NOVEL GENE ASSOCIATED WITH SUPPRESSION OF TUMOR DEVELOPMENT

Abstract: This invention provides a novel gene, OVCA1, isolated from human chromosome 17p13.3. Disruption of the OVCA1 gene is associated with cellular proliferation and tumor development. The OVCA1 gene, along with its encoded protein and antibodies thereto, provides a biological marker for early diagnosis of metastatic disease. The gene also will be useful in gene replacement therapy for treating various forms of cancer.

Description: NOVEL GENE ASSOCIATED WITH SUPPRESSION OP TUMOR DEVELOPMENT Pursuant to 35 U.S.C. §202 (c) , it is hereby acknowledged that the U.S. Government has certain rights in the invention described herein, which was made in part with funds from the National Institutes of Health. This application is a continuation-in-part of U.S. Application No. 08/338,728, filed March 6, 1995. FIELD OF THE INVENTION The present invention relates to diagnosis and treatment of neoplastic disease. In particular, this invention provides a novel gene, OVCAl, the disruption of which is associated with cellular proliferation and tumor development. The OVCAl gene provides a biological marker for early diagnosis of metastatic disease and may be useful in gene replacement therapy for treating various forms of cancer. BACKGROUND OF THE INVENTION The molecular basis of cancer has been the subject of a massive research effort over the past several years. Through this effort, it has been discovered that abnormal cellular proliferation results not only from activation of oncogenes, but from disruption of certain genes whose function appears to be important in maintaining normal cell division. As a well-known example, mutations in the p53 tumor suppressor gene are common in human cancer and can be identified in about half of all cases (see Harris, Science 262: 1980-1981, 1993) . Important regulatory genes such as p53 are often identified by mapping rearrangements or deletions of chromosomes that correlate with the occurrence of a particular type of cancer. The molecular genetic basis of breast cancer and ovarian cancer has been elucidated in part in this manner. Although certain oncogenes are amplified and/or overexpressed, the inactivation of multiple tumor suppressor genes appears to be important in the etiology of breast and ovarian cancers, as evidenced by observed allelic losses for polymorphic DNA markers on nearly every chromosome arm. Rearrangements or deletions of chromosome 17 are the most frequently observed changes identified in ovarian and breast cancer tumors. One strategy for locating putative suppressor genes is to survey tumors for high rates of loss of heterozygosity ("LOH") . Combined data from four separate allelotyping studies of ovarian cancers revealed that greater than 30% of the tumors analyzed showed LOH on chromosome 6, 9, 13q, 17, 18q, 19p, 22q and Xp, with the highest LOH rates on 17q (q21, q22- q23) , 17p (pl3.3, 13.1) , 18q (q21.3-qter, distal 2DCC) , 6q (q26-q27) , llq (q23.3-qter) , and lip (pl3-pl5.5), in descending order. 17p, 17q, 6q, 18q and lip are frequently deleted in breast carcinomas as well, continuing the genetic parallels between the two cancer sites. Non-random chromosomal deletions and loss of heterozygosity of a segment of the genome are considered indicative of the presence of a tumor suppressor gene in that region. On the basis of these and other studies of breast and ovarian cancer tumors, it has been suggested that multiple loci on chromosome 17 may be important in the etiology of these diseases. Recent studies (Miki et al., Science 266: 66-71, 1994) have resulted in the identification of the BRCA1 gene, which is responsible for a portion of breast cancer and the majority of ovarian cancer cases caused by inherited susceptibility. Initial studies have indicated however that BRCA1 appears to play little or no role in common, nonhereditary forms of breast and ovarian cancer, suggesting that the genetic basis for more than 90% of cancers of the breast and ovary is still unknown (see Futreal et al., Science 266: 120- 122, 1994) . Chromosome 17 has a number of additional potential cancer causing genes, including TP53 at 17pl3.1 the BRCAl gene 17q21, and genes nearby, such as prohibitin and NM23 with plausible tumor suppressor characteristics, and the proto-oncogene CERBB2. Mutations inactivating the tumor suppressing potential of the TP53 gene have also been reported in sporadic breast and ovarian cancer. However, two studies reported a high frequency of LOH on 17p in breast tumors possessing wild-type TP53 (Coles et al., Lancet 336: 761-763, 1990; Cornells et al., Cancer Res. 54: 4200-4206 1994) . It has been shown recently that alterations at 17pl3.3 may be an important early event in stage 1 ovarian carcinomas and tumors of low malignant potential. In low malignant potential tumors, allelic losses at 17pl3.3 were not accompanied by LOH at TP53, suggesting a more distal suppressor gene and that loss of this gene's function is required for early tu origenesiε. This same region shows frequent loss of heterozygosity in breast cancers, small-cell lung cancers, colon cancers, primitive neuroectodermal tumors, carcinoma of the cervix uteri, medulloblastoma, and astrocytoma, suggesting that a tumor suppressor gene(s) residing on chromosome 17pl3.3 is involved in the development of many types of cancers. Ovarian cancer is the fifth leading cause of cancer-related deaths among women in the United States and the most lethal gynecologic malignancy. Furthermore, more than two-thirds of the women with ovarian cancer are diagnosed with advanced disease when existing therapeutic measures are often ineffective. Breast cancer is one of the most common and important diseases affecting women. Survival rates of breast cancer patients are highest among patients with early stage disease confined to the breast without axillary lymph node involvement. At present, there are no effective presymptomatic clinical signs or biomarkers of susceptibility to ovarian cancer or breast cancer, making early detection a high priority in medical management of the disease. Efforts to discover prognostic indicators have sought correlations between clinical pathological data and various biochemical parameters. Survival of cancer, whether of the breast, ovaries or another target, is increased through recognition of individuals who are at high risk of a disease, as well as early detection, since current therapeutic strategies for early stage disease have a higher cure rate than for diseases at later stages. For this reason, the identification of molecular markers of oncogenesis will assist in early diagnosis as well as prognostic monitoring of ongoing disease. Furthermore, if such molecular markers comprise mutations or deletions of genes essential for maintaining normal cellular division, such genes may also be developed as therapeutic agents to treat malignant disease. SUMMARY OF THE INVENTION In accordance with the present invention, a recombinant DNA molecule is provided which comprises a DNA segment from human chromosome 17pl3.3. The DNA segment is at least 20 kilobase pairs in length. In a preferred embodiment, the DNA is isolated from human placental DNA and includes locus D17S28 of chromosome 17pl3.3. This segment comprises a gene, referred to herein as OVCAl, the disruption of which is associated with malignant cell growth. As is typical of many eucaryotic genes, the OVCAl gene is composed of several exons and introns. The exons of the OVCAl gene form an open reading frame which has a sequence that encodes a 60 kDa polypeptide, about 530-550 amino acids in length. In a preferred embodiment, the open reading frame encodes an amino acid sequence substantially the same as Sequence I.D. No. 2, set forth in Figure 2. In a particularly preferred embodiment, the open reading frame comprises Sequence I.D. No. 1, also shown in Figure 2. The recombinant DNA molecule of the invention may further comprise an additional exon having a sequence substantially the same as Sequence I.D. No. 3, shown in Figure 5. According to another aspect of the present invention, an isolated nucleic acid molecule is provided, which comprises an open reading frame of a gene located on human chromosome I7pl3.3, the gene occupying a segment of that chromosome, at least twenty kilobase pairs in length. In preferred embodiments of the invention, this nucleic acid molecule comprises a sequence such as: (1) Sequence I.D. No. 1; (2) a sequence hybridizing with part or all of Sequence I.D. No. 1, and encoding a polypeptide substantially the same as part or all of the polypeptide encoded by Sequence I.D. No. 1; and (3) a sequence encoding part or all of a polypeptide having amino acid Sequence I.D. No. 2. Oligonucleotides that specifically hybridize with portions of the OVCAl gene or OVCAl open reading frame described above are also provided. According to another aspect of the present invention, a polypeptide is provided that is produced by expression of isolated nucleic acid molecule comprising part or all of an open reading frame of gene located on human chromosome 17pl3.3, the gene occupying a segment of the chromosome at least 20 kb pairs in length. In a preferred embodiment, this polypeptide comprises an amino acid sequence substantially the same as part or all of sequence I.D. No. 2. According to another aspect of the present invention, antibodies are provided that are immunologically specific for the aforementioned polypeptide or fragments thereof. The OVCAl gene, along with its encoded protein and antibodies thereto, provide a much-needed molecular marker for oncogenesis that will assist in early diagnosis and prognostic monitoring of malignant disease, particularly breast cancer and ovarian cancer. The gene also will be useful in gene replacement therapy or for the development of other therapeutic agents to treat various forms of malignant disease. BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1. Allelic deletion patterns of ovarian tumors for the short arm of chromosome 17. DNA samples from normal blood and ovarian tumor tissue were typed with STRPs on 17p. For each tumor, all informative loci are shown. Blackened squares represent constitutional heterozygosity with LOH; open squares, constitutional heterozygosity with no LOH; blank spaces, homozygous. With the assumption that alleles in all regions between loci showing allelic loss are lost, solid lines indicate retained regions of chromosome 17q and open areas show regions of allelic loss. Dashed lines represent regions that are uncertain in tumors with loss of heterozygosity for some loci. FIGURE 2. Nucleotide (Sequence I.D. No. 1) and predicted amino acid (Sequence I.D. No. 2) sequences for the OVCAl open reading frame and flanking regions. The predicted amino acid sequences are shown above in the three-letter code. Numbers in the left and right margins correspond to the respective nucleotide and amino acid sequences. The OVCAl amino acid sequence shown begins at the putative NH2-terminal methionine (nucleotide 1) and ends at nucleotide 1613. The underlining of nucleotides 2153-2158 indicates the putative polyadenylation signal. The sequence shown was obtained from cDNA clones fb67-l and 77-1, and cosmid clone 7-2, which were isolated from a human fetal brain cDNA and a human placental geno ic library, respectively. FIGURE 3. Schematic diagram of chromosome 17pl3.3 containing the OVCAl gene. Black rectangles correspond to the open reading frames of OVCAl and white rectangle corresponds to the first exon of OVCA2. Cosmid clones, used to identify OVCAl and 2, which span the minimal region of deletion in ovarian cancer are indicated. Hatched areas denote locations of loci D17S28 and D17S5. FIGURE 4. Comparison of the predicted amino acid sequence of the OVCAl protein with the S . cerevisiae chromosome IX cosmid 9150 (Sequence I.D. No. 4) and Caenorhabditis elegans cosmid C14B1 (Sequence I.D. No. 5) predicted proteins. Arrows above sequence indicate the approximate position of OVCAl introns. FIGURE 5. Nucleotide sequence of OVCA2 (Sequence I.D. No. 3). DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, a new gene from human chromosome 17 has been isolated, which appears to be involved in suppression of tumor development in at least two forms of cancer. This gene, referred to herein as OVCAl (Ovarian Cancer 1 gene), maps to 17pl3.3 and is mutated in a number of tumors and tumor cell lines. Northern blot analysis revealed that a 2.3kb OVCAl mRNA is expressed in normal surface epithelial cells of the ovary, but is significantly reduced or is undetectable in 90% (11 of 13) ovarian tumors and tumor cell lines analyzed. Moreover, analysis of fresh ovarian tumors and tumor cell lines has revealed a number of potential cancer- causing mutations in OVCAl in both tumors and cell lines. These mutations were not detected in patients' matching lymphocyte DNA, suggesting that these alterations resulted from acquired somatic mutations and therefore are not likely to be random polymorphisms. These initial data are consistent with the classification of OVCAl as a tumor suppressor gene. The OVCAl gene spans approximately 20kb of DNA in chromosome 17pl3.3, and is composed of 13 exons. The OVCAl exons form an open reading frame that encodes a protein of about 538 amino acids with a predicted molecular weight of approximately 60 kDa. The OVCAl open reading frame (Sequence I.D. No. 1) and corresponding deduced amino acid sequence (Sequence I.D. No. 2) are shown in FIGURE 2. In addition, a nucleic acid that represents a unique exon, positioned in the intron between exon 12 and 13 of OVCAl, has been isolated. This sequence (Sequence I.D. No. 3) is referred to as OVCA2 and is shown in FIGURE 5. Sequence comparisons of cDNA clones of OVCAl and OVCA2 and their predicted proteins (using Genbank/EMBL and Swissplot databases) revealed sequence identity (at the amino acid level) to predicted proteins of unknown function, from Caenorhabditis eleganε Cosmid C14B1 and the Saccharomyces cerevisiae chromosome IX cosmid. High-stringency southern blotting of DNA samples from several different mammalian species with OVCAl revealed strongly hybridizing fragments in all species examined (see Example 1 for stringency conditions) . The OVCAl gene having the reading frame represented by Sequence I.D. No. l was isolated by using a number of deletion mapping and positional cloning methods, as described in Example 1. Allelic variants and natural mutants of Sequence I.D. No. 1 (as well as Sequence I.D. Nos. 2 and 3) are likely to exist within the human genome and within genomes of other species. Because such variants are expected to possess certain differences in nucleotide and amino acid sequence, this invention provides an isolated nucleic acid molecule and its encoded protein, having at least about 50-60% (preferably 60-80%, most preferably over 80%) sequence homology in the coding region with the nucleotide sequences set forth as Sequence I.D. No. 1 or No. 3 (and, preferably, specifically comprising the coding region of Sequence I.D. No. 1 or No. 3), and the amino acid sequence of Sequence I.D. No. 2. Because of the natural sequence variation likely to exist among OVCAl genes and their encoded proteins, one skilled in the art would expect to find up to about 40-50% variation in the coding sequence, while still maintaining the unique properties of the coding sequence and the encoded protein of the present invention. Such an expectation is due in part to the degeneracy of the genetic code, as well as the known evolutionary success of conservative amino acid sequence variations, which do not appreciably alter the nature of a protein. Accordingly, such variants are considered substantially the same as one another and are included within the scope of the present invention. Of course, the introns of the OVCAl gene are likely to possess even greater sequence variation, in keeping with the known variability of introns in eucaryotic genes. For purposes of this invention, the term "substantially the same" refers to nucleic acid or amino acid sequences having sequence variations that do not materially affect the nature of the protein (i.e., the structure and/or biological activity of the protein) . With particular reference to nucleic acid sequences, the term "substantially the same" is intended to refer to the coding region and to conserved sequences governing expression, and refers primarily to degenerate codons encoding the same amino acid, or alternate codons encoding conserved substitute amino acids in the encoded polypeptide. With reference to amino acid sequences, the term "substantially the same" refers generally to conservative substitutions and/or variations in regions of the polypeptide not involved in determination of structure or function. Persons skilled in the art will appreciate that nucleotide sequences having sufficient homology (as discussed above) to be considered "substantially the same" are often identified by hybridization to one another under appropriate hybridization conditions. Identification and isolation of nucleic acids of the invention by hybridization under various stringency conditions is described in greater detail below. The following description sets forth the general procedures involved in practicing the present invention. To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to limit the invention. Unless otherwise specified, the general cloning procedures, such as those set forth in Sambrook et al., Molecular Cloning, Cold Spring Harbor Laboratory (1989) (hereinafter "Sambrook et al.") are used. I. Preparation of OVCAl nucleic acid molecules, encoded proteins and antibodies thereto A. Nucleic Acid Molecules Nucleic acid molecules comprising part or all of the OVCAl gene of the invention may be prepared by two general methods: (1) they may be synthesized from appropriate nucleotide triphosphates, or (2) they may be isolated from biological sources. Both methods utilize protocols well known in the art. The availability of nucleotide sequence information, such as Sequence I.D. Nos. 1 and 3, enables preparation of an isolated nucleic acid molecule of the invention by oligonucleotide synthesis. Synthetic oligonucletoides may be prepared by the phosphoramadite method employed in the Applied Biosyste s 38A DNA Synthesizer or similar devices. The resultant construct may be purified by high performance liquid chromatography (HPLC) . Long, double-stranded polynucleotides, such as a DNA molecule of the present invention, must be synthesized in stages, due to the size limitations inherent in current oligonucleotide synthetic methods. Thus, for example, a double- stranded DNA molecule several kilobases in length may be synthesized as multiple smaller segments of appropriate complementarily. Complementary segments thus produced may be annealed such that each segment possesses appropriate cohesive termini for attachment of an adjacent segment. Adjacent segments may be ligated by annealing cohesive termini in the presence of DNA ligase to construct an entire double-stranded molecule. A synthetic DNA molecule so constructed may then be cloned and amplified in an appropriate vector. OVCAl nucleic acid sequences may be isolated from appropriate biological sources using methods known in the art. In a preferred embodiment, a cDNA clone is isolated from an expression library of human origin. In another preferred embodiment, human genomic clones containing OVCAl may be isolated. Alternatively, cDNA or genomic clones from other species may be obtained. In accordance with the present invention, nucleic acids having the appropriate sequence homology with part or all of Sequence I.D. Nos. 1 or 3 may be identified by using hybridization and washing condition of appropriate stringency. For example, hybridizations may be performed, according to the method of Sambrook et al., using a hybridization solution comprising: 5 x SSC, 5 x Denhardt's reagent, 1.0% SDS, 100 μg/ml denatured, fragmented salmon sperm DNA, 0.05% sodium pyrophosphate and up to 50% formamide. Hybridization is carried out at 37-42°C for at least six hour. Following hybridization, filters are washed as follows: (1) 5 minutes at room temperature in 2 x SSC and 1% SDS; (2) 15 minutes at room temperature in 2 x SSC and 0.1% SDS; (3) 30 minutes-1 hour at 37°C in 1 x SSC and 1% SDS; (4) 2 hours at 42-65°in 1 X SSC and 1% SDS, changing the solution every 30 minutes. In a preferred embodiment, hybridizations are performed in hybridization solution comprising 0.5 M NaP0 4 , 2mM EDTA, 7% SDS and 0.1% sodium pyrophosphate (pH 7.1) at about 65°C for 20 hours. For high-stringency conditions, membranes are subsequently washed sequentially for 1 hour each in: (1) 2X SSC, 0.5X SET, 0.1% sodium pyrophosphate; and (2) 0.1X SSC, 0.5X SET, 0.1% sodium pyrophosphate. For low-stringency conditions, membranes are washed at 50°C for 30 minutes in 2X SSC, 0.5X SET, 0.1% sodium pyrophosphate. Nucleic acids of the present invention may be maintained as DNA in any convenient cloning vector. In a preferred embodiment, genomic clones are maintained in a cosmid vector, such as pWE15 (Stratagene) . In another preferred embodiment, clones are maintained in plasmid cloning/expression vector, such as pBluescript (Stratagene, La Jolla, CA) , which is propagated in a suitable E . coli host cell. OVCAl nucleic acid molecules of the invention (including 0VCA2) include cDNA, genomic DNA, RNA, and fragments thereof which may be single- or double- stranded. Thus, this invention provides oligonucleotides (sense or antisense strands of DNA or RNA) having sequences capable of hybridizing with at least one sequence of a nucleic acid molecule of the present invention, such as selected segments of Sequence I.D. Nos. 1 and 3 or selected intron sequences from genomic clones isolated in accordance with the present invention (such as those found in cosmid 7-2, described in Example 1) . Such oligonucleotides are useful as probes for detecting OVCAl genes (and specific mutations) in test samples, e.g. by PCR amplification, or as potential regulators of gene expression. B. Proteins A full-length OVCAl-encoded protein of the present invention may be prepared in a variety of ways, according to known methods. The protein may be purified from appropriate sources, e.g., human or animal cultured cells or tissues, by immunoaffinity purification. However, due to the limited amount of such a protein that may be present in a sample at any given time, particularly in tumors or tumor cell lines, conventional purification techniques are not preferred in the present invention. The availability of the isolated OVCAl coding sequence enables production of protein using in vi tro expression methods known in the art. For example, a cDNA or gene may be cloned into an appropriate in vitro transcription vector, such a pSP64 or pSP65 for in vitro transcription, followed by cell-free translation in a suitable cell-free translation system, such as wheat germ or rabbit reticulocytes. In vitro transcription and translation systems are commercially available, e.g., from Promega Biotech, Madison, Wisconsin or BRL, Rockville, Maryland. Alternatively, according to a preferred embodiment, the recombinant protein may be produced by expression in a suitable procaryotic or eucaryotic system. For example, part or all of a DNA molecule, such as the cDNA having Sequence I.D. No. 1 or No. 3, may be inserted into a plasmid vector adapted for expression in a bacterial cell, such as E . coli , or into a baculovirus vector for expression in an insect cell. Such vectors comprise the regulatory elements necessary for expression of the DNA in the bacterial host cell, positioned in such a manner as to permit expression of the DNA in the host cell. Such regulatory elements required for expression include promoter sequences, transcription initiation sequences and, optionally, enhancer sequences. Production of a recombinant OVCAl protein by expression in a procaryotic system is described in greater detail in Example 2. The protein produced by OVCAl gene expression in a recombinant procaryotic or eucaryotic system may be purified according to methods known in the art. In a preferred embodiment, a commercially available expression/secretion system can be used, whereby the recombinant protein is expressed and thereafter secreted from the host cell, to be easily purified from the surrounding medium. If expression/secretion vectors are not used, an alternative approach involves purifying the recombinant protein by affinity separation, such as by im unological interaction with antibodies that bind specifically to the recombinant protein. Such methods are commonly used by skilled practitioners. Proteins prepared by the aforementioned methods may be analyzed according to standard procedures. For example, such proteins may be subjected to amino acid sequence analysis, according to known methods. The present invention also provides antibodies capable of immunospecifically binding to proteins of the invention. Polyclonal antibodies directed toward OVCAl-encoded proteins may be prepared according to standard methods. In a preferred embodiment, monoclonal antibodies are prepared, which react immunospecifically with various epitopes of the proteins. Monoclonal antibodies may be prepared according to general methods of Kόhler and Milstein, following standard protocols. Polyclonal or monoclonal antibodies that immunospecifically interact with OVCAl- encoded proteins can be utilized for identifying and purifying such proteins. For example, antibodies may be utilized for affinity separation of proteins with which they immunospecifically interact. Antibodies may also be used to immunoprecipitate proteins from a sample containing a mixture of proteins and other biological molecules. Other uses of antibodies are described below. II. Uses of OVCAl Nucleic Acids, Encoded Proteins and Antibodies Thereto As is typical of tumor suppressor genes, rearrangements and mutations in OVCAl have been found to be associated with the tumorigenic state in tissues and cell lines. Accordingly, isolated OVCAl nucleic acids, proteins and antibodies thereto will find wide utility as prognostic indicators of neoplastic disease and as therapeutic agents for the treatment of many types of cancer including, but not limited to cancers of the breast, lungs, colon, ovaries and cervix, and other carcinomas such as neuroectoder al tumors, medulloblaεtoma and astrocytoma. A. OVCAl Nucleic Acids Nucleic acids comprising part or all of the OVCAl gene may be used for a variety of purposes in accordance with the present invention. As has been done for other tumor suppressor genes, such as p53, selected OVCAl sequences (DNA, RNA or fragments thereof) may be used as probes to identify mutations or rearrangements in a patient's DNA, and/or monitor the level of OVCAl transcripts in tissues suspected of being malignant. As discussed earlier, mutations in OVCAl appear to be associated with sporadic (as opposed to familial) breast cancer as well as with development of ovarian carcinomas, among others. Accordingly, early identification of disruptions in the OVCAl gene will facilitate diagnosis of malignancies at early stages when the chance for their successful treatment is much greater. OVCAl sequences may be utilized as probes in a variety of assays known in the art, including but not limited to: (1) in situ hybridization; (2) Southern hybridization; (3) northern hybridization; and (4) assorted amplification reactions, such as polymerase chain reaction (PCR). The OVCAl nucleic acids of the invention may also be utilized as probes to identify related genes either from humans or from other species. As discussed above, high-stringency hybridization studies have shown that OVCAl exists in other mammalian species including but not limited to cow, cat, dog, horse, mouse, pig and rat. As is well known in the art, hybridization stringency may be adjusted so as to allow hybridization of nucleic acid probes with complementary sequencing of varying degrees of homology. As described above, the coding region of OVCAl is also used to advantage to produce substantially pure OVCAl encoded proteins or selected portions thereof. As described below, these proteins may also be used in diagnosis and therapy of metastatic disease. Because OVCAl appears to be important in maintenance of normal cell division, a preferred embodiment of the present invention involves gene therapy in which a normal OVCAl gene or transcript is supplied to a patient having cells or tissues lacking OVCAl, or in which OVCAl has been disrupted, for the purpose of encouraging normal growth in otherwise tumorigenic tissue. This type of gene therapy may be particularly applicable to cancers of the blood, wherein bone marrow or peripheral blood is subjected to genetic transformation protocols ex vivo , during the course of a normal autologous stem cell transplantation procedure. OVCAl nucleic acid molecules, or fragments thereof, may also be utilized to control the expression of endogengous OVCAl genes. If desired, the nucleic acid molecules of the invention may be used to reduce or prevent expression of OVCAl genes in a targeted cell population. In this embodiment, antisense oligonucleotides are employed which are targeted to specific regions of OVCAl that are critical for gene expression. The use of antisense oligonucleotides to reduce or eliminate expression of a pre-determined gene is known in the art. In a preferred embodiment, such antisense oligonucleotides are modified in various ways to increase their stability and membrane permeability, so as to maximize their effective delivery to target cells in vitro and in vivo . Such modifications include the preparation of phosphorothioate or ethylphosphonate derivatives, among many others, according to procedures known in the art. This embodiment of the invention may be particularly applicable to the study of cellular proliferation and tumor development in vi tro , for the purpose of elucidating the mechanism of cancer development and for developing anti-cancer drugs. B. OVCAl-Encoded Proteins and Antibodies Thereto The OVCAl-encoded protein, or fragments thereof, may be used to produce polyclonal or monoclonal antibodies, which also may serve as sensitive detection reagents for the presence and accumulation of the OVCAl-encoded polypeptide in cultured cells or tissues from living patients (the term "patient" refers to both humans and animals) . Because the OVCAl-encoded protein has not yet been isolated from natural sources, such antibodies will greatly accelerate the identification, isolation and characterization of this protein in mammalian cells and tissues. Recombinant techniques enable expression of fusion proteins containing part or all of the OVCA1- encoded protein. The full-length protein or fragments of the protein may be used to advantage to generate an array of monoclonal antibodies specific for various epitopes of the protein, thereby potentially providing even greater sensitivity for detection of the protein in cells or tissues. Polyclonal or monoclonal antibodies immunologically specific for the OVCAl-encoded protein may be used in a variety of assays designed to localized and/or quantitate the protein. Such assays include, but are not limited to: (1) flow cytometric analysis; (2) immunoche ical localization of the protein in cultured cells or tissues; and (3) im unoblot analysis (e.g. , dot blot, Western blot) of extracts from cells and tissues. Additionally, as described above, such antibodies can be used for the purification of OVCAl-encoded proteins (e.g, affinity column purification, immunoprecipitation) . From the foregoing discussion, it can be seen that OVCAl nucleic acids, protein and antibodies thereto can be used in many ways for diagnosis and prognosis of human neoplastic diseases. However, one skilled in the art will appreciate that these tools will also be useful in animal and cultured cell experimentation with respect to various carcinomas. They can be used to monitor the effectiveness of potential anti-cancer agents on cellular proliferation in vitro , and/or to assess the development of neoplasms or other malignant diseases in animal model systems. The following examples are provided to describe the invention in further detail. These examples are intended to illustrate and not to limit the invention. EXAMPLE 1 Identification of OVCAl, a Candidate Tumor Suppressor Gene on Chromosome 17P13.3 Rearrangements or deletions of chromosome 17 are one of the most frequently observed changes identified in breast and ovarian tumors, among others. Molecular analysis suggests that, in addition to the BRCAl gene on 17q21 and the TP53 gene on 17pl3.1, there is at least one other tumor suppressor gene on chromosome 17 involved in the genesis of ovarian and/or breast cancer. Loss of heterozygosity (LOH) identified within regions of 17pl3.3 occurs frequently in ovarian tumors which express wild type TP53. This example describes the use of deletion mapping and positional cloning methods to identify a novel gene, OVCAl (ovarian cancer 1 gene) that maps to 17pl3.3, and is mutated in a number of tumors and tumor cell lines. MATERIALS .AND METHODS Isolation of DNA and RNA from Tumors and Matched Blood Samples. Preparation of RNA for Northern blotting, and DNA isolation for LOH and SSCP analysis is by methods described in Godwin et al., Am. J. Hum. Genet. 5_5: 666-677 (1994) . cDNA cloning. Human cDNA libraries derived from an ovarian cancer cell line, A2780, a cervical cancer cell line, HeLa, normal thymus (Stratagene) , and fetal brain (Stratagene) were screened by probing with conserved genomic fragments of cosmid 7-2 (described below) . Membranes were hybridized at 1.5xl0 6 cpm/ml of hybridization solution (0.5M NaP0 4 , 2mM EDTA, 7% SDS, and 0.1% sodium pyrophosphate (NaPPi) , 65°C for 20 hours. The membranes were sequentially washed at high stringency, i.e., 65°C for 1 hour in 2x SSC, 0.5x SET (lx SET is 1% SDS, 5mM EDTA, lOmM Tris-HCl) , 0.1% NaPPi; and O.lx SSC,0.5x SET, 0.1% NaPPi, respectively. Washed membranes were exposed to Kodak XAR-5 film with a Lightning Plus intensifying screen (NEN-Dupont) at -70°C. DNA probes containing repetitive sequences were pre-annealed using human placental (Sigma, St. Louis, MO) and Cot-1 (Bethesda Research Laboratories, Gaithersburg, MD) DNA prior to hybridization. Positive clones were obtained by screening roughly one million plaques from an oligo(dT) -primed fetal brain cDNA library constructed in pBlueScript (Stratagene) by hybridization with a 1.6kbpEcoRI fragment of cosmid 7-2 as probe. For low-stringency Southern hybridizations, membranes were hybridized as above, but were washed at 50°C for 30 min. in 2x SSC, 0.5x SET, 0.1% NaPPi. Washed membranes were exposed to Kodak XAR-5 film with a Lightning Plus intensifying screen (NEN-Dupont) at -70°C. DNA probes containing repetitive sequences were pre-annealed using human placental (Sigma, St. Louis, MO) and Cot-1 (Bethesda Research Laboratories, Gaithersburg, MD) DNA prior to hybridization. Single Strand Conformational Polymorphism (SSCP) Analysis. PCR was carried out in a reaction volume of 10ml containing lOOng of genomic DNA template, lOmM tris-HCl pH 8.3, 50mM KCl, 1.5 mM MgCl 2 , 0.001% gelatin, ImM each of forward and reverse primer, 60mM each dATP, dGTP, dCTP, and dTTP, O.lmCi [ - 2 P]- dATP (DuPont, NEN) , 5% dimethyl sulfoxide (DMSO) , and 0.5U Amplitaq DNA polymerase (Perkin Elmer) . Following an initial denaturation step at 94°C for 4 minutes, DNA was amplified through 20 cycles consisting of 1 minute denaturing at 94°C, 1 minute annealing at 68°C- 0.5°C/cycle and 1 minute extension at 72°C. The ' samples were then subjected to an additional 25 cycles, consisting of 1 minute denaturation at 9 °C, 1 minute at 58°C, and 1 minute extension at 72°C, and a final extension at 72°C for 5 minutes. PCR reaction products were diluted 1:10 in denaturing loading dye (95% formamide, lOmM NaOH, 0.25% bromophenol blue, and 0.25% xylene cyanol) , heated at 94°C for 5 minutes, and flash cooled on ice. Four microliters were loaded onto a 0.5xMDE gel (AT Biochem) prepared according to the manufacturer's specifications, and run at 5 watts for 12-16 hours at room temperature in 0.6XTBE (lx=0.09M Tris, 0.09M boric acid, 0.002M EDTA) . Following electrophoresis, the gel was dried and exposed to autoradiography film at -80°C for 1-12 hours. Variant and normal SSCP bands were cut out from the gels after alignment with the autoradiograph, and the DNA eluted in lOOμl of ddH 2 0 at 37°C for 3 hours. DNA Sequencing. Sequencing was performed on double stranded plasmid DNA using the dideoxy method, with SK, KS or primers derived from obtained sequences (See Table 2) . For direct sequencing of the variant SSCP bands, 2μl of the eluted DNA was used as template for secondary PCR reactions carried out using the conditions described above, except radiolabelled dATP was omitted. Following amplification, the DNA was collected on Wizard resin (Pro ega) , eluted in 50μl of ddH 2 0, and the purified PCR product was subjected to cycle sequencing using the fmol DNA Sequencing System (Promega) . PCR analysis of simple tandem repeat polymorphisms. Simple tandem repeat polymorphisms (STRPs) were typed in a PCR based assay containing 15- 30ng of genomic DNA, lOmM Tris-HCl pH 8.3, 50mM KC1, 1.5 M MgCl 2 , 0.001% gelatin, 0.4μM of each primer, ' dCTP, dGTP, and TTP each 16μM, dATP at 2μM, 0.65Ci [α- 35 S]-dATP (DuPont, New England Nuclear) , 5% DMSO, and 0.25U Amplitaq DNA polymerase (Perkin Elmer) in a final volume of 5μl. Alleles were amplified as described above. PCR reaction products were diluted 1:1 in loading buffer (90% formadmide, 20mM ETDA, 0.3% bromophenol blue, 0.3% xylene cyanol) , denatured at 94°C for 5 minutes and loaded (4μl) onto a 6% denaturing polyacrylamide gel, then electrophoresed at 90 watts in lxTBE. After electrophoresis, gels were dried at 70°C under vacuum, and exposed to Kodak XAR 5 film for 24-28 hours. RESULTS Interstitial deletions are helpful in defining the smallest region of overlapping deletion ih which a tumor suppressor gene may be found. Previous studies have reported that sporadic ovarian tumors of low malignant potential and low-stage carcinomas have allelic loss at chromosome I7pl3.3, whereas TP53 at 17pl3.1 and the BRCAl locus at 17q21 are retained. Using DNA isolated from 150 ovarian tumors, a panel of polymorphic DNA markers was evaluated for LOH on 17p. A detailed deletion map of cases showing limited LOH on 17p revealed a common region of deletion, distal to YNH37.3 (D17S28) and proximal to YNZ22 (D17S5) , which spans less than 20 kilobase pairs (kbp) and is located on chromosome 17pl3.3 (Figure 1) . Cosmid clones surrounding and including the two loci were isolated from a human placental DNA cosmid library constructed in vector pWE15 (Stratagene) . Several strategies were employed to evaluate these clones for potential expressed sequences. First, DNA fragments were evaluated for potential growth suppressor function. We introduced by transfection cosmid clones containing genomic inserts spanning the limited region of deletion and a selectable marker (Neo r ) and evaluated clonal outgrowth in the presence of geneticin. Of the cosmids tested, clone pWE15/7-2, containing approximately 40kbp of genomic DNA, was the most effective at suppressing colony formation. Cosmid clone pWE15/7-2 is deposited with the American Type Culture Collection and assigned ATCC Accession No. [not yet assigned]. Next, clone 7-2 was evaluated using exon amplification methods. A lOlbp exon was identified, which mapped to a 1.6kbp £coRI DNA fragment of clone 7-2. Hybridization of the lOlbp fragment a low stringency (see Materials and Methods) to a "zoo" blot (see below) revealed conservation among other mammals. Sequencing of the 1.6kb .EcoRI fragment revealed a second potential open reading frame 150bp away from the putative lOlbp exon. Four human cDNA libraries, derived from an ovarian cancer cell line, cervical cancer cell line, normal thymus, and fetal brain were screened at high stringency (see Materials and Methods) using the 1.6kbp .EcoRI fragment as a probe. Several positive clones were isolated from the human fetal brain cDNA library constructed in a pBluescript vector (Stratagene) . Only two of the clones (fb67-l and 77-1) hybridized to any of the clones of the 17pl3.3 cosmid "contig", indicating the presence of a potential family of genes at loci other than 17pl3.3. Related OVCAl clones isolated from the fetal brain cDNA library were labeled as follows: fb50-l-l, fb52-l-l, fb53-l-l, fb57-l-l, fb63-l-l, fb69-l-l and fb73-l-l. Partial sequence analysis of these clones has been performed. Other clones that have not been sequenced include fb43-l-l, fb43-2-l and fb-46-1-1. Because the aforementioned clones were isolated by hybridization with a segment of cosmid clone 7-2 (containing part of Sequence I.D. No. 1) , the clones are considered to be "substantially the same" as their corresponding sequences in Sequence I.D. No. 1, within the scope of the present invention. Sequence analysis of clones fb67-l and fb77-l revealed a consensus of 2158bp (zero bp of the 5'- untranslated, 1589bp of coding region and 569bp of the 3 ' -untranslated region) . Identification of a presumptive initation codon flanked by sequences resembling the Kozak consensus seqeunce was accomplished using an "achored" PCR method (Rapid Amplification of cDNA Ends, Gibco/BRL) . Thirty-five additional nucleotides were identified, including 18 bases of the 5 '-untranslated region and two potential initation codons. The reading frame using the first AUG encodes a protein of 538 amino acids with a predicted molecular weight of about 60 kDa (Figure 2) . Using the second AUG codon, the predicted protein is about 533 amino acids long with a predicted molecular weight of about 59 kDa. A polyadenylation signal was observed 18bp upstream from the polyadenylation site (Figure 2) . Northern blot analysis, using the 5'- portion of the fb77-l cDNA insert as probe, detected a 2.3kb transcript of RNA from ovarian surface epithelial cells. The length of the cDNA plus l50-200bp of poly(A) tail probably account for the entire length of the transcript detected in northern blot analysis. Genomic DNA samples from several different species were also probed with a full-length OVCAl cDNA fragment. High stringency blots (see Materials and Methods) revealed strongly hybridizing fragments in tissue from human, cow, cat, dog, horse, mouse, pig, and rat. These results suggest that OVCAl is highly conserved in mammals. BLAST searches of the Genbank/EMBL and Swissplot databases, respectively, revealed extensive sequence identity (both at the nucleotide or the amino acid level) to two recently identified sequences: S . cerevisiae chromosome IX cosmid 9150 and Caenorhabditis elegans cosmid C14B1 (Figure 4) . The predicted gene product of OVCAl showed significant sequence similarity over 315 and 375 of the 538 amino acid residues (51% and 44% identity) when compared to the yeast and nematode proteins, respectively. The function of these two predicted proteins is unknown at present time; the sequences were identified as the result of yeast and ne atode genome sequencing projects. Restriction mapping of genomic clones using cDNA probes and sequence comparison between cDNA and genomic clones indicated that OVCAl consists of 13 exons, which span approximately 20kbp of genomic DNA. The entire OVCAl cDNA sequence is present in the insert of cosmid 7-2. The position of the 13 exons relative to the common region of deletion defined by DNA markers D17S28 and D17S5 is shown in Figure 3. Hybridization of RNA blots to a labeled fragment of the entire fb77-l cDNA insert revealed two distinct transcripts of 2.3kb and l.lkb. The two transcripts are readily detected in all tissue examined at similar levels. Northern blot analysis reveals that the 2.3kb OVCAl mRNA is expressed in normal surface epithelial cells of the ovary, but the level of the 2.3kb transcript is significantly reduced or is undetectable in a majority (11/13) of the ovarian tumors and tumor cell lines. We have also cloned the smaller transcript and have found that it is composed of exon 13 of OVCAl and a unique exon positioned in the intron between exon 12 and 13 of OVCAl. We refer to this transcript as OVCA2 (Figure 5) . Ovarian carcinomas were typed for LOH, using four highly polymorphic simple tandem repeat markers: D17S926, D17S796 which lie distal to OVCAl and D17S786, D17S513, which lie proximal to OVCAl. Thirty-seven of 68 (54%) informative ovarian tumors exhibited LOH frequencies consistent with previous measurements. This panel, plus 32 additional ovarian tumors (LOH status undetermined) were examined for OVCAl mutations. The panel represents Caucasian, Hispanic, and African American patients of varying ages (Table 1) . Table 1. Age of ovarian cancer onset and race of patients studied. FCCC, Fox Chase Cancer Center, LH, Lankenau Hospital, GOG, and Gynelogic Oncology Group; Cau, Caucasian, H, Hispanic, Af Am, African American. AGE RACE 45 or under Over 45 Cau H Af Am FCCC 5 53 56 0 2 LH 7 20 22 0 5 GOG 15 40 43 5 7 The complete coding region and intron-exon boundary sequences of OVCAl was screened in this tumor set by a combination of single-strand conformation polymorphism (SSCP) analysis and direct sequencing. Based on genomic sequence analysis, polymerase chain reaction (PCR) primers were designed to screen the complete coding region (1613) and intron-exon boundaries of OVCAl. Since exon 13 is too large (831bp) to analyze effectively in one piece by SSCP, three overlapping primer sets were designed for this exon, each with a length of 200-350bp (Table 2). Table 2. Oligonucleotide primers for OVCAl (Numbers in parentheses are Sequence I.D. Nos.) 5'-primer -primer exonl CGCCCCTATCTCCTCCTTTA (6) TGGTCCTGTCCCTAACTTGG (7) exon2 CATCTCAATCTGGCTTCAGC (8) AACCCCAGCTCAATGATCAC (9) exon3 CTAGCCCTCCACCTCTCAT (10) AGCCTGGCTCACCCTCCT (11) exon4 AGGGTGGGTCTCTCCTAC (12) ATGGGGAAGATGAATGTG (13) exon5 CCTCTGCTGCTCCTACCT (14) TGTCCACCCTACAGGAGG (15) exonβ CTCTCCTGCCCCAGCCGTTGG (16) GATGAACCTAAGACTCCCTCC (17) exon7 CTTCTGCTGCCCTAAACCAC (18) AGTGGCAGGGAATCTCACC ( 19) exonβ CTGAGTCAGGATCTGTGTGCA (20) TGTTCCCAGTCACTTCCCTC (21) exon9 TAGGCCACAGGTTCAGCTTT (22) CAGCCTTCAAGACGAGCTG (23) exonlO CACTGTCACGTTCTTCAGCA (24) ACCCCACTCCACTCCAGAC (25) exonl1 ACACTGGCAGATGTTATTGTCC (26) CTCCTCCCTCCTGGAAGC (27) exonl2 GGAGGGAAACGCAGGGTC (28) AGGCGTTCCCATGACAAC (29) exonl3a GAGGCTGGTGGTTTTCAGAGC (30) GGGACAGAAACTAGACACCAAG (31) exonl3b GGGTTTATCCTCTTGGTGTCT (32) CATTTCTTGATCTTTCACTCT (33) exonl3c TGGACCAGTTTGCAGAGTGA (34) TATGTGGCAGTCACCATCGT (35) Preliminary studies of 100 fresh ovarian tumors (primarily high grade and late stage) and 13 tumor cell lines for mutations in OVCAl has revealed a number of potential cancer-causing mutations in both tumors and cell lines (Table 3) . Table 3. Mutations in OVCAl, Patient # Location Codon Mutation Result GOG19 int3 A—G Unknown OVCAR4 ex4 138 G—T Splicing error OVCAR4 ex4 105 G—C Metl05Ile A2780/4E int4 G—A Splicing error 1A9 ext4 102 G—A Alal02Thr GOG4 int4 G—A Splicing error GOG25 int4 T—A Splicing error GOG40 int4 C—A Splicing error UPN61 ex4 99 C—G Phe99Leu UPN92 int4 C—G Unknown UPN106 ex4 105 A—G Metl05Val UPN123 ex4 105 A—G Metl05Val CP70 ex8 298 G—C Gly298Ala UPN62 ex9 329 insC Frameshift UPN96 exl3 563 G—T Met563Arg A total of fifteen mutations, many in the introns flanking exon 4, have been detected. Moreover, these mutations are not detected in the patients' matching lymphocyte DNA, suggesting that these alterations are the result of acquired somatic mutations and are therefore not likely to be random polymorphisms. Multiple common and rare polymorphisms were also identified in the OVCAl coding sequence (Table 4) and were used to directly assess the frequencey of LOH for OVCAl. Table 4. Polymorphisms in OVCAl Exon Codon Location ide Change Result 1 7 2 C—T Ala—Val 2 32 2 C—A Ala—Asp 4 104 3 G—A Val—Val 5 188 3 G—A Ser—Ser 5 N.D N. N.D. N.D. 9 336 1 C—G Leu— al 9 338 3 C—T Pro—Pro EXAMPLE 2 Production of Fusion OVCAl Proteins Fragments of the OVCAl cDNA (Sequence I.D. No. 1) were ligated in the BamHI and £coRI sites of the pGEX bacterial expression vector (commercially available) . When expressed in bacteria, the pGEX vector produces a fusion protein between bacterial glutathione S-tranferase and the desired portions of the OVCAl protein. E . coli cells were transformed with these constructs and the proteins prepared by inducing expression from an overnight culture with 0. ImM IPTG for 2 hours. The cells were pelleted, washed with phosphate-buffered saline (PBS) and then sonicated. The bacterial debris was pelleted by centrifugation and the supernatant passed over a glutathione-Sepharose column. The protein was eluted using 5mM glutathione in 50mM Tris-HCl, pH 8.0. Protein yields have not yet been quantitated or optimized; however, this expression system routinely yields 1 mg of protein from 200 ml of bacterial cells. The present invention is not limited to the embodiments described and exemplified above, but is capable of variation and modification without departure from the scope of the appended claims. SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: Godwin, Andrew K. (ii) TITLE OF INVENTION: Novel Gene Associated with Suppression of Tumor Development (iii) NUMBER OF SEQUENCES: 35 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: Dann, Dorfman, Herrell & Skillman (B) STREET: 1601 Market Street, Suite 720 (C) CITY: Philadelphia (D) STATE: PA (E) COUNTRY: USA (F) ZIP: 19103 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Patentin Release #1.0, Version #1.30 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: US 08/399,986 (B) FILING DATE: 06-MAR-1995 (C) CLASSIFICATION: (viii) ATTORNE /AGENT INFORMATION: (A) NAME: Reed, Janet E. (B) REGISTRATION NUMBER: 36,252 (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: (215) 563-4100 (B) TELEFAX: (215) 563-4044 (2) INFORMATION FOR SEQ ID NO:l: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2202 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (vi) ORIGINAL SOURCE: (A) ORGANISM: Human (viii) POSITION IN GENOME: (A) CHROMOSOME/SEGMENT: 17pl3.3 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:l: CTGTCTTTTT AGTACCACAT GCGCAGGCAG GTGATGGCGG CGCTGGTCGT ATCCGGGGCA 60 GCGGAGCAGG GCGGCCGAGA CGGCCCTGGC AGAGGTCGGG CCCCTCGGGG CCGCGTGGCC 120 AATCAGATCC CCCCTGAGAT CCTGAAGAAC CCTCAGCTGC AGGCAGCAAT CCGGGTCCTG 180 CCTTCCAACT ACAACTTTGA GATCCCCAAG ACCATCTGGA GGATCCAACA AGCCCAGGCC 240 AAGAAGGTGG CCTTGCAAAT GCCGGAAGGC CTCCTCCTCT TTGCCTGTAC CATTGTGGAT 300 ATCTTGGAAA GGTTCACGGA GGCCGAAGTG ATGGTGATGG GTGACGTGAC CTACGGGGCT 360 TGCTGTGTGG ATGACTTCAC AGCGAGGGCC CTGGGAGCTG ACTTCTTGGT GCACTACGGC 420 CACAGTTGCC TGATTCCCAT GGACACCTCG GCCCAAGACT TCCGGGTGCT GTACGTCTTT 480 GTGGACATCC GGATAGACAC TACACACCTC CTGGACTCTC TCCGCCTCAC CTTTCCCCCA 540 GCCACTGCCC TTGCCCTGGT CAGCACCATT CAGTTTGTGT CGACCTTGCA GGCAGCCGCC 600 CAGGAGCTGA AAGCCGAGTA TCGTGTGAGT GTCCCACAGT GCAAGCCCCT GTCCCCTGGA 660 GAGATCCTGG GCTGCACATC CCCCCGACTG TCCAGAGAGG TGGAGGCCGT TGTGTATCTT 720 GGAGATGGCC GCTTCCATCT GGAGTCTGTC ATGATTGCCA ACCCCAATGT CCCCGCTTAC 780 CGGTATGACC CATATAGCAA AGTCCTATCC AGAGAACACT ATGACCACCA GCGCATGCAG 840 GCTGCTCGCC AAGAAGCCAT AGCCACTGCC CGCTCAGCTA AGTCCTGGGG CCTTATTCTG 900 GGCACTTTGG GGCGCCAGGG CAGTCCTAAG ATCCTGGAGC ACCTGGAATC TCGACTCCGA 960 GCCTTGGGCC TTTCCTTTGT GAGGCTGCTG CTCTCTGAGA TCTTCCCCAG CAAGCTTAGC 1020 CTACTTCCCG AGGTGGATGT GTGGGTGCAG GTGGCATGTC CACGTCTCTC CATTGACTGG 1080 GGCACAGCCT TCCCCAAGCC GCTGCTGACA CCCTATGAGG CGGCCGTGGC TCTGAGGGAC 1140 ATTTCCTGGC AGCAGCCCTA CCCGATGGAC TTCTACGCTG GCAGATCCTT GGGGCCCTGG 1200 ACGGTGAACC ACGGGCAGGA CCGTCGTCCC CACGCCCCGG GTCGGTCCGC GCGGGGGAAG 1260 GTGCAGGAGG GGTCCGCGCG TCCCCCTTCG GTCGTGGTTT GCGAGGACTG CAGCTGCAGG 1320 GACGAGAAGG TGGCGCCGGT GGATCCTTGG ACGCGCTCCC GGGCCTCAGG GTCCTGCCCT 1380 CCGGAGGAGC AGCCTCGAGG CTGGTGGTTT TCAGAGCAGG AGGCCGACGT TTTCTCCGCA 1440 TTGGAAGAGC CCGCCGTCTG CAGGGGCCTG GAGGAATCAC TGGGGATGGT GGCACAGGCA 1500 CTGAACAGGC TGGGGCCTTT TGACGGCCTT CTTGGTTTCA GCCAAGGGGC TGCGCTAGCA 1560 GCCCTTGTGT GTACCCTGGG CCAGGCAGGC GATCCCCGCT TCCCCTTACC ACGGGTTTAT 1620 CCTCTTGGTG TCTAGTTTCT GTCCCCGGGG CATTGGGTTC AAGGAATCCA TCCTCCAAAG 1680 GCCCTTGTCA TTGCCTTCGC TCCATGTTTT TGGGGACACT GACAAAGTCA TCCCCTCTCA 1740 GGAGAGTGTG CAACTGGCCA GCCAATTTCC CGGAGCCATC ACCCTCACCC ACTCTGGTGG 1800 CCACTTCATT CCAGCAGCTG CACCCCAGCG TCAGGCCTAC CTCAAGTTCT TGGACCAGTT 1860 TGCAGAGTGA AAGATCAAGA AATGTCTCTG CTCCTACATC CAGCTCCTCT AGGGGCAGCC 1920 TCCGTCATCC ATGCCCTCCC AGGACCCTCC ACTCACTGCT GTGAGTGCGC CTCACCAGAA 198 CCAGTTAAGA GACAACTATC AATTCTTGAG ACCCAAATTA TAAGGGCCCT GCCCTGTACT 204 GAAGAAAAGG GGAGCACAAG GCCTTAATGG ACATTGACTT GTGAAAACGC AAACATGAAT 210 ATGGTTGGAG AGCCCTGGAT TAGGAGGGTG ACATGGGGAA GGCAGAGGCT GGCACGATGG 216 TGACTGCCAC ATAATAAAGT GGTGATTTGG ATTTTGNAAA AA 220 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 538 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: Met Arg Arg Gin Val Met Ala Ala Leu Val Val Ser Gly Ala Ala Glu 1 5 10 15 Gin Gly Gly Arg Asp Gly Pro Gly Arg Gly Arg Ala Pro Arg Gly Arg 20 25 30 Val Ala Asn Gin lie Pro Pro Glu lie Leu Lys Asn Pro Gin Leu Gin 35 40 45 Ala Ala lie Arg Val Leu Pro Ser Asn Tyr Asn Phe Glu lie Pro Lys 50 55 60 Thr lie Trp Arg lie Gin Gin Ala Gin Ala Lys Lys Val Ala Leu Gin 65 70 75 80 Met Pro Glu Gly Leu Leu Leu Phe Ala Cys Thr lie Val Asp lie Leu 85 90 95 Glu Arg Phe Thr Glu Ala Glu Val Met Val Met Gly Asp Val Thr Tyr 100 105 110 Gly Ala Cys Cys Val Asp Asp Phe Thr Ala Arg Ala Leu Gly Ala Asp 115 120 125 Phe Leu Val His Tyr Gly His Ser Cys Leu lie Pro Met Asp Thr Ser 130 135 140 Ala Gin Asp Phe Arg Val Leu Tyr Val Phe Val Asp lie Arg lie Asp 145 150 155 160 Thr Thr His Leu Leu Asp Ser Leu Arg Leu Thr Phe Pro Pro Ala Thr 165 170 175 Ala Leu Ala Leu Val Ser Thr lie Gin Phe Val Ser Thr Leu Gin Ala 180 185 190 Ala Ala Gin Glu Leu Lys Ala Glu Tyr Arg Val Ser Val Pro Gin Cys 195 200 205 Lys Pro Leu Ser Pro Gly Glu lie Leu Gly Cys Thr Ser Pro Arg Leu 210 215 220 Ser Arg Glu Val Glu Ala Val Val Tyr Leu Gly Asp Gly Arg Phe His 225 230 235 240 Leu Glu Ser Val Met lie Ala Asn Pro Asn Val Pro Ala Tyr Arg Tyr 245 250 255 Asp Pro Tyr Ser Lys Val Leu Ser Arg Glu His Tyr Asp His Gin Arg 260 265 270 Met Gin Ala Ala Arg Gin Glu Ala lie Ala Thr Ala Arg Ser Ala Lys 275 280 285 Ser Trp Gly Leu lie Leu Gly Thr Leu Gly Arg Gin Gly Ser Pro Lys 290 295 300 lie Leu Glu His Leu Glu Ser Arg Leu Arg Ala Leu Gly Leu Ser Phe 305 310 315 320 Val Arg Leu Leu Leu Ser Glu lie Phe Pro Ser Lys Leu Ser Leu Leu 325 330 335 Pro Glu Val Asp Val Trp Val Gin Val Ala Cys Pro Arg Leu Ser lie 340 345 350 Asp Trp Gly Thr Ala Phe Pro Lys Pro Leu Leu Thr Pro Tyr Glu Ala 355 360 365 Ala Val Ala Leu Arg Asp lie Ser Trp Gin Gin Pro Tyr Pro Met Asp 370 375 380 Phe Tyr Ala Gly Arg Ser Leu Gly Pro Trp Thr Val Asn His Gly Gin 385 390 395 400 Asp Arg Arg Pro His Ala Pro Gly Arg Ser Ala Arg Gly Lys Val Gin 405 410 415 Glu Gly Ser Ala Arg Pro Pro Ser Val Val Val Cys Glu Asp Cys Ser 420 425 430 Cys Arg Asp Glu Lys Val Ala Pro Val Asp Pro Trp Thr Arg Ser Arg 435 440 445 Ala Ser Gly Ser Cys Pro Pro Glu Glu Gin Pro Arg Gly Trp Trp Phe 450 455 460 Ser Glu Gin Glu Ala Asp Val Phe Ser Ala Leu Glu Glu Pro Ala Val 465 470 475 480 Cys Arg Gly Leu Glu Glu Ser Leu Gly Met Val Ala Gin Ala Leu Asn 485 490 495 Arg Leu Gly Pro Phe Asp Gly Leu Leu Gly Phe Ser Gin Gly Ala Ala 500 505 510 Leu Ala Ala Leu Val Cys Thr Leu Gly Gin Ala Gly Asp Pro Arg Phe 515 520 525 Pro Leu Pro Arg Val Tyr Pro Leu Gly Val 530 535 (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1028 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: GNCCATTACC AATCGCGAAA CCAGCGACCC CTGCGGGTCC TGTGCCTGGC GGGCTTCCGG 6 CAGAGCGAGC GGGGCTTCCG TGAGAAGACC GGGGCGCTGA GGAAGGCGCT GCGGGTCGCG 12 CCGAGCTCGT GTGCCTCAGC GCCCGCACCC GGTCCCCGAC CCCCCGGGCC CCGAGGGCGC 18 CAGATCAGAC TTCGGGTCCT GCCCTCCGGA GGAGCAGCCT CGAGGCTGGT GGTTTTCAGA 24 GCAGGAGGCC GACGTTTTCT CCGCATTGGA AGAGCCCGCC GTCTGCAGGG GCCTGGAGGA 30 ATCACTGGGG ATGGTGGCAC AGGCACTGAA CAGGCTGGGG CCTTTTGACG GCCTTCTTGG 36 TTTCAGCCAA GGGGCTGCGC TAACAATCCC TTGTGTGTAC CCTGGGCCAG GCAGGCGATC 42 CCCGCTTCCC CTTACCACGG GTTTATCCTC TTGGTGTCTA GTTTCTGTCC CCGGGGCATT 48 GGGTTCAAGG AATCCATCCT CCAAAGGCCC TTGTCATTGC CTTCGCTCCA TGTTTTTGGG 54 GACACTGACA AAGTCATCCC CTCTCAGGAG AGTGTGCAAC TGGCCAGCCA ATTTCCCGGA 60 GCCATCACCC TCACCCACTC TGGTGGCCAC TTCATTCCAG CAGCTGCACC CCAGCGTCAG 66 GCCTACCTCA AGTTCTTGGA CCAGTTTGCA GAGTGAAAGA TCAAGAAATG TCTCTGCTCC 72 TACATCCAGC TCCTCTAGGG GCAGCCTCCG TCATCCATGC CCTCCCAGGA CCCTCCACTC 78 ACTGCTGTGA GTGCGCCTCA CCAGAACCAG TTAAGAGACA ACTATCAATT CTTGAGACCC 84 AAATTATAAG GGCCCTGCCC TGTACTGAAG AAAAGGGGAG CACAAGGCCT TAATGGACAT 90 TGACTTGTGA AAACGCAAAC ATGAATATGG TTGGAGAGCC CTGGATTAGG AGGGTGACAT 96 GGGGAAGGCA GAGGCTGGCA CGATGGTGAC TGCCACATAA TAAAGTGGTG ATTTGGATTT 102 TGNAAAAA 102 (2) INFORMATION FOR SEQ ID NO:4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 526 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (vi) ORIGINAL SOURCE: (A) ORGANISM: S. cerevisiae (viii) POSITION IN GENOME: (A) CHROMOSOME/SEGMENT: IX cosmid 9150 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: Met Ser Gly Ser Thr Glu Ser Lys Lys Gin Pro Arg Arg Arg Phe lie 1 5 10 15 Gly Arg Lys Ser Gly Asn Ser Asn Asn Asp Lys Leu Thr Thr Val Ala 20 25 30 Glu Asn Gly Asn Glu lie lie His Lys Gin Lys Ser Arg He Ala Leu 35 40 45 Gly Arg Ser Val Asn His Val Pro Glu Asp He Leu Asn Asp Lys Glu 50 55 60 Leu Asn Glu Ala He Lys Leu Leu Pro Ser Asn Tyr Asn Phe Glu He 65 70 75 80 His Lys Thr Val Trp Asn He Arg Lys Tyr Asn Ala Lys Arg He Ala 85 90 95 Leu Gin Met Pro Glu Gly Leu Leu He Tyr Ser Leu He He Ser Asp 100 105 110 He Leu Glu Gin Phe Cys Gly Val Glu Thr Leu Val Met Gly Asp Val 115 120 125 Ser Tyr Gly Ala Cys Cys He Asp Asp Phe Thr Ala Arg Ala Leu Asp 130 135 140 Cys Asp Phe He Val His Tyr Ala His Ser Cys Leu Val Pro He Asp 145 150 155 160 Val Thr Lys He Lys Val Leu Tyr Val Phe Val Thr He Asn He Gin 165 170 175 Glu Asp His He He Lys Thr Leu Gin Lys Asn Phe Pro Lys Gly Ser 180 185 190 Arg He Ala Thr Phe Gly Thr He Gin Phe Asn Pro Ala Val His Ser 195 200 205 Val Arg Asp Lys Leu Leu Asn Asp Glu Glu His Met Leu Tyr He He 210 215 220 Pro Pro Gin He Lys Pro Leu Ser Arg Gly Glu Val Leu Gly Cys Thr 225 230 235 240 Ser Glu Arg Leu Asp Lys Glu Gin Tyr Asp Ala Met Val Phe He Gly 245 250 255 Asp Gly Arg Phe His Leu Glu Ser Ala Met He His Asn Pro Glu He 260 265 270 Pro Ala Phe Lys Tyr Asp Pro Tyr Asn Arg Lys Phe Thr Arg Glu Gly - 36 - 275 280 285 Tyr Asp Gin Lys Gin Leu Val Glu Val Arg Ala Glu Ala He Glu Val 290 295 300 Ala Arg Lys Gly Lys Val Phe Gly Leu He Leu Gly Ala Leu Gly Arg 305 310 315 320 Gin Gly Asn Leu Asn Thr Val Lys Asn Leu Glu Lys Asn Leu He Ala 325 330 335 Ala Gly Lys Thr Val Val Lys He He Leu Ser Glu Val Phe Pro Gin 340 345 350 Lys Leu Ala Met Phe Asp Gin He Asp Val Phe Val Gin Val Ala Cys 355 360 365 Pro Arg Leu Ser He Asp Trp Gly Tyr Ala Phe Asn Lys Pro Leu Leu 370 375 380 Thr Pro Tyr Glu Ala Ser Val Leu Leu Lys Lys Asp Val Met Phe Ser 385 390 395 400 Glu Lys Tyr Tyr Pro Met Asp Tyr Tyr Glu Ala Lys Gly Tyr Gly Arg 405 410 415 Gly Glu Thr Pro Lys Glu Ala He Glu Met Leu Lys Val Glu Lys Phe 420 425 430 Lys Lys Leu Lys Arg Phe Glu Val Tyr Tyr Cys Leu Lys Asn Ser Phe 435 440 445 Leu Glu Glu Val Asp He Glu Met Lys Tyr Ser Cys Ser He Thr Thr 450 455 460 He Lys Ser Asn Gly Ser Ala Ser Leu Leu Met Asn Trp Glu Glu Leu 465 470 475 480 Thr Pro Gly His Cys Phe Thr Ser Tyr Thr Thr Asn Pro He Ala Gly 485 490 495 Asp Tyr Gly Leu Asn Ala Ser Ala He Asp Gly His Thr Glu Glu Leu 500 505 510 Val Ala Thr His Pro Ala Gly Thr Leu Glu Asn Ala Thr Gin 515 520 525 (2) INFORMATION FOR SEQ ID NO: 5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 660 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (vi) ORIGINAL SOURCE: (A) ORGANISM: C. elegans (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5: Met He Thr Phe Gin Leu Pro Ser Asn Tyr Thr Phe Glu Val Pro Lys 1 5 10 15 Thr He Trp Lys He Arg Ser Thr Glu Ser Lys Tyr Val Ala Leu Gin 20 25 30 Phe Pro Glu Gly Leu He Met Tyr Ala Cys Val He Ala Asp He Leu 35 40 45 Glu Lys Tyr Thr Gly Cys Asp Thr Val He Met Gly Asp Val Thr Tyr 50 55 60 Gly Ala Cys Cys Val Asp Asp Tyr Thr Ala Lys Ser Met Gly Cys Asp 65 70 75 80 Leu Leu Val His Tyr Gly His Ser Cys Leu Val Pro He Gin Asn Thr 85 90 95 Asp Gly He Ala Met Leu Tyr Val Phe Gly Lys Arg Leu Val Val Val 100 105 110 Ser Thr Val Gin Phe He Pro Ser Leu Gin Thr Leu Arg Thr Thr Phe 115 120 125 Asn Lys Asp Asp Ser Ser He Arg He Asp He Pro Gin Cys Lys Pro 130 135 140 Leu Ser Pro Gly Glu Val Leu Gly Cys Thr Ser Pro Arg Leu Asp Ala 145 150 155 160 Ser Lys Tyr Asp Ala He Val Tyr Leu Gly Asp Gly Arg Phe His Leu 165 170 175 Glu Ser He Met He His Asn Pro Glu He Glu Ala Phe Gin Tyr Asp 180 185 190 Pro Tyr Ser Arg Lys Leu Thr Arg Glu Phe Tyr Asp His Asp Leu Met 195 200 205 Arg Lys Asn Arg He Gly Ser He Glu He Ala Arg Lys Cys Thr Thr 210 215 220 Phe Gly Leu He Gin Gly Thr Leu Gly Arg Gin Gly Asn Leu Lys Val 225 230 235 240 Val Glu Glu Leu Glu Ala Gin Leu Glu Arg Lys Gly Lys Lys Phe Leu 245 250 255 Arg Val Leu Leu Ser Glu He Phe Pro Glu Lys Leu Ala Met Phe Pro 260 265 270 Glu Val Asp Cys Trp Val Gin Val Ala Cys Pro Arg Leu Ser He Asp 275 280 285 Trp Gly Thr Gin Phe Pro Lys Pro Leu Leu Tyr Pro Phe Glu Leu Ala 290 295 300 Val Ala Leu Asp Asn Val Ser Phe Lys Phe Arg Cys Leu Gin He Thr 305 310 315 320 Gly Gin Trp Thr He He Arg Met He Pro Trp Val Leu Gly Arg He 325 330 335 He Met Lys Arg Thr Val Arg Asn Gly Arg Asn Gly Asn Leu He Leu 340 345 350 Leu Ser Lys Pro Lys He His Ser Arg Glu Leu Ser Tyr Phe Asn Glu 355 360 365 Glu Lys Ala Lys Arg He Gly Glu Arg Phe Glu Gly Gly Lys Leu Ala 370 375 380 Lys Lys Val His Lys Ser He Glu Gin Leu Lys Arg His Asp Pro Asp 385 390 395 400 Trp Gin He Ser Thr Glu Pro Thr Lys Tyr Leu Leu Val Ser Asn Ser 405 410 415 Ser lie Leu Cys Gly Val Ser Leu Glu Glu Leu Glu Glu He Phe Leu 420 425 430 Pro Leu Asp Glu Leu Ala Glu Phe He Val Tyr Pro Asn Lys Arg Ser 435 440 445 Tyr Ser Phe Val Gin Cys Ser Ser He Glu Lys Ser He Gin Val Arg 450 455 460 Tyr Glu Leu His Gly Leu He Pro Pro Ser Leu Lys Asn Ser His Gin 465 470 475 480 Pro Phe Ala He Ser Tyr Val Glu Asn Leu Pro Glu Ala Thr Lys Cys 485 490 495 Glu Asp Phe Arg Pro Ala Asn Leu Lys He He Glu Glu Tyr Val Ser 500 505 510 Ser Asp Leu Glu Lys Glu Leu Val Asp Leu Val Thr Asn His Pro Ser 515 520 525 Val Gin Ser Leu Lys His Arg Ala Val Val His Phe Gly His Val Phe 530 535 540 Asp Tyr Ser Thr Asn Ser Ala Ser Glu Trp Lys Glu Ala Asp Pro He 545 550 555 560 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: CGCCCCTATC TCCTCCTTTA 2 (2) INFORMATION FOR SEQ ID NO: : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: TGGTCCTGTC CCTAACTTGG 20 (2) INFORMATION FOR SEQ ID NO:8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: CATCTCAATC TGGCTTCAGC 20 (2) INFORMATION FOR SEQ ID NO:9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (Xi) SEQUENCE DESCRIPTION: SEQ ID NO:9; AACCCCAGCT CAATGATCAC 20 (2) INFORMATION FOR SEQ ID NO: 10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 19 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10: CTAGCCCTCC ACCTCTCAT (2) INFORMATION FOR SEQ ID NO:11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11: AGCCTGGCTC ACCCTCCT (2) INFORMATION FOR SEQ ID NO: 12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12: AGGGTGGGTC TCTCCTAC (2) INFORMATION FOR SEQ ID NO: 13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: ATGGGGAAGA TGAATGTG 18 (2) INFORMATION FOR SEQ ID NO: 14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 14: CCTCTGCTGC TCCTACCT 18 (2) INFORMATION FOR SEQ ID NO: 15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 15: TGTCCACCCT ACAGGAGG 18 (2) INFORMATION FOR SEQ ID NO:16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 21 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16: CTCTCCTGCC CCAGCCGTTG G 21 (2) INFORMATION FOR SEQ ID NO: 17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 21 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: not relevant (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17: GATGAACCTA AGACTCCCTC C 2 (2) INFORMATION FOR SEQ ID NO: 18: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18: CTTCTGCTGC CCTAAACCAC 2 (2) INFORMATION FOR SEQ ID NO: 19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 19 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19: AGTGGCAGGG AATCTCACC 1 (2) INFORMATION FOR SEQ ID NO:20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 21 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20: CTGAGTCAGG ATCTGTGTGC A 21 (2) INFORMATION FOR SEQ ID NO:21: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21: TGTTCCCAGT CACTTCCCTC 20 (2) INFORMATION FOR SEQ ID NO:22: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iϋ) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: TAGGCCACAG GTTCAGCTTT 20 (2) INFORMATION FOR SEQ ID NO:23: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 19 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) ( ii i ) HYPOTHETICAL : NO ( iv ) ANTI -SENSE : YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: CAGCCTTCAA GACGAGCTG 1 (2) INFORMATION FOR SEQ ID NO:24: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24: CACTGTCACG TTCTTCAGCA 2 (2) INFORMATION FOR SEQ ID NO: 25: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 19 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25: ACCCCACTCC ACTCCAGAC 1 (2) INFORMATION FOR SEQ ID NO:26: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26: ACACTGGCAG ATGTTATTGT CC 22 (2) INFORMATION FOR SEQ ID NO:27: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27: CTCCTCCCTC CTGGAAGC 18 (2) INFORMATION FOR SEQ ID NO:28: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28: GGAGGGAAAC GCAGGGTC 18 (2) INFORMATION FOR SEQ ID NO:29: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: AGGCGTTCCC ATGACAAC 18 (2) INFORMATION FOR SEQ ID NO:30: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 21 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30: GAGGCTGGTG GTTTTCAGAG C 2 (2) INFORMATION FOR SEQ ID NO: 31: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: Single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31: GGGACAGAAA CTAGACACCA AG 2 (2) INFORMATION FOR SEQ ID NO: 32: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 21 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32: GGGTTTATCC TCTTGGTGTC T 2 (2) INFORMATION FOR SEQ ID NO: 33: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 21 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33: CATTTCTTGA TCTTTCACTC T 21 (2) INFORMATION FOR SEQ ID NO:34: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34: TGGACCAGTT TGCAGAGTGA 20 (2) INFORMATION FOR SEQ ID NO: 35: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: not relevant (ii) MOLECULE TYPE: DNA (genomic) (ϋi) HYPOTHETICAL: NO (iv) ANTI-SENSE: YES (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 35: TATGTGGCAG TCACCATCGT 20

Claims: What is claimed is: 1. A recombinant DNA molecule comprising a vector into which is inserted a heterologous DNA segment from human chromosome 17pl3.3, said DNA segment being at least 20 kilobase pairs in length, said segment including locus D17S28 of said chromosome 17pl3.3, said segment comprising a gene, the disruption of which is associated with malignant cell growth. 2. The recombinant DNA molecule of claim 1, wherein said gene is composed of exons that form an open reading frame having a sequence that encodes a polypeptide about 530-550 amino acids in length. 3. The recombinant DNA molecule of claim 2, wherein said open reading frame encodes an amino acid sequence substantially the same as Sequence I.D. No. 2. 4. The recombinant DNA molecule of claim 3, wherein said open reading frame encodes amino acid sequence I.D. No. 2. 5. The recombinant DNA molecule of claim 4, wherein said open reading frame comprises Sequence I.D. No. 1. 6. The recombinant DNA molecule of claim 1, wherein said vector is a cosmid vector. 7. The recombinant DNA molecule of claim 6, which is pWE15/7-2. 8. An oligonucleotide between about 10 and 100 ' nucleotides in length, which specifically hybridizes with a portion of the recombinant DNA molecule of claim 7 comprising the heterologous DNA segment from human chromosome 17pl3.3. 9. The recombinant DNA molecule of claim 1, which comprises, as a portion of said heterologous DNA segment from human chromosome 17pl3.3, a sequence substantially the same as Sequence I.D. No. 3. 10. The recombinant DNA molecule of claim 9, which comprises Sequence I.D. No. 3. 11. An isolated and substantially purified protein, which is a product of expression of the gene of claim 1. 12. An isolated nucleic acid molecule comprising an open reading frame of a gene located on human chromosome 17pl3.3, said gene occupying a segment of said chromosome 17pl3.3 at least 20 kilobase pairs in length that includes locus D17S28. 13. The nucleic acid molecule of claim 12, having a sequence selected from the group consisting of: a) Sequence I.D. No. 1; b) a sequence hybridizing with part or all of Sequence I.D. No. 1 and encoding a polypeptide substantially the same as part or all of a polypeptide encoded by Sequence I.D. No. 1; and c) a sequence encoding part or all of a polypeptide having amino acid Sequence I.D. No. 2. 14. The nucleic acid molecule of claim 12, wherein said sequence is a clone from a fetal brain cDNA library, selected from the group consisting of fb67-l, fb77-l, fb50-l-l, fb52-l-l, fb53-l-l, fb57-l-l, fb63-l-l, " fb69-l-l, fb73-l-l, fb43-l-l, fb43-2-l and fb46-l-l. 15. An oligonucleotide between about 10 and 100 nucleotides in length, which specifically hybridizes with a portion of the nucleic acid molecule of claim 13. 16. A polypeptide produced by expression of an isolated nucleic acid molecule comprising part or all of an open reading frame of a gene located on human chromosome 17pl3.3, said gene occupying a segment of said chromosome 17pl3.3 at least 20 kilobase pairs in length that includes locus D17S28. 17. The polypeptide of claim 16, produce by expression of a sequence selected from the group consisting of: a) Sequence I.D. No. 1; b) a sequence hybridizing with part or all of Sequence I.D. No. 1 and encoding a polypeptide substantially the same as part or all of a polypeptide encoded by Sequence I.D. No. 1; and c) a sequence encoding part or all of a polypeptide having amino acid Sequence I.D. No. 2. 18. The polypeptide of claim 17, having an amino acid sequence substantially the same as part or all of Sequence I.D. No. 2. 19. The polypeptide of claim 18, having the amino acid sequence of part or all of Sequence I.D. No. 2. 20. An antibody im unologically specific for the polypeptide of claim 16. 21. An isolated nucleic acid molecule having a sequence substantially the same as Sequence I.D. No. 1. 22. A polypeptide encoded by the nucleic acid molecule of claim 21. 23. An antibody immunologically specific for the polypeptide of claim 22. 24. An isolated and purified polypeptide having an amino acid sequence substantially the same as Sequence I.D. No. 2. 25. A nucleic acid molecule having a sequence encoding the polypeptide of claim 24. 26. An antibody immunologically specific for the polypeptide of claim 24. 27. An isolated nucleic acid molecule having a sequence substantially the same as Sequence I.D. No. 3.

Inventors: GODWIN ANDREW K, GODWIN, ANDREW, K.
Applicants: FOX CHASE CANCER CENTER, GODWIN ANDREW K, GODWIN, ANDREW, K.
Application year: 1996
Main classification: C07K14
IPC codes: C07K14