitous, well-conserved family of
calcium-
dependent, cysteine proteases. Calpain I and II are heterodimeric with
distinct large
subunits associated with common small subunits. CAPN4 (CAPNS 1 ) gene encodes
a small
subunit common to both calpain I and II and is associated with myotonic
dystrophy.
[0385] CPS 284 corresponds to MGST1L1 (PTGES) which encodes prostaglandin E
synthase. This gene.has LocusID: 9536, and is located on chromosome 9 with
reported
cytogenetic location 9q34.3. The gene resides in genomic locus NT 029366 (NCBI
Genome Annotation). Prostaglandin (PG) E synthase is involved in eicosanoid
and
glutathione metabolism. It is a member of superfamily of membrane associated
proteins.
[0386] CPS 285 corresponds to C1NH (SERPING1) which encodes serine (or
cysteine) proteinase inhibitor, Glade G (C1 inhibitor), member 1, (angioedema,
hereditary).
This gene has LocusID: 710, and is located on chromosome 11 with reported
cytogenetic
location 11q12-q13.1. The gene resides in genomic locus NT 033903 (NCBI Genome
Annotation). The protein encoded by C1NH gene can inhibit activated Clr and
Cls of the
first complement component and thus regulate complement activation. Deficiency
of the
encoded protein may be associated with hereditary angioneurotic oedema (HANE).
The
encoded protein is a member of the serine protease inhibitor (serpin)
superfamily.
[0387] Affymetrix annotation suggests that CPS 286 corresponds to H1FX. H1FX
encodes Hl histone family, member X. It has LocusID: 8971.
[0388] CPS 287 corresponds to IL1B which encodes interleukin 1, beta. This
gene
has LocusID: 3553, and is located on chromosome 2 with reported cytogenetic
location
2q14. The gene resides in genomic locus NT 022135 (NCBI Genome Annotation).
Interleukin 1 beta may initiate and amplify the immune and inflammatory
responses.
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[0389] CPS 288 corresponds to F3 which encodes coagulation factor III
(thromboplastin, tissue factor). This gene has LocusID: 2152, and is located
on
chromosome 1 with reported cytogenetic location 1p22-p21. The gene resides in
genomic
locus NT 021979 (NCBI Genome Annotation). Coagulation factor III which is a
cell
surface glycoprotein. This factor enables cells to initiate the blood
coagulation cascades,
and it functions as the high-affinity receptor for the coagulation factor VII.
The resulting
complex provides a catalytic event that is respo isible for initiation of the
coagulation
protease cascades by specific limited proteolysis. There are at least three
distinct domains
of this factor: extracellular, transmembrane, and cytoplasmic. The factor
functions in
normal hemostasis, and is a component of the cellular immune response.
[0390] CPS 289 corresponds to DUSP4 which encodes dual specificity phosphatase
4. This gene has LocusID: 1846, and is located on chromosome 8 with reported
cytogenetic
location 8p 12-p 11. The gene resides in genomic locus NT 030743 (NCBI Genome
Annotation). The protein encoded by this gene is a member of the dual
specificity protein
phosphatase subfamily. These phosphatases inactivate their target kinases by
dephosphorylating both the phosphoserine/threonine and phosphotyrosine
residues. They
negatively regulate members of the mitogen-activated protein (MAP) kinase
superfamily
(MAPK/ERK, SAPK/JNK, p38), which are associated with cellular proliferation
and
differentiation. DUSP4 gene product can inactivate ERKl, ERK2 and JNK, is
expressed in
a variety of tissues, and is localized in the nucleus. Two alternatively
spliced transcript
variants, encoding distinct isoforms, have been observed for this gene. In
addition, multiple
polyadenylation sites have been reported.
[0391] Affymetrix annotation suggests that CPS 290 corresponds to HUMRTVLH3.
HUMRTVLH3 encodes endogenous retroviral protease. The gene has LocusID: 51354.
[0392] CPS 291 corresponds to UNK AL049250 (BANP) which encodes BTG3
associated nuclear protein. This gene has LocusID: 54971, and resides in
.genomic locus
NT 010859 on chromosome 18 (NCBI Genome Annotation). The gene product can
interact with CAF1, a component of the general transcription multisubunit
complex. It is
thought that BTG3 is involved in negative control of the cell cycle. The
protein encoded by
BTG3 gene binds to BTG3. Studies with mouse homolog suggest that this protein
may also
interact with a specific nuclear matrix/scaffold-associated region (MAR).
Transcript
variants encoding different isoforms have been described for this .gene. The
alignment
between CPS 291 and BANP overlaps LOC124302 which encodes a protein similar to
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nuclear pore complex interacting protein. LOC124302 resides in .genomic locus
NT 010859 with reported cytogenetic location 18p11.1.
[0393] CPS 291 also aligns with other genes and chromosomal regions with at
least
97% sequence identity. These genes and chromosomal regions include LOC92267,
LOC146181, LOC146136, KIAA0220, LOC253666, and an intron of LOC220565, a
region
near LOC255019, a region near LOC83985, a region 5' to the protein-coding
sequence of
NPIP, and a region 3' to the protein-coding sequence of EIF3S8. LOC92267
encodes a
protein similar to hypothetical protein FLJ12363. LOC92267 resides in NT
010441 with
reported cytogenetic location 16p12.1. CPS 291 aligns with the non-protein-
coding strand
of LOC92267. LOC146181 encodes a protein similar to Hypothetical protein
KIAA0220,
and resides in genomic locus NT 010441 with reported cytogenetic location
16p12.2.
LOC146136 encodes a protein similar to nuclear pore complex interacting
protein, and
resides in genomic locus NT Ol 0441 with reported cytogenetic location 16p
12.1.
KIAA0220 _has LocusID: 23117, and resides in genomic locus NT 035362 with
reported
cytogenetic location 16p12.1. LOC253666 has similarity to rat kidney-specific
(KS) gene.
LOC253666 resides in genomic locus NT 010604 on chromosome 16. LOC220565
encodes a protein similar to PI-3-kinase-related kinase SMG-l, isoform 1;
lambda/iota
protein kinase C-interacting protein; phosphatidylinositol 3-kinase-related
protein kinase:
LOC220565 _is located at chromosome 16q13, and resides in genomic locus NT
033291.
LOC255019 encodes a protein similar to nuclear pore complex interacting
protein, and
resides in genomic locus NT 035360 on chromosome 16. LOC83985 encodes spinster-
like
protein, and has LocusID: 83985. LOC83985 resides in genomic locus NT 035372
with
reported cytogenetic location 16q13. NPIP (LocusID: 9284) encodes a nuclear
pore
complex interacting protein, and resides in genomic locus NT 035359 with
reported
cytogenetic location 16p13-p11. EIF3S8 encodes eukaryotic translation
initiation factor 3,
subunit 8 (110kD). EIF3S8 has LocusID: 8663, and resides in genomic locus NT
010589
with reported cytogenetic location 16p11.2. LOC146452 encodes a protein
similar to
I~IAA0251 hypothetical protein. It resides in genomic locus NT 010478 with
reported
cytogenetic location 16q22.3.
[0394] Nucleotides 1 to 196 of CPS 291 have about 86% sequence identity with
LOC118735. LOCI 18735 encodes a protein similar to apoptosis response protein
(prostate
apoptosis response protein 4). LOC118735 resides in NT 030059 with reported
cytogenetic location l Oq24.2.
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[0395] CPS 292 corresponds to UNIT AB002308 (KIAA0310) which encodes
KIAA0310 gene product. This gene has LocusID: 9919, and is located on
chromosome 9
with reported cytogenetic location 9q34.3. The gene resides in genomic locus
NT 033215
(NCBI Genome Annotation).
[0396] Affymetrix annotation suggests that CPS 293 corresponds to EDNl which
encodes endothelin I. The gene has LocusID: 1906, and is located at chromosome
6p24.1.
(0397] CPS 293 aligns with IL1B with at least 99% sequence identity. IL1B
encodes interleukin 1, beta.
[0398] CPS 295 corresponds to FR.AT2 which encodes fiequently rearranged in
advanced T-cell lymphomas 2. This gene has LocusID: 23401, and is lccated on
chromosome 10 with reported cytogenetic location 1Oq23-q24.1. The gene resides
in
genomic locus NT 03005 (NCBI Genome Annotation).
[0399] CPS 297 corresponds to IL8 which encodes interleukin 8. This gene has
LocusID: 3576, and is located on chromosome 4 with reported cytogenetic
location 4q13-
q2I. The gene resides in genomic locus NT 006216 (NCBI Genome Annotation).
Interleukin 8 is a cytokine that plays a role in chemoattraction and
activation of neutrophils.
It has similarity to several platelet-derived factors.
[0400] Affymetrix annotation suggests that CPS 298 corresponds to FSCN2.
FSCN2 'encodes fascin homolog 2, actin-bundling protein, retinal
(Strongylocentrotus
purpuratus). The gene has LocusID: 25794, and is located at chromosome 17q25.
(0401] CPS 300 corresponds to CAMP which encodes cathelicidin antimierobial
peptide. This gene has LocusID: 820, and is located on chromosome 3 with
reported
cytogenetic location 3p21.3. The gene resides in genomic locus NT 022567 (NCBI
Genome Annotation). Cathelicidin antimicrobial peptide is a precur sor of a
pc;ptide with
antibacterial activity.
[0402] CPS 301 corresponds to FCGR1A which encodes Fc fragment of IgG, high
affinity Ia, receptor for (CD64). This gene has LocusID: 2209, and is located
on
chromosome 1 with reported cytogenetic location I q21.2-q21.3. The gene
resides in
genomic locus NT 032962 (NCBI Genome Annotation). The gene product, also known
as
Fc gamma RI, is a receptor for the Fc domain of IgG. It is a member of the
irnmunoglobulin superfamily, and may have a role izi immune response.
[0403] CPS 302 corresponds to MAT1A which encodes methionine
adenosyltransferase I, alpha. This gene has LocusID: 4143, and is located on
chromosome
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with reported cytogenetic location 1Oq22. The .gene resides in .genomic locus
NT 033890 (NCBI Genome Annotation). Methionine adenosyltransferase I {alpha
isoform) catalyzes the formation of S-adenosylmethionine from methionine and
ATP. Both
the beta and alpha isoforms may be encoded by MATIA. Methionine
adenosyltransferase
deficiency is known to be caused by recessive as well as dominant mutations,
the latter
identified in autosomal dominant persistant hypermethioninemia.
[0404] CPS 303 corresponds to C~'P4B 1 which encodes cytochrome P450,
subfamily IVB, polypeptide 1. This gene has LocusID: 1580, and is located on
chromosome 1 with reported cytogenetic location 1p34-p12. The gene resides in
genomic
locus NT 004386 (NCBI Genome Annotation). This gene product is a member of the
cytochrome P450 heme-binding monooxygenase superfamily, and can metabolize
steroids,
fatty acids and xenobiotics.
[0405] Affymetrix annotation suggests that CPS 304 corresponds to MUC3. MUC3
is also known as MUC3A, and encodes mucin 3A, intestinal. The gene has
LocusID: 4584
and reported cytogenetic location 7q22.
[0406] Blast search of the Entrez human genome sequence database shows that
CPS
304 aligns to regions 5' to the protein-coding strand of MUC3B with 80-81%
sequence
identity. MUC3B encodes mucin 3B. It has LocusID: X7876 and reported
cytogenetic
location 7q22. The gene resides in genornic locus NT 007933.
[0407] CPS 305 corresponds to B7 which encodes B7 protein. This gene has
LocusID: 10233, and is located on chromosome 12 with reported cytogenetic
location
12p13. The gene resides in genomic locus NT 035206 (NCBI Genome Annotation).
The
gene product has similarity to the regulatory subunit of protein phosphatases.
It contains
leucine rich repeats, and may mediate protein-protein interactions.
[0408] CPS 306 corresponds to SCYA20 which encodes small inducible cytokine
subfamily A (Cys-Cys), member 20. This gene has LocusID: 6364, and is located
on
chromosome 2 with reported cytogenetic location 2q33-q37. The gene resides in
genomic
locus NT 005403 (NCBI Genome Annotation). The protein encoded by this gene is
a
chemotactic factor for lymphocytes.
[0409] CPS 307 corresponds to IL1RN which encodes interleukin 1 receptor
antagonist. This gene has LocusID: 3557, and is located on chromosome 2 with
reported
cytogenetic location 2q1.4.2. The gene resides in genomic locus NT 02213 (NCBI
Genome
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Annotation). Interleukin 1 receptor antagonist binds to and inhibits the IL-1
receptor. It is a
member of the interleukin-1 (IL-1) family.
[0410] CPS 308 corresponds to ZNF261 which encodes zinc finger protein 261.
This gene has LocusID: 9203, and is located on chromosome X with reported
cytogenetic
location Xq13.1. The gene resides in genomic locus NT 019696 (NCBI Genome
Annotation). The gene product contains a putative zinc-binding motif (MYM).
[0411] CPS 309 corresponds to LGALS2 which encodes lectin, galactoside-
binding,
soluble, 2 (galectin 2). This gene has LocusID: 3957, and is located on
chromosome 22
with reported cytogenetic location 22q13.1. The gene resides in genomic locus
NT 011520
(NCBI Genome Annotation). Galectin 2 is an actose-binding Iectin involved in
cell growth
regulation.
[0412] CPS 310 corresponds to TGN51 (TGOLN2) which encodes trans-golgi
network protein 2. This gene has LocusID: 10618, and is located on chromosome
2 with
reported cytogenetic location 2pII.2. The gene resides in genomic locus NT
015805
(NCBI Genome Annotation).
[0413] The biological mechanisms underlying the CCI-779 modulation of the
expression levels of the CCI-779 activity genes have yet to be elucidated.
Without being
limited to any specific theory, the modulation may be attributed to the direct
effect of CCI-
779 on PBMCs or other blood cells. It may also be caused by the effect of CCI-
779 on
renal cell carcinoma tumors, which in turn induce the change of the gene
expression profile
in the peripheral blood cells.
[0414] Sorne of the CCI-779 activity genes are RCC disease genes that are
differentially expressed in PBMCs of RCC patients relative to tumorfree
humans. These
genes include, for example, TUBB, CTSL, SCYA2, PAI2, UNK AI679353, SCYA7,
IL1R1, THBS1, NCFl, ATP2B1, GR02, PRF1, DBP, FCGR3B, ADFP, GRO3, C1~QR,
RNASE2, CBP2, HK3, FOS, PDI2, UNK U12471 (THBSl), EREG, SPP1, STX1A,
TKTL1, DUX1, SPINK1, UNK AL049963 (LOC64116), BNIP3, Gi201, IL1B, F3,
UNK AL049250, EDN1, FCGR1A, MUC3, B7, SCYA20, IL1RN, and ZNF261. Over the
course of CCI-779 therapy, at least one subset of these genes, which are
elevated or
suppressed in RCC patients, return to the normal baseline levels.
[0415] Table 6 shows examples of RCC disease genes whose expression profiles
in
PBMCs can be modulated by CCI-779. Modulation of the expression profiles of
these
genes in ex vivo conditions is also indicated.
113
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[0416] In one experiment, peripheral blood mononuclear cells isolated from
tumor-
free humans were treated with CCI-779 ex vivo. Comparison of the genes
sensitive to CCI-
779 treatment ex vivo with the CCI-779 activity genes of the present invention
revealed a
common set of genes. These genes represent surrogate markers of CCI-779 drug
activity in
vivo as well as ex vivo.
[0417] As appreciated by those skilled in the art, the above-described
methodology
can be employed to identify genes whose expression profiles in PBMCs can be
modulated
by other drugs.
114
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CA 02515677 2005-08-09
WO 2004/072265 PCT/US2004/004118
C. Monitoring CCI-779 Drug Activities
[0418] The CCI-779 activity genes identified in the present invention can be
used to
monitor CCI-779 drug activities in a patient who is subject to a CCI-779
treatment.
Peripheral blood samples can be isolated at different stages of the CCI-779
treatment. The
expression profile of one or more CCI-779 activity genes in these peripheral
blood samples
can be determined and compared to a reference expression profile. A change in
the gene
expression profile indicates irc vivo activities of CCI-779. In one
embodiment, the patent
has RCC or another solid tumor.
[0419] Numerous methods are available for detecting gene expression profiles.
In
one aspect, the expression profiles of CCI-779 activity genes are determined
by measuring
the levels of RNA transcripts of these genes in peripheral blood samples.
Suitable methods
for this purpose include, but are not limited to, RT-PCT, Northern Blot, i~z
situ
hybridization, slot-blotting, nuclease protection assay, and nucleic acid
arrays. The
peripheral blood samples can be, without limitation, whole blood samples or
samples
containing enriched P.BMCs.
[0420] In one embodiment, RNA isolated from peripheral blood samples can be
first
amplified to cDNA or cRNA. The amplification can be specific or non-specific.
Suitable
amplification methods include, but are not limited to, reverse transcriptase
PCR, isothermal
amplification, ligase chain reaction, and Qbeta replicase. The amplified
nucleic acid
products can be detected or quantitated, for instance, through hybridization
to labeled
probes.
[0421] Amplification primers and hybridization probes for a CCI-779 activity
gene
can be prepared from the gene sequence or its corresponding CPS using numerous
methods.
Gene sequences suitable for this purpose include, but are not limited to,
exons, introns, or
the 3' or 5' untranslated regions, or any combination thereof. In one
embodiment,
probes/primers axe designed based on the sequence in or near the 3' protein-
coding region
of a CCI-779 activity gene. For instance, the nucleotide sequence encoding the
last 100 to
300 amino acid residues in the C-terminus region of the CCI-779 activity gene
product can
be selected to design probes or primers. Where a CCI-779 activity gene is a
hypothetical or
putative gene whose expression is supported only by EST or mRNA data, or where
the
genomic locations) of a CCI-779 activity gene has not been determined or the
gene may
correspond to multiple genomic loci, the probes/primers for the .gene can be
designed based
on the corresponding CPS, or the oligonucleotide probes of the corresponding
qualifier.
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WO 2004/072265 PCT/US2004/004118
Table 5 lists example sequences that are useful for designing probes/primers
for detecting
the expression profiles of CCI-779 activity genes.
[0422] The length of the probeslprimers can be selected to achieve the desired
hybridization or amplification effect. For instance, each probe can comprise
at least 15, 20,
25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 400 or more
nucleotides.
In one embodiment, each probe/primer has relatively high sequence complexity
and does
not have any ambiguous residue (undetermined "n"; residues). In another
embodiment, the
probes/primers can hybridize to the target gene such as its RNA transcripts or
the
complements thereof, under stringent or highly stringent conditions.
[0423] As used herein, "stringent conditions" are at least as stringent as,
fox
example, conditions G-L shown in Table 7. "Highly stringent conditions" are at
least as
stringent as conditions A-F shown in Table 7. As used in Table 7,
hybridization is carried
out under the hybridization conditions (Hybridization Temperature and Buffer)
for about
four hours, followed by two 20-minute washes under the corresponding wash
conditions
(Wash Temp. and Buffer).
Table 7. Stringency Conditions
Poly-
StringencynucleotideHybrid Hybridization Wash Temp.
ConditionH brid Len h Tem erature and BufferHand BufferH
b )1
A DNA:DNA 50 65C; lxSSC -or- 65C; 0.3xSSC
2C; IxSSC, 50% formamide
B DNA:DNA 50 TB*; lxSSC B*; lxSSC
C DNA:RNA 50 67C; lxSSC -or- 67C; 0.3xSSC
5C; 1xS
SC, 50/o formamide
D _ <50 _ TD*; lxSSC
DNA:RNA TD*; lxSSC
E RNA:RNA 50 70C; IxSSC -or- 70C; 0.3xSSC
50C; lxSSC, 50% formamide
F A:RNA 50 TF*; lxSSC Tf*; 1xS'SC
G DNA:DNA 50 65C; 4xSSC -or- 65C; lxSSC
2C; 4xSSC, 50% formamide
H DNA:DNA 50 TH*; 4xSSC TH*; 4xSSC
I DNA:RNA 50 67C; 4xSSC -or- . 67C; lxSSC
5C; 4xSSC, 50% formamide
J DNA:RNA 50 TJ*; 4xSSC ' TJ*; 4xSSC
K RNA:RNA 50 70C; 4xSSC -or- 67C; lxSSC
50C; 4xSSC, 50% formamide
L RNA:RNA 50 TL*; 2xSSC , TL*; 2xSSC
1: The hybrid length is that anticipated for the hybridized r~egion(s) 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
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WO 2004/072265 PCT/US2004/004118
polynucleotide. When polynucleotides of known sequence 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.
SSPE (lxSSPE is O.15M NaCI, iOmM NaH2P04, and 1.25mM.EDTA, pH 7.4)
can be substituted for SSC (lxSSC is O.15M NaCl and lSmM podium citrate) in
the
hybridization and wash buffers.
TB* - TR*: The hybridization temperature for hybrids anticipated to be less
than 50
base pairs in length should be 5-10°C less than the melting temperature
(Tm) of the hybrid,
where Tm is determined according to the following equations. For hybrids less
than 18 base
pairs in length, Tm(°C) = 2(# of A + T bases) + 4(# of G + C bases).
For hybrids between
18 and 49 base pairs in length, Tm(°C) = 81.~ + 16.6(logloNa~) +
0.41(%G + C) -.(600/N),
where N is the number of bases in the hybrid, and Na+ is the molar
concentration of °sodium
ions in the hybridization buffer (Na+ for lxSSC = 0.165M).
[0424] In one embodiment, the probes/primers for a CCI-779 activity gene are
selected from regions which significantly diverge from the sequences of other
;genes. Such
regions can be determined by checking the probelprimer sequences against a
human
genome sequence database, such as the Entrez database at the NCBI. One
algorithm
suitable for this purpose is the BLAST algorithm. This algorithm involves
.first identifying
high scoring sequence pairs (HSPs) by identifying short words of length VV in
the query
sequence, which either match or satisfy some positive-valued threshold score T
when
aligned with a word of the same length in a database sequence. T is refeiTed
to as the
neighborhood word score threshold. These initial nei-ghborhood word hits act
as seeds for
initiating searches to find longer HSPs containing them. The word hits are
then extended in
both directions along each sequence to increase the cumulative alignment
score.
Cumulative scores are calculated using, for nucleotide sequences; the
parameters M (reward
score for a pair of matching residues; always >0) and N (penalty score for
mismatching
residues; always <0). The BLAST algorithm parameters W, T, and ~ determine the
sensitivity and speed of the alignment. These parameters can be adjusted for
different
purposes, as appreciated by one of ordinary skill in the art.
[0425] In one aspect, quantitative RT-PCR (such as TaqMan, ABI) is used for
detecting and comparing the peripheral blood expression profiles of CCI-779
activity genes.
Quantitative RT-PCR involves reverse transcription (RT) of RNA to cDNA
followed by
relative quantitative PCR (RT-PCR).
[0426] In PCR, the number of molecules of the amplified target DNA increases
by a
factor approaching two with every cycle of the reaction until some reagent
becomes
limiting. Thereafter, the rate of amplification becomes increasingly
diminished until there
is not an increase in the amplified target between cycles. If one plots a
graph on which the
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WO 2004/072265 PCT/US2004/004118
cycle number is on the X axis and the log of the concentration of the
amplified target DNA
is on the Y axis, one observes that a curved line of characteristic shape is
formed by
connecting the plotted points. Beginning with the first cycle, the slope of
the line is positive
and constant. This is said to be the linear portion of the curve. After some
reagent becomes
limiting, the slope of the line begins to decrease and eventually becomes
zero. At this point
the concentration of the amplified target DNA becomes asymptotic to some fixed
value.
This is said to be the plateau portion of the curve. i
[0427] The concentration of the target DNA in the linear portion of the PCR is
proportional to the starting concentration of the target before the PCR was
begun. By
determining the concentration of the PCR products of the target DNA in PCR
reactions that
have completed the same number of cycles and are in their linear ranges, it is
possible to
determine the relative concentrations of the specific target sequence in the
original DNA
mixture. If the DNA mixtures are cDNAs synthesized from RNAs isolated from
different
tissues or cells, the relative abundances of the specific mRNA from which the
target
sequence was derived may be determined for the respective tissues or cells.
This direct
proportionality between the concentration of the PCR products and the relative
mRNA
abundances is true in the linear range portion of the PCR reaction.
[0428] The final concentration of the target DNA in the plateau portion of the
curve
is determined by the availability of reagents in the reaction mix and is
independent of the
original concentration of target DNA. Therefore, the sampling and quantifying
of the
amplified PCR products can be carried out when the PCR reactions are in the
linear portion
of their curves. In addition, relative concentrations of the arnplifiable
cDNAs can be
normalized to some independent standard, which may be based on either
internally existing
RNA species or externally introduced RNA species. The abundance of a
particular mRNA
species may also be determined relative to the average abundance of all mRNA
species in
the sample.
[Q429] In one embodiment, the PCR amplification utilizes internal PCR
standards
that are approximately as abundant as the target. This strategy is effective
if the products of
the PCR amplifications are sampled during their linear phases. If the products
are sampled
when the reactions are approaching the plateau phase, then the less abundant
product may
become relatively over-represented. Comparisons of relative abundances made
for many
different RNA samples, such as is the case when examining RNA samples for
differential
expression, may become distorted in such a way as to make differences in
relative
12.2
CA 02515677 2005-08-09
WO 2004/072265 PCT/US2004/004118
abundances of RNAs appear less than they actually are. This can be improved if
the
internal standard is much more abundant than the target. If the internal
standard is more
abundant than the target, then direct linear comparisons may be made between
RNA
samples.
[0430] A problem inherent in clinical samples is that they are of variable
quantity or
quality. This problem can be overcome if the RT-PCR is performed as a relative
quantitative RT-PCR with an internal standard in which the internal standard
is an
amplifiable cDNA fragment that is larger than the target cDNA fragment and in
which the
abundance of the mRNA encoding the internal standard is roughly 5-100 times
higher than
the mRNA encoding the target. This assay measures relative abundance, not
absolute
abundance of the respective mRNA species.
[0431] In another embodiment, the relative quantitative RT-PCR uses an
external
standard protocol. Under this protocol, the PCR products are sampled in the
linear portion
of their amplification curves. The number of PCR cycles that are optimal for
sampling can
be empirically determined for each target cDNA fragment. In addition, the
reverse
transcriptase products of each RNA population isolated from the various
samples can be
normalized for equal concentrations of amplifiable cDNAs. While empirical
determination
of the linear range of the amplification curve and normalization of cDNA
preparations are
tedious and time-consuming processes, the resulting RT-PCR assays may, in
certain cases,
be superior to those derived from a relative quantitative RT-PCR with an
internal standard.
[0432] Nucleic acid arrays can also be used to detect and compare the
expression
patterns of CCI-779 activity genes in peripheral blood samples isolated at
different CCI-779
treatment stages. Probes suitable for detecting the CCI-779 activity genes can
be stably
attached to known discrete regions on a support substrate. These probes
maintain their
positions relative to the respective discrete regions during hybridization and
subsequent
washes. Construction of nucleic acid arrays is well known in the art. Suitable
substrates for
making nucleic acid arrays include, but are not limited to, glasses, silica,
ceramics, nylons,
quartz wafers, gels, metals, papers, beads, tubes, fibers, films, membranes,
column matrixes,
or microtiter plate wells.
[0433] A nucleic acid array of the present invention can comprise at Ieast 2,
5, 10,
15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, or more
different
polynucleotide probes, each different probe capable of hybridizing to a
different respective
CCI-779 activity gene. Multiple probes for the same gene can be used on a
single nucleic
123
CA 02515677 2005-08-09
WO 2004/072265 PCT/US2004/004118
acid array. Examples of probes suitable for this invention are listed in the
Qualifier Table.
Probes for other drug activities genes can also be included in the nucleic
acid arrays of this
invention. The probe density on the array can be in any range. For instance,
the density
may be 50, 100, 200, 300, 400, 500, or more probes/cm2.
[0434] In one embodiment, a substantial portion of all polynucleotide probes
on a
nucleic acid array of the present invention are probes for CCI-779 or other
drug activity
genes. For instance, at least 10%, 20%, 30%, 40~ o, 50%, or more of all probes
on the
nucleic acid array can hybridize under stringent or nucleic acid array
hybridization
conditions to RNA transcripts, or the complements thereof; of drug activity
genes.
[0435] In another embodiment, nuclease protection assays are used to quantify
RNAs derived from the peripheral blood samples. There are many different
versions of
nuclease protection assays. The common characteristic of these nuclease
protection assays
is that they involve hybridization of an antisense nucleic acid with the RNA
to be
quantified. The resulting hybrid double-stranded molecule is then treated with
a nuclease
which digests single-stranded nucleic acids more eff ciently than double-
stranded
molecules. The amount of antisense nucleic acid that survives digestion is a
measure of the
amount of the target RNA species to be quantified. An example of nuclease
protection
assays is the RNase protection assay manufactured by Ambion, Inc. (Austin,
Texas).
[0436] In another aspect, the peripheral blood expression profiles of CCI-779
activity genes are determined by measuring the levels of polypeptides encoded
by these
genes. Methods suitable for this purpose include, but are not limited to,
immunoassays such
as ELISA, RIA, FACS, dot blot, Western Blot, immunohistochemistry, and
antibody-based
radioimaging. Other methods such as 2-dimensional SDS-polyacrylamide gel
electrophoresis can also be used.
[U437] One exemplary method suitable for detecting the levels of target
proteins in
peripheral blood samples is ELISA. In an exemplifying ELISA, antibodies
capable of
binding to the target proteins encoded by one or more CCI-779 activity genes
are
immobilized onto a selected surface exhibiting protein affinity, such as wells
in a
polystyrene or polyvinylchloride microtiter plate. Then, peripheral blood
samples to be
tested are added to the wells. After binding and washing to remove non-
specifically bound
immunocomplexes, the bound antigens) can be detected. Detection can be
achieved by the
addition of a second antibody which is specific for the target proteins and is
linked to a
detectable label. Detection may also be achieved by the addition of a second
antibody,
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followed by the addition of a third antibody that has binding affinity for the
second
antibody, with the third antibody being linked to a detectable label. Before
being added to
the microtiter plate, cells in the peripheral blood samples can be lysed using
various
methods known in the art. Proper extraction procedures can be used to separate
the target
proteins from potentially interfering substances.
[0438] In another exemplifying ELISA, the peripheral blood samples suspected
of
containing the target proteins are immobilized onto the well surface and then
contacted with
the antibodies of the invention. After binding and washing to remove non-
specifically
bound immunocomplexes, the bound antigen is detected. Where the initial
antibodies are
linked to a detectable label, the immunocomplexes can be detected directly.
The
immunocomplexes can also be detected using a second antibody that has binding
affinity for
the first antibody, with the second antibody being linked to a detectable
label.
[0439] Another exemplary ELISA involves the use of antibody competition in the
detection. In this ELISA, the target proteins are immobilized on the well
surface. The
labeled antibodies are. added to the well, allowed to bind to the target
proteins, and detected
by means of their labels. The amount of the target proteins in an unknown
sample is then
deterniined by mixing the sample with the labeled antibodies before or during
incubation
with coated wells. The presence of the target proteins in the unknown sample
acts to reduce
the amount of antibody available for binding to the well and thus reduces the
ultimate
signal.
[0440] Different ELTSA formats can have certain features in common, such as
coating, incubating or binding, washing to remove non-specifically bound
species, and
detecting the bound immunocornplexes. For instance, iii coating a plate with
either antigen
or antibody, the wells of the plate can be incubated with a ~ solution of the
antigen or
antibody, either overnight or for a specified period of hours. The wells of
the plate are then
washed to remove incompletely adsorbed material. Any remaining available
surfaces of the
wells are then "coated" with a nonspecific protein that is antigenically
neutral with regard to
the test samples. Examples of these nonspecific proteins include bovine serum
albumin
(BSA), casein and solutions of milk powder. The coating allows for blocking of
nonspecific adsorption sites on the immobilizing surface and thus reduces the
background
caused by nonspecific binding of antisera onto the surface.
[0441] In ELISAs, a secondary or tertiary detection means can also be used.
After
binding of a protein or antibody to the well, coating with a non-reactive
material to reduce
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background, and washing to remove unbound material, the immobilizing surface
is
contacted with the control or clinical or biological sample to be tested under
conditions
effective to allow immunocomplex (antigen/antibody) formation. These
conditions may
include, for example, diluting the antigens and antibodies with solutions such
as BSA,
bovine gamma globulin (BGG) and phosphate buffered saline .(PBS)lTween and
incubating
the antibodies and antigens at room temperature for about 1 to 4 hours or at
4°C overnight.
Detection of the immunocomplex then requires a labeled secondary binding
ligand or
antibody, or a secondary binding ligand or antibody in conjunction with a
labeled tertiary
antibody or third binding ligand.
[0442] Following all incubation steps in an ELISA, the contacted surface can
be
washed so as to remove non-complexed material. For instance, the surface may
be washed
with a solution such as PBSlTween, or borate buffer. Following the formation
of specific
immunocomplexes between the test sample and the originally bound material, and
subsequent washing, the occurrence of the amount of immunocomplexes can be
determined.
[0443] To provide a detection means, the second or third antibody can have an
associated label. In one embodiment, the Iabe1 is an enzyme that generates
color
development upon incubating with an appropriate chromogenic substrate. Thus,
for
example, one may contact and incubate the first or second immunocomplex with a
urease,
glucose oxidase, alkaline phosphatase or hydxogen peroxidase-conjugated
antibody for a
period of time and under conditions that favor the development of further
immunocomplex
formation (e.g., incubation for 2 hours at room temperature in a PBS-
containing solution
such as PBS-Tween).
[0444] After incubation with the Labeled antibody, and subsequent to washing
to
remove unbound material, the amount of label is quantified, e.g., by
incubation with a
chromogenic substrate such as urea and bromocresol purple or 2,2'-azido-di-(3-
ethyl)-
benzthiazoline-6-sulfonic acid (ABTS) and H202, in the case of peroxidase as
the enzyme
label. Quantitation can be achieved by measuring the degree of color
generation, e.g., using
a spectrophotometer.
[0445] Another method suitable for this invention is RIA (radioimmunoassay).
An
exemplary RIA is based on the competition between radiolabeled-polypeptides
and
unlabeled polypeptides for binding to a limited quantity of antibodies.
Suitable radiolabels
include, but are not limited to, has. In one embodiment, a fixed concentration
of Ilas-labeled
polypeptide is incubated with a series of dilution of an antibody specif c to
the polypeptide.
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When the unlabeled polypeptide is added to the system, the amount of the Ilz~-
polypeptide
that binds to the antibody is decreased. A standard curve can therefore be
constructed to
represent the amount of antibody-bound Ilzs-polypeptide as a function of the
concentration
of the unlabeled polypeptide. From this standard curve, the concentration of
the
polypeptide in unknown samples can be determined.
[0446] Suitable antibodies for this invention include, but are not limited to,
polyclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized
antibodies,
single chain antibodies, Fab fragments, or fragments produced by a Fab
expression library.
Methods for making these antibodies are well known in the art.
[0447] In one embodiment, the antibodies of the present invention can bind to
the
corresponding CCI-779 activity gene products or other desired antigens with a
binding
affinity constant I~ of at least 104 M-1, 105 M-1, 106 M-1, 107 M-1, 108 M-1,
or more.
[0448] The antibodies of this invention can be labeled with one or more
detectable
moieties to allow for detection of antibody-antigen complexes. The detectable
moieties can
include compositions. detectable by spectroscopic, enzymatic, photochemical,
biochemical,
bioelectronic, immunochemical, electrical, optical or chemical means. The
detectable
moieties include, but are not limited to, radioisotopes, chemiluminescent
compounds,
labeled binding proteins; heavy metal atoms, spectroscopic markers such as
fluorescent
markers and dyes, magnetic labels, linked enzymes, mass spectrometry tags,
spin labels,
electron transfer donors and acceptors, and the like.
[0449] Moreover, the levels of polypeptides in peripheral blood samples can be
determined by detecting the biological activities associated with the
polypeptides. If a
biological function/activity of a polypeptide is known, suitable in vitro
bioassays can be
designed to evaluate the biological function/activity, which in turn can be
used to determine
the amount of the polypeptide in the sample.
[0450] Comparison between the expression profile of a patient of interest and
a
reference expression profile can be conducted manually or electronically. The
reference
expression profile can be a baseline expression profile representing gene
expression in
peripheral blood samples isolated prior to a drug treatment. The reference
profile can also
be an expression profile in peripheral blood samples isolated after initiation
of the drug
treatment. The reference expression profile can be determine using sample
isolated from
the patient of interest or other reference patient or patients. In many
embodiments, the
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process or methodology that is used to determine the reference expression
profile and the
expression profile being compared is identical or comparable.
[0451] In one example, comparison is carried out by comparing each component
in
the expression profile of the patient of interest to the corresponding
component in the
reference expression profile(s). The component can be the expression level of
a drug
activity gene, a ratio between the expression levels of two drug activity
genes, or another
measure capable of representing gene expression p j tterns. The expression
level of a gene
can be an absolute level, or a normalized or relative level. The difference
between two
corresponding components can be assessed by fold changes, absolute
differences, or other
suitable means.
[0452] Comparison between expression profiles can also be conducted using
pattern
recognition or comparison programs. In addition, the serial analysis of gene
expression
(SAGE) technology, the GEMTOOLS gene expression analysis program (Incyte
Pharmaceuticals), the GeneCalling and Quantitative Expression Analysis
technology
(Curagen), and other suitable methods, programs or systems can be used.
[0453] Multiple drug activity genes can be used in the comparison of
expression
profiles. For instance, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40, 50, or
more drug activity
genes can be used.
(0454] In one embodiment, the drug activity genes) used in the comparison can
be
selected to have relatively small p-values or large differential expression
ratios. In one
example, the drug activity genes used in the comparison have p-values (e.g.,
under an
ANOVA analysis) of no greater than 0.05, 0.01, 0.001, 0.0005, 0.0001, or less.
In another
example, the expression level after or during a drug treatment is increased or
decreased by
at least 2-fold, 3-fold, 4-fold, 5-fold, or more over the baseline expression
level.
[0455] In another embodiment, comparison of the expression profiles is
performed
electronically, such as by using a computer system. The computer system
includes a
processor coupled to a memory or storage medium which stores data representing
the
expression profiles being compared. In one example, the memory or storage
medium is
readable or rewritable. The stored expression data can be changed, retrieved,
or otherwise
manipulated. The memory can also store one or more programs capable of causing
the
processor to compare the expression profiles. In one embodiment, the processor
is coupled
to a nucleic acid array scanner which sends signals to the processor for
analysis.
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[0456] In vivo activities of other drugs can be similarly monitored using the
drug
activities genes of the present invention, as appreciated by those skilled in
the art.
[0457] At least a subset of the drug activity genes of the present invention
may be
used as disease regression indicators. This subset of genes may be responsive
to the effect
of CCI-779 or other drugs on RCC or other diseases. In one example, CCI-779 or
another
drug may cause regression of tumors, and the decrease in tumor size or
activity may cause a
decreased immune response which is reflected in gene expression changes in the
peripheral
blood cells. Consequently, the drug activity genes of the present invention
can be used as
molecular markers for monitoring the efficacy of CCI-779 or other drugs for
treating RCC
or other diseases. In many cases, diseases amendable to the present invention
include those
whose regression can produce changed immune responses.
[0458] Tt should be understood that the above-described embodiments and the
following examples are given by way of illustration, not limitation. -Various
changes and
modifications within the scope of the present invention will become apparent
to those
skilled in the art from the present description.
E. Examples
Example 1 Isolation of RNA and Preparation of Labeled Microarray Targets
[0459] PBMCs from the CCI-779 clinical trials were isolated from whole blood
samples (8mL) and collected into CPT tubes according to the standard
prbcedure. PBMCs
were purified over Ficoll gradients, washed two times with PBS and counted.
Total RNA
was isolated from PBMC pellets using the RNeasy mini kit (Qiagen, Valencia,
CA).
Labeled target for oligonucleotide arrays was prepared using a modification of
~ the
procedure described in Lockhart, et al., Nature Biotechnology 14: 1675-80
(1996). 2 ~,g
total RNA was converted to cDNA by priming with an oligo-dT primer containing
a T7
DNA polymerase promoter at the 5' end. The cDNA was used as the template for
i~ vitro
transcription using a T7 DNA polymerase kit (Ambion, Woodlands, TX) and
biotinylated
CTP and UTP (Enzo). Labeled cRNA was fragmented in 40 mM Tris-acetate pH 8.0,
100
mM KOAc, 30 mM MgOAc for 35 minutes at 94°C in a final volume of 40 ~1.
Example 2 Hybridization to Affymetrix Microarrays and Detection of
Fluorescence
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[0460] Individual samples were hybridized to HgU95A .genechip (Affymetrix). No
samples were pooled. 110 RCC patients were involved in the study. Each patient
received
25, 75, or 250 mg of CCI-779 once weekly through intravenous infusion. Blood
samples
were collected immediately before the first CCI-779 infusion, eight weeks
after the first
infusion, and sixteen weeks after the first infusion.
[0461] 10 ~,g of labeled target was diluted in~l x MES buffer with 100 ~,g/ml
hernng
sperm DNA and 50 ~.g/ml acetylated BSA. To normalize arrays to each other and
to
estimate the sensitivity of the oligonucleotide arrays, ih vitro synthesized
transcripts of 11
bacterial genes were included in each hybridization reaction as described in
Hill et al.,
Science, 290: 809-812 (2000). The abundance of these transcripts ranged from
1:300,000
(3 ppm) to 1:1000 (1000 ppm) stated in terms of the number of control
transcripts per total
transcripts. As determined by the signal response from these control
transcripts, the
sensitivity of detection of the arrays ranged between about 1:300,000 and
1:100,000
copies/million. Labeled probes were denatured at 99°C for 5 minutes and
then 45°C for 5
minutes, and hybridized to oligonucleotide arrays comprised of over 12,500
human gene
probes (HgU95A, Affymetrix). Arrays were hybridized for 16 hours at
45°C. The
hybridization buffer was comprised of 100 mM MES, 1 M [Na+], 20 mM EDTA, and
0.01
Tween 20. After hybridization, the cartridges were washed extensively with non-
stringent
wash buffer (6 x SSPET), such as three 10-minute washes at room temperature.
These
hybridization and wash conditions are herein collectively referred to as
"nucleic acid array
hybridization conditions." The washed cartridges were then stained with
phycoerythrin
coupled to streptavidin.
[0462] 12 x MES stock contains 1.22 M MES and 0.89 M [Na+]. For 1000 ml, the
stock can be prepared by mixing 70.4 g MES free acid monohydrate, 193.3 g MES
sodium
salt and 800 ml of molecular biology grade water, and adjusting volume to 1000
ml. The
pH should be between 6.5 and 6.7. 2 x hybridization buffer can be prepared by
mixing 8.3
mL of 12 x MES stock, 17.7 mL of 5 M NaCI, 4.0 mL of 0.5 M EDTA, 0.1 mL of 10%
Tween 20 and 19.9 mL of water. 6 x SSPET contains 0.9 M NaCI, 60 mM NaH2P04, 6
mM
EDTA, pH 7.4, and 0.005% Triton X-100. In some cases, the wash buffer can be
replaced
with a more stringent wash buffer. 1000 ml stringent wash buffer can be
prepared by
miring 83.3 mL of 12 x MES stock, 5.2 mL of 5 M NaCI, 1.0 mL of 10% Tween 20
and
910.5 mL of water.
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Example 3. Gene Expression Data Analysis
[0463] Data analysis was performed on raw fluorescent intensity values using
GENECHIP 3.2 software (Affymetrix). GeneChip 3.2 software uses an algorithm to
calculate the likelihood as to whether a gene is "absent" or "present" as well
as a specific
hybridization intensity value or "average difference" for each transcript
represented on the
array. The algorithms used in these calculations are described in the
Affymetrix GeneChip
Analysis Suite User Guide (Affymetrix). The "average difference" for each
transcript was
normalized to "frequency" values according to the procedures of Hill et al.,
Science, 290:
809-812 (2000). This was accomplished by referring the average difference
values on each
chip to a calibration curve constructed from the average difference values for
the 11 control
transcripts with known abundance that were spiked into each hybridization
solution. This
process also served to normalize between arrays.
[0464] Specific transcripts were evaluated further if they met the following
criteria.
First, genes that were designated "absent" by the GENECHIP 3.2 software in all
samples
were excluded from the analysis. Second, in comparisons of transcript levels
between
arrays, a gene was required to be present in at least one of the arrays.
Third, for
comparisons of transcript levels between groups, an ANOVA was applied to
identify a
subset of transcripts that had a significant (p < 0.05) differences in
frequency values.
[0465] A ANOVA was used to compare PBMC expression profiles measured
immediately before the first infusion of CCI-779, to PBMC expression profiles
measured at
eight and sixteen weeks after the first infusion. In the' comparisons, a p
value < 0.05 was
used to indicate statistical significance. Transcripts that were altered, on
average, by 2-fold
or more between any two time points can be selected.
Example 4. Ex Vivo Assay
[0466] Drug modulable transcripts in the surrogate tissue, such as peripheral
blood,
can provide early evidence of drug exposure ira vivo. PBMC ex vivo assays that
mimic
peripheral blood gene expression in disease states as well as the in vivo
response to drug
treatments can further validate the surrogate markers identified in in vivo
studies. In
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addition, ex yivo assays that overlay with disease-associated biomarkers may
provide
evidence for markers of drug-dependent disease amelioration.
[0467] Many factors should be considered in designing suitable ex vivo assays.
These factors include, but are not limited to, PBMC seeding density, culture
media and
other conditions, velucle control, dose response, time course, and dose
schedule .(e.g.,
preincubation, coincubation, or postincubation).
[0468] In one embodiment, phytohemagglutinin (PHA) was used to stimulate gene
expression in PBMCs. The genes whose expressioJ can be stimulated by PHA in
PBMCs
had a substantial overlap with disease-associated transcripts in RCC PBMCs
that appear to
result from T-cell activation. In some cases, PHA-stimulated PBMCs mimicked
anti-
CD3/anti-CD28 stimulated T-cell profiles in BioExpress. In addition, CCI-779
inhibited
certain PHA-inducible transcripts in a dose-dependent manner. The inhibition
by CCI-779
appeared to be specific, rather than global. In one example, CTSL, SCYA2,
FABPS,
SCYA7, ATP2B1, and IL1R1 genes were directly repressed by 300 nm CCI-779 in
PHA-
stimulated PBMCs in an ex vivo assay. Databases of disease-associated profiles
and ex vivo
activation signatures can be created to identity most appropriate culture
conditions for
identification of drug modulated biomarkers in specific disease settings.
[0469] The foregoing description of the present invention provides
illustration and
description, but is not intended to be exhaustive or to limit the invention to
the precise one
disclosed. Modifications and variations are possible consistent with the above
teachings or
may be acquired from practice of the invention. Thus, it is noted that the
scope of the
invention is defined by the claims and their equivalents.
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