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  Genes and polypeptides relating to hepatocellular or colorectal carcinomaUSPTO Application #: 20060019252Title: Genes and polypeptides relating to hepatocellular or colorectal carcinoma Abstract: The present application provides novel human genes WDRPUH and KRZFPUH and PPIL1 whose expression is markedly elevated in a great majority of HCCs and colorectal cancers, respectively, compared to corresponding non-cancerous tissues, as well as novel human gene APCDD1 whose expression is elevated in primary colon cancers and down-regulated in response to the transduction of wild-type APC1 into colon-cancer cells. The genes and polypeptides encoded by the genes can be used, for example, in the diagnosis of a cell proliferative disease, and as target molecules for developing drugs against the disease. (end of abstract) Agent: Townsend And Townsend And Crew, LLP - San Francisco, CA, US Inventors: Yusuke Nakamura, Yoichi Furukawa USPTO Applicaton #: 20060019252 - Class: 435006000 (USPTO) Related Patent Categories: Chemistry: Molecular Biology And Microbiology, Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test Strip, Involving Nucleic Acid The Patent Description & Claims data below is from USPTO Patent Application 20060019252. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present application is related to U.S. Ser. No. 60/386,985, filed Jun. 6, 2002, which is incorporated herein by reference. TECHNICAL FIELD [0002] The present invention relates to the field of biological science, more specifically to the field of cancer research. In particular, the present invention relates to novel genes, WDRPUH, KRZFPUH, PPIL1, and APCDD1, involved in the proliferation mechanism of cells, as well as polypeptides encoded by the genes. The genes and polypeptides of the present invention can be used, for example in the diagnosis of cell proliferative disease, and as target molecules for developing drugs against the disease. BACKGROUND ART [0003] Hepatocellular carcinoma (HCC) and colorectal carcinomas are leading causes of cancer death worldwide (Akriviadis et al., Br J Surg 85(10): 1319-31 (1998)). Although recent medical advances have made great progress in diagnosis and therapeutic strategies, a large number of patients with cancers are still diagnosed at advanced stages and their complete cures from the disease are matters of pressing concern. Recent advances in molecular studies have revealed that alteration of tumor suppressor genes and/or oncogenes are involved in carcinogenesis, however the precise mechanisms still remain to be elucidated. [0004] Recent advances in molecular biology suggest that multi-step processes underlie hepatocarcinogenesis as they do the genesis and progression of colon tumors. These processes involve qualitative and quantitative alterations of various gene products. The .beta.-catenin/Tcf signaling pathway has been reported to be involved in morphogenesis during development (Wodarz and Nusse, Annu Rev Cell Dev Biol 14: 59-88 (1998); Polakis, Genes Dev 14: 1837-51 (2000); Bienz and Clevers, Cell 103: 311-20 (2000)). Recent progress in cancer research has underscored the importance of the signaling pathway in the development of human tumors, whether arising in the colon, liver, prostate, stomach, brain, endometrium, or elsewhere (Bullions and Levine, Curr Opin Oncol 10: 81-7 (1998)). Adenomatous polyposis coli (APC), a tumor suppressor, interacts with .beta.-catenin, Axin, conductin, and glycogen synthase kinase-3.beta. (GSK-3.beta.) and facilitates the degradation of .beta.-catenin via the ubiquitin-proteosome system (Polakis, Genes Dev 14: 1837-51 (2000)). Most sporadic colorectal tumors accumulate .beta.-catenin in the cytoplasm and/or nucleus due to either the inactivating mutations in APC, AXIN1 or AXIN2 (conductin), or to stabilizing oncogenic mutations in CTNNB1 (.beta.-catenin), which results in constitutive activation of .beta.-catenin/Tcf transcriptional complex (Polakis, Genes Dev 14: 1837-51 (2000); Korinek et al., Science 275: 1784-7 (1997)). Consequently the complex activates target genes such as c-myc, cyclin D1, matrilysin (MMP-1), c-jun, fra-1, urokinase-type plasminogen activator receptor (uPAR), connexin43, CD44, PPAR-.differential., AF-17 and ENC-1 (He et al., Science 281: 1509-12 (1998); Shtutman et al., Proc Natl Acad Sci USA 96: 5522-7 (1999); Brabletz et al., Am J Pathol 155: 1033-1038 (1999); Crawford et al., Oncogene 18: 2883-91 (1999); Mann et al., Proc Natl Acad Sci USA 96: 1603-8 (1999); van der Heyden et al., J Cell Sci 111: 1741-9. (1998); Wielenga et al., Am J Pathol 154: 515-23 (1999); He et al., Cell 99: 33545(1999); Lin et al. Cancer Res 61: 6345-9 (2001); Fujita et al., Cancer Res 61: 7722-6 (2001)). However, the precise mechanism of tumorgenesis by activation of this pathway in colorectal cancer remains to be solved. [0005] Another protein, stathmin is also known to be associated with a wide range of cancers (Hanash et al., J Biol Chem 263: 12813-5 (1988); Roos et al., Leukemia 7: 1538-46 (1993); Nylander et al.; Histochem J 27: 155-60 (1995); Friedrich et al., Prostate 27: 102-9 (1995); Bieche et al., Br J Cancer 78: 701-9 (1998)). Stathmin (Sobel et al., J Biol Chem 264: 3765-72 (1989); Sobel et al., Trends Biol Sci 16: 301-5 (1991)) is a cytosolic phosphorprotein consisting of 148 amino acid residues (19 kD) that has also been referred to as p19, prosolin, Lap18, oncoprotein 18, metablastin, and Op 18. The expression of stathmin was revealed, to be very high in various multipotential embryonic carcinoma cells and in multipotential cells of the inner cell mass of the mouse blastocyst (Doye et al., Differentiation 50:89-96 (1992)). Stathmin exists in cells under several non-phosphorylated and phosphorylated forms, the pattern of which is depending on the state of proliferation, differentiation, or activation of the cells in many biological systems (Sobel et al., Trends Biol Sci 16: 301-5 (1991)). Further, the microtuble depolymerizing activity of stathmin is known to be regulated by the changes in its phosphorylation level, and the microtuble depolymerizing activity of stathmin is reported to play a critical role in the regulation of the dynamic instability of microtubles during the different phases of the cell cycle (Marklund et al., EMBO J 15: 5290-8 (1996); Horwitz et al., J Biol Chem 272: 8129-31 (1997)). Extensive phosphorylation of stathmin occurs during mitosis (Strahler et al., Biochem Biophy Res Commun 185: 197-203 (1992); Luo et al., J Biol Chem 269: 10312-8 (1994); Brattsand et al., Eur J Biochem 220:359-68 (1994)) and seems essential for the progression of the cell cycle. However, the precise mechanism of the phosphorylation of stathmin and its relation to canceration remains to be elucidated. [0006] cDNA microarray technologies have enabled to obtain comprehensive profiles of gene expression in normal and malignant cells (Okabe et al., Cancer Res 61: 2129-37(2001); Lin et al., Oncogene 21: 4120-8 (2002); Hasegawa et al., Cancer Res 62: 7012-7 (2002)). This approach enables to disclose the complex nature of cancer cells, and helps to understand the mechanism of carcinogenesis. Identification of genes that are deregulated in tumors can lead to more precise and accurate diagnosis of individual cancers, and to develop novel therapeutic targets (Bienz and Clevers, Cell 103:311-20 (2000)). To disclose mechanisms underlying tumors from a genome-wide point of view, and discover target molecules for diagnosis and development of novel therapeutic drugs, the present inventors have been analyzing the expression profiles of tumor cells using a cDNA microarray of 23040 genes (Okabe et al., Cancer Res 61: 2129-37 (2001); Kitahara et al., Cancer Res 61: 3544-9 (2001); Lin et al, Oncogene 21: 4120-8 (2002); Hasegawa et al., Cancer Res 62: 7012-7 (2002)). [0007] Studies designed to reveal mechanisms of carcinogenesis have already facilitated identification of molecular targets for anti-tumor agents. For example, inhibitors of farnexyltransferase (FTIs) which were originally developed to inhibit the growth-signaling pathway related to Ras, whose activation depends on posttanslational farnesylation, has been effective in treating Ras-dependent tumors in animal models (He et al., Cell 99: 335-45 (1999)). Clinical trials on human using a combination of anticancer drugs and anti-HER2 monoclonal antibody, trastuzumab, have been conducted to antagonize the proto-oncogene receptor HER2/neu; and have been achieving improved clinical response and overall survival of breast-cancer patients (Lin et al., Cancer Res 61: 6345-9 (2001)). A tyrosine kinase inhibitor, STI-571, which selectively inactivates bcr-ab1 fusion proteins, has been developed to treat chronic myelogenous leukemias wherein constitutive activation of bcr-ab1 tyrosine kinase plays a crucial role in the transformation of leukocytes. Agents of these kinds are designed to suppress oncogenic activity of specific gene products (Fujita et al., Cancer Res 61: 7722-6 (2001)). SUMMARY OF THE INVENTION [0008] An object of the present invention is to provide novel proteins involved in the proliferation mechanism of hepatocellular or colorectal carcinoma cells and the genes encoding the proteins, as well as methods for producing and using the same in the diagnosis and treatment of hepatocellular carcinoma (HCC) or colorectal cancer. [0009] To disclose the mechanism of hepatocellular and colorectal carcinogenesis and identify novel diagnostic markers and/or drug targets for the treatment of these tumors, the present inventors analyzed the expression profiles of genes in hepatocellular and colorectal carcinogenesis using a genome-wide cDNA microarray containing 23040 genes. From the pharmacological point of view, suppressing oncogenic signals is easier in practice than activating tumor-suppressive effects. Thus, the present inventors searched for genes that are up-regulated during hepatocellular and colorectal carcinogenesis. [0010] Among the transcripts that were commonly up-regulated in hepatocellular carcinomas, novel human genes WDRPUH (WD40 repeat protein up-regulated in HCC) and KRZFPUH (Kruppel-type zinc finger protein up-regulated in HCC) were identified on chromosome band 17 p13 and 16p11, respectively. Gene transfer of WDRPUH or KRZFPUH promoted proliferation of cells. Furthermore, reduction of WDRPUH or KRZFPUH expression by transfection of their specific anti-sense S-oligonucleotides inhibited the growth of HCC cells. Many anticancer drugs, such as inhibitors of DNA and/or RNA synthesis, metabolic suppressors, and DNA intercalators, are not only toxic to cancer cells but also for normally growing cells. However, agents suppressing the expression of WDRPUH and KRZFPUH may not adversely affect other organs due to the fact that normal expression of these genes are restricted to testis, and placenta and testis, respectively, and thus may be of great importance for treating cancer. [0011] Further, among the transcripts that were commonly up-regulated in colorectal cancers, gene PPIL1 (Peptidyl prolyl isomerase-like 1) assigned at chromosomal band 6p21.1 was identified. In addition, immunoprecipitation assay revealed that PPIL1 protein associates with SNW1 (SKI interacting protein), a protein involved in transcriptional activity of vitamin D receptor, and stathmin, a cytosolic phosphorprotein involved in progression of the cell cycle. The present inventors also searched for genes regulating .beta.-catenin/Tcf4 complex that is abnormally up-regulated in hepatomas and colorectal cancers, and identified a novel gene APCDD1 (Down-regulated by adenomatosis polyposis coli) assigned at chromosomal band 18p11.2. Its expression was reduced by the transduction of wild-type APC and elevated in a great majority of colon cancer tissues. Gene transfer of PPIL1 or APCDD1 promoted proliferation of cells that lacked endogenous expression of either of these genes. Furthermore, reduction of PPIL1 or APCDD1 expression by transfection of specific antisense S-oligonucleotides to PPIL1 or APCDD1 inhibited the growth of colorectal cancer cells. [0012] Thus, the present invention provides isolated novel genes, WDRPUH, KRZFPUH, PPIL1, and APCDD1, which are candidates as diagnostic markers for cancer as well as promising potential targets for developing new strategies for diagnosis and effective anti-cancer agents. Further, the present invention provides polypeptides encoded by these genes, as well as the production and the use of the same. More specifically, the present invention provides the following: [0013] The present application provides novel human polypeptides, WDRPUH, KRZFPUH, PPIL1, and APCDD1, or a functional equivalent thereof, that promotes cell proliferation and is up-regulated in cell proliferative diseases, such as HCC and colorectal carcinoma. [0014] In a preferred embodiment, the WDRPUH polypeptide includes a putative 620 amino acid protein with 11 WD40 repeat domains encoded by the open reading frame of SEQ ID NO: 1. The WDRPUH polypeptide preferably includes the amino acid sequence set forth in SEQ ID NO: 2. The present application also provides an isolated protein encoded from at least a portion of the WDRPUH polynucleotide sequence, or polynucleotide sequences at least 15%, and more preferably at least 25% complementary to the sequence set forth in SEQ ID NO: 1. [0015] On the other hand, in a preferred embodiment, the KRZFPUH polypeptide includes a putative 500 amino acid protein with homology to a rat gene zinc finger protein HIT-39 (GenBank Accession No. AF277902) and included a Krupple-type zinc finger domain (KRAB) encoded by the open reading frame of SEQ ID NO: 3. The KRZFPUH polypeptide preferably includes the amino acid sequence set forth in SEQ ID NO: 4. The present application also provides an isolated protein encoded from at least a portion of the KRZFPUH polynucleotide sequence, or polynucleotide sequences at least 15%, and more preferably at least 25% complementary to the sequence set forth in SEQ ID NO: 3. [0016] Furthermore, in a preferred embodiment, the PPIL1 polypeptide includes a putative 166 amino acid protein showing 98.1% identity to PPIL1, 41.6% to PPIA, 57.4% to Cyp2, and 50% to CypE encoded by the open reading frame of SEQ ID NO: 5. The PPIL1 polypeptide preferably includes the amino acid sequence set forth in SEQ ID NO: 6. The present application also provides an isolated protein encoded from at least a portion of the PPIL1 polynucleotide sequence, or polynucleotide sequences at least 15%, and more preferably at least 25% complementary to the sequence set forth in SEQ ID NO: 5. [0017] Furthermore, in a preferred embodiment, the APCDD1 polypeptide includes a putative 514 amino acid protein showing 31% identity to endo-1,4-beta-xylanase of Themobacillus xylanilyticus encoded by the open reading frame of SEQ ID NO: 7. The APCDD1 polypeptide preferably includes the amino acid sequence set forth in SEQ ID NO: 8. The present application also provides an isolated protein encoded from at least a portion of the APCDD1 polynucleotide sequence, or polynucleotide sequences at least 15%, and more preferably at least 25% complementary to the sequence set forth in SEQ ID NO: 7. [0018] The present invention further provides novel human genes, WDRPUH and KRZFPUH, whose expressions are markedly elevated in a great majority of HCCs as compared to corresponding non-cancerous liver tissues. The isolated WDRPUH gene includes a polynucleotide sequence as described in SEQ ID NO: 1. In particular, the WDRPUH cDNA includes 2152 nucleotides that contain an open reading frame of 1860 nucleotides. The present invention further encompasses polynucleotides which hybridize to and which are at least 15%, and more preferably at least 25% complementary to the polynucleotide sequence set forth in SEQ ID NO: 1, to the extent that they encode a WDRPUH protein or a functional equivalent thereof. Examples of such polynucleotides are degenerates and allelic mutants of SEQ ID NO: 1. On the other hand, the isolated KRZFPUH gene includes a polynucleotide sequence as described in SEQ ID NO: 3. In particular, the KRZFPUH cDNA includes 2744 nucleotides that contain an open reading frame of 1500 nucleotides. The present invention further encompasses polynucleotides which hybridize to and which are at least 15%, and more preferably at least 25% complementary to the polynucleotide sequence set forth in SEQ ID NO: 3, to the extent that they encode a KRZFPUH protein or a functional equivalent thereof. Examples of such polynucleotides are degenerates and allelic mutants of SEQ ID NO: 3. [0019] Furthermore, the present invention provides a novel human gene, PPIL1, whose expression is markedly elevated in a great majority of colorectal cancers as compared to corresponding non-cancerous tissues. The isolated PPIL1 gene includes a polynucleotide sequence as described in SEQ ID NO: 5. In particular, the PPIL1 cDNA includes 1734 nucleotides that contain an open reading frame of 498 nucleotides. The present invention further encompasses polynucleotides which hybridize to and which are at least 15%, and more preferably at least 25% complementary to the polynucleotide sequence set forth in SEQ ID NO: 5, to the extent that they encode a PPIL1 protein or a functional equivalent thereof. Examples of such polynucleotides are degenerates and allelic mutants of SEQ ID NO: 5. [0020] Moreover, the present invention provides a novel human gene, APCDD1, whose expression is markedly elevated in a great majority of primary colon cancers as compared to corresponding non-cancerous tissues and down regulated in response to the transduction of wild-type APC1 into, colon cancer cells. The isolated APCDD1 gene includes a polynucleotide sequence as described in SEQ ID NO: 7. In particular, the APCDD1: cDNA includes 2607 nucleotides that, contain an open reading frame of 1542 nucleotides. The present invention further encompasses polynucleotides which hybridize to and which are at least 15%, and more preferably at least 25% complementary to the polynucleotide sequence set forth in SEQ ID NO: 7, to the extent that they encode a APCDD1 protein or a functional equivalent thereof. Examples of such polynucleotides are degenerates and allelic mutants of SEQ ID NO: 7. [0021] As used herein, an isolated gene is a polynucleotide the structure of which is not identical to that of any naturally occurring polynucleotide or to that of any fragment of a naturally occurring genomic polynucleotide spanning more than three separate genes. The term therefore includes, for example, (a) a DNA which has the sequence of part of a naturally occurring genomic DNA molecule in the genome of the organism in which it naturally occurs; (b) a polynucleotide incorporated into a vector or into the genomic DNA of a prokaryote or eukaryote in a manner such that the resulting molecule is not identical to any naturally occurring vector or genomic DNA; (c) a separate molecule such as a cDNA, a genomic fragment, a fragment produced by polymerase chain reaction (PCR), or a restriction fragment; and (d) a recombinant nucleotide sequence that is part of a hybrid gene, i.e., a gene encoding a fusion polypeptide. Continue reading... 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