InK4c-p18 AND InK4D-p19, INHIBITORS OF CYCLIN-DEPEDENT KINASES CDK4 AND CDK6, AND USES THEREOF

Abstract: Members of the InK4 (<u>In</u>hibitors of CD<u>K4</u>) family inhibit the activities of specific cyclin D-dependent kinases (CDK4 and/or CDK6), thereby arresting cell cycle progression in G1 phase and preventing chromosomal DNA replication. Disclosed herein are novel mammalian InK4 family members, having apparent molecular masses of 18,000 and 19,000 daltons, designated "InK4c-p18" and "InK4d-p19", respectively, or simply "p18" and "p19". In particular, the invention provides p19 genes and proteins isolated from murine or human cells and p18 genes and proteins from murine cells. When constitutively expressed in cells, p19 inhibits cyclin D-dependent kinase activity in vivo and induces G1 phase arrest. Materials and methods disclosed herein include (1) nucleic acids that encode p18 or p19; (2) methods for detecting nucleic acids encoding p18 or p19 proteins; (3) methods for producing p18 or p19 proteins using nucleic acids that encode p18 or p19, respectively; (4) purified p18 or p19 proteins and peptide fragments, oligopeptides, or fusion proteins derived therefrom; (5) methods of inhibiting cells from replicating their chromosomal DNA using purified p18 or p19 proteins or derivatives thereof; (6) antibodies that specifically bind p18 or p19; (7) methods for detecting p18 and p19 proteins; (8) method of stimulating cell growth by blocking p18 or p19 expression via antisense oligonucleotides; (9) methods of gene therapy using nucleic acids that encode p18 or p19; and (10) methods of making transgenic non-human animals that have alterations in the gene encoding p18 or p19, or in both genes.

Description: InK4c-pl8 and InK4d-pl9, Inhibitors of Cyclin-Dependent Kinases CDK4 and CDK6, and Uses Thereof Field of the Invention This invention relates to the regulation of cellular growth, and methods of cancer detection and treatment, involving two related but distinct proteins, the first called "InK4c-pl 8," "pl8INK4c," "pi S 1 ™ 40 ," or simply "P18," and the second called "InK4d-pl9," "pl9INK4d," » p i9 INK*l ," or simply "pl9," that regulate the eukaryotic cell cycle and, when overexpressed, inhibit cells from proceeding past the Gl phase of the cell cycle, i.e., prevent cells from initiating the replication of chromosomal DNA molecules. In particular, materials and methods disclosed herein include (1) nucleic acids that encode pi 8 or pi 9 polypeptide sequences, isolated from mice, humans and other mammals; (2) methods for detecting nucleic acids encoding p 18 or p 19 proteins, or alterations in such nucleic acids; (3) methods for producing proteins having p 18 or p 19 polypeptide sequences using nucleic acids that encode p 18 or p 19, respectively; (4) purified p 18 or pi 9 proteins and peptide fragments, oligopeptides, or fusion proteins derived therefrom; (5) methods of inhibiting cells from replicating their chromosomal DNA using purified pi 8 or pi 9 proteins or derivatives thereof; (6) antibodies that specifically bind pl8 or pl9; (7) methods for detecting pl8 and pl9 proteins; (8) methods of stimulating cell growth by blocking pi 8 or pi 9 expression using antisense oligonucleotides that contain nucleotide sequences complementary to nucleic acids that encode p 18 or p 19 polypeptide sequences; (9) methods of gene therapy using nucleic acids that encode pi 8 or pi 9; and (10) methods of making transgenic non-human animals that have a genetically engineered alteration in the gene encoding p 18 or p 19, or in both genes. Statement as to Rights to Inventions Made Under Federally-Sponsored Research and Development This invention was made with U.S. Government support under grants CA-47064 and CA-20150, awarded by the National Institutes of Health, and Cancer Center CORE grant CA-21765. The U.S. Government has certain rights in this invention. Support for this invention was also provided by the Howard Hughes Medical Institute and the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital. Background of the Invention Neoplasia, the pathological process by which tumors develop, necessarily involves unregulated, or at best misregulated, cellular growth and division. The molecular pathways that regulate cellular growth must inevitably intersect with those that regulate the cell cycle. The cell cycle consists of a cell division phase and the events that occur during the period between successive cell divisions, known as interphase. Interphase is composed of successive Gl, S, and G2 phases, and normally comprises 90% or more of the total cell cycle time. Most cell components are made continuously throughout interphase; it is therefore difficult to define distinct stages in the progression of the growing cell through interphase. One exception is DNA synthesis, since the DNA in the cell nucleus is replicated only during a limited portion of interphase. This period is denoted as the S phase (S = synthesis) of the cell cycle. The other distinct stage of the c cycle is the cell division phase, which includes both nuclear division (mitosis) and the cytoplasmic divisi (cytokinesis) that follows. The entire cell division phase is denoted as the M phase (M = mitotic). T leaves the period between the M phase and the start of DNA synthesis, which is called the Gl phase (G gap), and the period between the completion of DNA synthesis and the next M phase, which is called t G2 phase (Alberts, B. et al., Molecular Biology of the Cell, Garland Publishing, Inc., New York & Lond (1983), pages 611-612.). Progression through different transitions in the eukaryotic cell cycle is positively regulated b family of master enzymes, the cyclin-dependent kinases (reviewed by Sherr, C.J., Cell 73:1059-10 (1993)). These holoenzymes are composed of two proteins, a regulatory subunit (the cyclin), and associated catalytic subunit (the actual cyclin-dependent kinase or CDK), the levels of which vary w different phases of the cell cycle (Peters, G., Nature 577:204-205 (1994)). Both cyclins and CDKs repres molecular families that encompass a variety of genetically related but functionally distinct protei Generally, different types of cyclins are designated by letters (i.e., cyclin A, cyclin B, cyclin D, cyclin etc.); CDKs are distinguished by numbers (CDK1, CDK2, CDK3, CDK4, CDK5, etc.; CDK1 is a.k CDC2). CDK-cyclin D complexes regulate the decision of cells to replicate their chromosomal DNA (She Cell 73:1059-1065 (1993)). As cells enter the cycle from quiescence, the accumulation of CDK-cyclin holoenzymes occurs in response to mitogenic stimulation, with their kinase activities being first detect in mid-Gl phase and increasing as cells approach the Gl/S boundary (Matsushime et al., Mol. Cell. Bi .4:2066-2076 (1994); Meyerson and Harlow, Mol. Cell. Biol. 74:2077-2086 (1994)). The cyclin regulatory subunits are highly labile, and premature withdrawal of growth factors in Gl phase results i rapid decay of CDK-cyclin D activity that correlates with the failure to enter S phase. In contrast, remo of growth factors late in Gl phase, although resulting in a similar collapse of CDK-cyclin D activity, h no effect on further progression through the cell cycle (Matsushime et al., Cell 65:701-713 (1991 Microinjection of antibodies to cyclin DI into fibroblasts during Gl prevents entry into the S phase, injections performed at or after the Gl/S transition are without effect (Baldin et al, Genes & Dev 7:812-821 (1993); Quelle etα/., Genes & Devel 7:1559-1571 (1993)). Therefore, CDK-cyclin D comple execute their critical functions at a late Gl checkpoint, after which cells become independent of mitoge for completion of the cycle. In mammals, cells enter the cell cycle and progress through Gl phase in response to extracellu growth signals which trigger the transcriptional induction of D-type cyclins. The accumulation of D cycli leads to their association with two distinct catalytic partners, CDK4 and CDK6, to form kinase holoenzym Several observations argue for a significant role of the cyclin D-dependent kinases phosphorylating the retinoblastoma protein, pRb, leading to the release of pRB-associated transcripti factors that are necessary to facilitate progression through the Gl - S transition. First, CDK-cyclin D complexes have a distinct substrate preference for pRb but do not phosphorylate the canonical CDK substrate, histone HI (Matsushime et al, Cell 77:323-334 (1992); Matsushime et al, Mol. Cell Biol. 74:2066-2076 (1994); Meyerson and Harlow, Mol. Cell. Biol. 74:2077-2086 (1994)). Their substrate specificity may be mediated in part by the ability of D-type cyclins to bind to pRb directly, an interaction which is facilitated by a Leu-X-Cys-X-Glu pentapeptide that the D cyclins share with DNA oncoproteins that also bind pRb (Dowdy et al, Cell 73:499-511 (1993); Ewen et al, Cell 73:487-497 (1993); Kato et al, Genes & Devel. 7:331-342 (1993)). Second, cells in which pRb function has been disrupted by mutation, deletion, or after transformation by DNA tumor viruses are no longer inhibited from entering S phase by microinjection of antibodies to D cyclin, indicating that they have lost their dependency on the cyclin D- regulated Gl checkpoint (Lukas et al., J. Cell Biol. 725:625-638 (1994); Tarn et al, Oncogene 2663-2674 (1994)). However, introduction of pRb into such cells restores their requirement for cyclin D function (Lukas etal,J. Cell Biol. 725:625-638 (1994)). Third, pRb-negative cells synthesize elevated levels of a 16 kDa polypeptide inhibitor of CDK4, "pl6 ln *" (a.k.a. * 'InK4a-pl6" or simply "pi 6"), which is a member of a recently discovered class of cell cycle regulatory proteins (Nasmyth and Hunt, Nature 366:634-635 (1993); Peters, G., Nature 377:204-205 (1994)). InK4a-pl6 is found in complexes with CDK4 at the expense of D-type cyclins during Gl phase (Bates et al, Oncogene 9:1633-1640 (1994); Serrano et al, Nature 366:704-707 (1993); Xiong et al, Genes & Devel. 7:1572-1583 (1993)). The fact that such cells cycle in the face of apparent CDK4 inhibition again implies that D-type cyclins are dispensable in the Rb- negative setting. A protein related to pl6 is a 15 kDa protein that inhibits both CDK4 and CDK6, "pl5 lnK4b " (a.k.a. "InK4b-pl5" or simply "pl5"), which is induced in human epithelial cells treated by transforming growth factor-β (TGF-β) (Hannon and Beach, Nature 377:257-261 (1994)). Thus, in contradistinction to the positive regulation of D-type cyclin synthesis by growth factors, extracellular inhibitors of Gl progression can negatively regulate the activity of D-type cyclin-dependent kinases by inducing InK4 proteins. Structurally, known InK4 proteins are composed of repeated 32 amino acid ankyrin motifs. Unlike other universal CDK inhibitors, such as p 21 Ci P | w * n (El-Deiry et al, Cell 75:817-825 (1993); Gu et al, Nature 366:707-710 (1993); Harper et al, Cell 75:805-816 (1993); Xiong et al, Nature 366:701-704 (1993)) and p27 Ki ' (Polyak et al, Genes & Devel. 8:9-22 (1994); Polyak et al, Cell 78:59-66 (1994); Toyoshima and Hunter, Cell 78:61-14 ( 1994)), the InK4 proteins selectively inhibit the activities of CDK4 and CDK6, but do not inhibit the activities of other CDKs (Guan et al, Genes & Devel. 5:2939-2952 (1994); Hannon and Beach, Nature 377:257-261 (1994); Serrano et al, Nature 366:704-707 (1993)). RelatedArt Mullis etal, U.S. Patent 4,965,188 (Oct. 23, 1990), describe methods for amplifying nucleic ac sequences using the polymerase chain reaction (PCR). Beach, published PCT patent application W 92/20796 (Nov. 26, 1992), describes genes encoding D cyclins and uses thereof. Berns, U.S. Pate 5,174,986 (Dec. 29, 1992), describes methods for determining the oncogenic potential of chemic compounds using a transgenic mouse predisposed to develop T-cell lymphomas. Crissman et al., U. Patent 5,185,260 (Feb. 9, 1993), describe methods for distinguishing and selectively killing transform (neoplastic) cells using synthetic Gl kinase inhibitors. Guan etal. (Genes & Devel. 5:2939-2952 (1994 describe the isolation of a gene encoding human pi 8, the apparent homolog of mouse pi 8 described herei Summary of the Invention The present invention relates to the discovery in mammalian cells of a novel cell cycle regulatory protein, having an apparent molecular mass of 19 kDa, here designated "InK4 pl9," "pl9 * ," or more simply "pl9". In particular, the invention relates to pl9 isolated from cel derived from a mouse or a human. The present invention also relates to the discovery in mouse cells of a novel cell cycle regulato protein, having an apparent molecular mass of 18 kDa, here designated "InK4c-pl 8," "pi 8 ," or mo simply "pi 8." Mouse pi 8 is the apparent homolog of human pi 8, the gene for which has been isolated a mapped to human chromosome 1 (Guan et al., Genes & Devel. 5:2939-2952 (1994)). The proteins of the invention belong to the InK4 gene family ("InK4" signifies føhibitors ofCDK known to include at least two other low molecular weight polypeptides, InK4a-pl6 and InK4b-pl 5 (Serran M. et al , Nature 366:704-707 (1993); Hannon G.J. and Beach, D., Nature 371 :257-261 ( 1994)). Membe of the InK4 family are typically composed of repeated ankyrin motifs, each of about 32 amino acids length. All known members of the InK4 family act to specifically inhibit enzymatic activities of D-ty cyclin-dependent kinases such as CDK4 and CDK6. Like many CDK inhibitors (CKIs) (Nasmyth and Hu Nature 366:634-635 (1993)), InK4 family members negatively regulate progression through the mammali cell cycle, in part in response to anti-proliferative extracellular signals. The InK4 proteins, by inhibiting t activities of a specific class of the D-type cyclin-dependent kinases (i.e., CDK4 and/or CDK6), arrest ce cycle progression in Gl phase and thus prevent cells from replicating their chromosomal DNA. InK4d-pl is periodically expressed during the cell cycle, being maximally induced as cells enter S phas Significantly, when constitutively expressed in mouse NIH-3T3 fibroblasts, pi 9 inhibits cyclin D-depende kinase activity in vivo and induces Gl phase arrest. One aspect of the invention is directed to methods of using the proteins of the invention to inhibit the growth of cancer cells and/or to prevent cancer cells from replicating their chromosomal DNA. Both InK4-pl6 and InK4-pl5 appear to act as tumor suppressors (Noburi, T. et al, Nature 365:753-756 (1994); Kamb, A. et al, Science 264:436-440 (1994)). The genes encoding pi 6 and pi 5 map in a tandem array to the short arm of human chromosome 9 within a region that is frequently deleted in cancer cells, and the resulting loss of their anti-proliferative functions can contribute to tumorigenesis (Noburi et al., Nature 365:753-756 (1994)). As members of the InK4 gene family, pl8 and pl9 have similar properties, namely, (1) they play a role in preventing the Gl - S phase transition in normal mammalian cells; (2) synthesis of pi 8 or pl9 is induced by particular anti-mitogenic compounds that arrest cells in Gl phase; (3) and deletion of the gene encoding pi 8 or pi 9, in subverting the possibility of such control, contributes to oncogenesis in some cancers. In another aspect, the invention provides nucleic acid sequences encoding pi 9 polypeptides from mice, humans and other mammals, and pi 8 polypeptides from non-human mammals. The nucleic acid sequences of the invention may be expressed in the form of isolated nucleic acids, such as cDNA clones, genomic DNA clones, mRNA transcribed from either cDNA or genomic DNA clones, synthetic oligonucleotides, and/or synthetic amplification products resulting from PCR, and may be single-stranded or double-stranded. In a related aspect, the invention provides methods for detecting nucleic acids encoding pi 8 or pi 9 using the nucleic acid sequences of the invention described above. The detection of deletions of, or other mutations in, the genes encoding p 18 or p 19 is predicative of a predisposition to, or diagnostic of, certain types of cancer. In another related aspect, the DNA molecules of the invention described above may be cloned into expression vectors and placed in an appropriate host in order to produce pi 8 or pi 9 proteins or fusion proteins containing pi 8 or p 19 polypeptide sequences. When placed in an animal that has cancer, this aspect of the invention relates to gene therapy for certain types of cancers. In another related aspect, the invention provides methods of stimulating cell growth by blocking pi 8 or pi 9 expression using antisense oligonucleotides that contain nucleotide sequences complementary to nucleic acids that encode pi 8 or pi 9 polypeptide sequences. These methods are used to stimulate cells, particularly hematopoietic stem cells, to replicate their chromosomal DNAs and to enter a proliferative state. In another aspect, the invention provides antibody compositions that bind specifically to p 18 or p 19 proteins. The antibody compositions of the invention may be polyclonal, monoclonal, or monospecific. The antibody compositions of the invention bind specifical ly to p 18 or p 19, or to fusion proteins or oligopeptides containing pi 8 or pi 9 polypeptide sequences. In a related aspect, the invention provides methods for detecting pi 8 or pl9 proteins using t antibody compositions described above. The detection of reduced amounts of, or altered forms of, pi 8 pl9 proteins is predicative of a predisposition to, or diagnostic of, certain types of cancer. In another aspect, the invention provides transgenic non-human animals that have at least o mutation in the gene(s) encoding pl8, pl9, or both pl8 and pl9. Because of the transgenic mutation introduced into the genome of the non-human animal, the animal has reduced levels of pi 8 and/or p activity compared to wild-type animals, and consequentially develops certain types of cancers in reproducible and thus predictable manner. In a related aspect, compositions are evaluated for their potential to stimulate or inhibit certain typ of cancers using the transgenic non-human animals of the invention. Brief Description of the Figures Figure 1 shows the amino acid sequences of mouse InK4c-pl8 (SEQ ID NO:l) and mouse InK4 pl9 (SEQ ID NO:2) aligned with human InK4a-pl6. In Panel A, the predicted amino acid sequences mouse pi 8 and human InK4a-pl6 are aligned (using the Intelligenetics FAST DB computer program) wi that of mouse pl9. The limits of the five ankyrin repeats are indicated by the arrows below the align sequences. In Panel B, Ankyrin repeats 1-3 of human pi 6 and of mouse pi 8 and pi 9 are shown as align with each other by visual inspection. Sequences shared between at least two of three repeats within the sa protein (e.g., between repeats 1 and 2 of pi 6) are indicated by bold type face, whereas sequences shared cognate repeats in at least one of the two homologous proteins (e.g., by repeats 1 in pl9 and pi 8) demarcated by double underlines. Nucleotide sequences of the cDNAs for mouse lnK4d-pl9 (SEQ NO:6) and mouse InK4c-pl 8 (SEQ ID NO:4) will be accessible from GENBANK under accession numb U 19597 and U 19596, respectively, after May 1, 1995. Figure 2 displays results demonstrating the binding of mouse pl9 to the cdk4 and cdkό ge products. Panel A is an autoradiograph of aliquots of the 35 S-methionine-labeled products, derived from t in vitro transcription and translation of plasmids containing cDNA coding sequences of the cdc or cdk ge indicated in the legend below lanes 1-6, separated by electrophoresis on denaturing polyacrylamide ge Equal aliquots of the "input" samples shown in lanes 1-6 were incubated with control beads (lanes 7-1 (i.e., GST-Sepharose; GST = glutathione S-transferase) or with beads containing a GST-pl9 fusion prote (lanes 13-18), after which the beads were washed, and adsorbed radiolabeled products were separated gels and autoradiographed. In Panel B, the experiments were performed as in panel A, except t radiolabeled cyclins D2 and D3 were substituted for cdk gene products; the cdk4 gene product was used a positive control. All autoradiographic exposure times were 15 hrs. Figure 3 presents results demonstrating that pl9 and pl8 inhibit the pRb kinase activities of CD cyclin D and CDK6-cyclin D. Active holoenzyme complexes composed of CDK4-cyclin D2 (panels A a C) and CDK6-cyclin D2 (panels B and D) were produced in insect Sf9 cells coinfected with the appropriate vectors (Kato et al, Genes __ Devel. 7:331-342 (1993)). Sf9 extracts infected with a wild-type baculovirus were used as controls for background kinase activity (lane 1 (mock) in all panels)). GST fusion proteins containing the complete coding sequences of mouse pi 9, mouse pi 8 or human pi 6 were purified and eluted from glutathione-Sepharose beads, and the amounts of protein (ng) indicated above each lane were added to fixed quantities of Sf9 lysates containing the indicated enzymes. The extracts were then assayed for pRb kinase activity as described (Kato et al, Genes & Devel. 7:331-342 (1993)) and the products resolved on denaturing gels. Panels C and D include similar experiments using GST proteins containing either mouse IκB (MAD3) (lanes 9 and 10) or a subdomain of the protein (amino acids 73-242) containing its ankyrin repeats (lanes 11 and 12). The autoradiographic exposure times were 15 hrs. Figure 4 shows results that demonstrate that pl9 specifically inhibits cyclin D-dependent kinases. Insect extracts containing the holoenzymes indicated below each panel or those derived from cells infected with a wild-type baculovirus (mock, lane 1 in each panel) were incubated with the amounts of purified GST- pl9 protein indicated at the tops of both panels. The extracts were then assayed for pRb kinase activity (Panel A) or for histone HI kinase activity (Panel B), and the products of the reactions were resolved on denaturing gels. Exposure times were 15 hrs (Panel A) and 4 hrs (Panel B). Figure 5 shows binding of pi 9 to the CDK4-cyclin D2 complex and inhibition of pRb kinase activity. Insect cells infected with a baculovirus encoding CDK4 (lanes 1 and 2), co-infected with vectors encoding both CDK4 and cyclin D2 (lanes 3, 4, 6-10), or mock infected with a wild-type baculovirus (lane 5) were metabolically labeled for the final 8 hrs of infection with 35 S-methionine. Lysates containing radiolabeled cdk4 and cyclin D2 were distributed into equal aliquots, and purified pl9 protein (0.3 ug) was added to two of the indicated extracts (lanes 9 and 10). Extracts were precipitated with nonimmune rabbit serum (NRS) or with the indicated antisera to cyclin D2 or CDK4. The immune complexes resolved in lanes 1-4 were separated directly on denaturing gels to quantify the recovery of radiolabeled cyclin D2 and CDK4, whose electrophoretic mobilities are indicated at the right of the panel. The remaining immune complexes were used to assay precipitated pRb kinase activity, after which the reaction products were separated similar¬ ly. The position of 32 P-labeled pRb is also indicated in the right margin. The autoradiographic exposure time was 15 hrs. Figure 6 shows the expression of pl9 and pi 8 mRNAs in cell lines and mouse tissues. Total cellular RNA was extracted from the indicated cell lines (panel A) or mouse tissues (panel B), electrophoretically separated on agarose gels containing formamide (10 ug/lane), transferred to nitrocellulose, and hybridized with the indicated 3 P-labeled cDNA probes. Autoradiographic exposure times were 5 days (pi 9), 12 days (pl8) and 2 days (G6PD). Figure 7 shows the expression of pi 9 and different cyclins during the macrophage cell cycle. BAC1.2F5 macrophages arrested in early Gl phase by CSF-1 starvation for 18 hrs were restimulated with CSF-1 to enter the cell cycle synchronously. Total RNA extracted from cells at the indicated times in hrs (Panel A) were subjected to Northern blotting analysis using the probes indicated at the left margin. The different cell cycle phases were determined by flow cytometric analysis of cellular DNA content (Panel B). The cells lost synchrony as they progressed into the second cell cycle, and their second Gl phase was shorter than the first (Matsushime et al. , Cell 65:701 -713 ( 1991 )). The concentration of p 19 mRNA, as quantitated with a phosphoimager, is shown in Panel C. Exposure times for the Northern blots were 6 days for pi 9, 8 days for pi 8, 2 days for cyclins Dl and A, and 1 day for G6PD mRNA. Figure 8 shows pl9 protein expression. In Panel A, NIH-3T3 fibroblasts (lanes 1-3) and BAC 1.2F5 macrophages (lanes 4 and 5) were metabolically labeled with 3S S-methionine for 1 hour, cell lysates immunoprecipitated with antiserum directed to a synthetic peptide based on the p 19 C-terminus and resolved on denaturing gels. No pi 9 was detected after competition with the cognate peptide (lanes 2 and 5), whereas an unrelated peptide had no competitive effect (lane 3). In Panel B, lysates of BAC 1.2F5 macrophages were immunoprecipitated with nonimmune rabbit serum (NRS, lane 1), antiserum to the pi 9 C-terminus (lane 2), and antiserum to CDK4 (lane 3), separated on denaturing gels, transferred to nitrocellulose and immunoblotted with antiserum to CDK4. In Panel C, CSF-1 starved macrophages stimulated to synchronously reenter cycle (as in Figure 7) were pulse labeled for 1 hour at the indicated times in hours (top) with 35 S-methionine, and precipitates prepared with antiserum to the pl9 C-terminus were separated on denaturing gels. Panel D shows the rate of synthesis of pl9 throughout the cell cycle, as determined by phosphoimaging analysis of the data shown in Panel C. Exposure times were 5, 2, and 4 days for Panels A, B, and C, respectively. Figure 9 displays results from experiments that demonstrate that vector-mediated pl9 expression induces G 1 phase arrest. NIH-3T3 cells transfected with a vector encoding both p 19 and CD8 were analyzed 48 hours later for CD8 fluorescence and DNA content (Panel A). Cells yielding a fluorescence profile equivalent to those obtained with CD8-negative fibroblasts (box Rl) and those expressing the highest level of CD8 antigen (box R2) were separately gated and analyzed for DNA content (Panel B). In panel C, immunoprecipitates from NIH-3T3 fibroblasts infected with a control CD8 vector or a vector containing pi 9 (as indicated at the bottom of the panel) were analyzed 48 hours later for pRb kinase activity. Immune complexes were obtained with normal rabbit serum (NRS), monoclonal antibody (D1-72-13G) to cyclin Dl (Dl), antiserum to the cdk4 C-terminus (CDK4), or antiserum to CDK4 plus competing cognate peptide (CDK4+P), as indicated at the top of the panel. Precipitates were prepared from cells engineered to overexpress cyclin Dl (3T3-D1, lanes 1-8) or from parental NIH-3T3 cells (3T3, lanes 9-11). To obtain matched autoradiographic signals, lysates were prepared from l/8th the number 3T3-D1 cells versus parental cells. The exposure time was 8 hrs. Figure 10 shows the cDNA nucleotide and predicted amino acid sequences of human InK4d-pl9 (Panel A) and the alignment of the polypeptide sequences of InK4 proteins: human pi 9 (Hu-P19), mouse pl9 (Mu-P19), human pl8 (Hu-P18), human pl6 (Hu-P16) and human pl5 (Hu-P15) (Panel B). Figure 11 shows the expression pattern of human INK4d-pl9. Northern blots were prepared using the indicated human adult and fetal tissues. Two μg of poly(A)+ RNA were electrophoretically separated on agarose gels containing formaldehyde, transferred to nylon, and hybridized with 3l P-labeled InK4d-pl9 cDNA probe (pl9 Λ4d ). Filters were then stripped and rehybridized with a β-actin probe ("actin") to assess the amount of RNA per lane. Autoradiographic exposure times were 18 hrs for pi 9, and 8 hrs for actin. Figure 12 shows the expression of pi 9 during the cell cycle in the human cervical carcinoma cell lineHeLa. Human HeLa cells were arrested in mitosis by a sequential thymidine/nocodazole block. Mitotic cells were then harvested by mechanical release and re-seeded into culture dishes in the presence of complete medium containing 10% FCS. Total cellular RNA was extracted from cells at the indicated times and subjected to Northern blot analysis using either the pi 9 (top panel) or β-actin probes (middle panel). The different cell cycle phases were determined by flow cytometric analysis of cellular DNA content (bottom panel). The membrane was visualized using a Molecular Dynamics Phosphoimager 400A for either 6 hrs (pi 9 or 1 hr (β-actin). Figure 13 shows the expression of pi 9 during Fas mediated apoptosis. Expression of pl9 was examined using human CEM-C7 immature T cells treated with a Fas monoclonal antibody (Fas Ab). Human CEM-C7 cells were grown at a density of 2 X 10 6 cells per ml and treated with a Fas Ab at 100 ng/ml. Equivalent numbers of cells (2 X 10 7 ) were collected at various times after Ab treatment and used for RNA and DNA isolation. In panel A, DNA was analyzed by electrophoresis on 2% agarose- TBE gels containing ethidium bromide and visualized under ultraviolet light. The characteristic DNA ladder is apparent approximately 2 hrs post-Ab treatment. In panel B, total RNA extracted from untreated and Fas Ab-treated CEM-C7 cells was probed with the human pi 9 cDNA probe (left panel). The time post Fas Ab treatment is shown below each lane. The same RNA gel is shown visualized by ethidium bromide, with 18S and 28S NRAs marked (right panel). The Northern blot was visualized using a Molecular Dynamics Phosphoimager 400A for 6 hrs. Figure 14 shows the results of fluorescent in situ hybridization (FISH) of human chromosomes using a genomic PI phage clone of human pl9 sequences as a probe. Detailed Description of the Disclosure Terms and Symbols Throughout the disclosure, abbreviations for amino acid and nucleotide residues present in, respectively, polypeptide and nucleic acid sequences, are as described in 37 C.F.R. § 1.822, revised as of July 1, 1994. The following additional abbreviations and definitions are used herein unless otherwise indicated. Glossary Amino acid sequence: The sequence of a polypeptide given in the order of from amino terminal (N- terminal), to carboxyl terminal (C-terminal). Synonymous with "polypeptide sequence," "peptide sequence," "protein sequence," or "primary protein sequence." Animal: (1) Excludes human beings, individually and collectively, in all stages of development, including embryonic and fetal stages, unless otherwise indicated; and (2) includes all other vertebrate animals, including an individual animal in any stage of development, including embryonic and fetal stages. "Non-human animal" has the same meaning as "animal." Animal model: A non-human animal that faithfully mimics a human disease and in which potential therapeutic compositions or potentially harmful compositions may be evaluated for their effect on the disease. Antibody: A protein molecule synthesized by a B-cell upon exposure to antigen capable of combining specifically with that antigen. Synonymous with immunoglobulin (Ig). Antibody, polyclonal: A composition that comprises an assortment of different antibodies that all recognize a particular antigen. Antibody, monoclonal: A unique, isolated antibody molecule produced by a hybridoma. Antibody, monospecific: A polyclonal antibody produced in immunological response to a single or few epitopes found in (1) a short, isolated, synthetic antigen or (2) a short, isolated, carrier-bound hapten. Antigen: A molecule or composition of matter which (1) induces an immune response in an animal, and (2) interacts specifically with antigen-recognizing components of an immune animal's immune system. Carrier: A molecule required in combination with a hapten in order for an immune response to the hapten to occur. That is, a molecule which puts a hapten in a molecular context in which the hapten has enhanced immunogenicity. Detectable label: A chemical moiety that is coupled to a biomolecule to enable detection of the biomolecule and which may be selected from the group consisting of a radiolabel, an enzyme such as horseradish peroxidase or alkaline phosphatase, streptavidin, biotin, an epitope recognized by an antibody, and equivalents thereof. Detectably labelled: A state of a biomolecule in which the biomolecule has covalently attached to it a detectable label. Disease: (1) Excludes pregnancy per se but not autoimmune and other diseases associated with pregnancy; (2) includes any abnormal condition of an organism or part, especially as a consequence of infection, inherent weakness, environmental stress, that impairs normal physiological functioning; and (3) includes cancers and tumors. DNA sequence: The sequence of contiguous nucleotide bases of a strand of DNA as read from 5' to 3'. Synonymous with "DNA molecule." Enzyme: Protein that is a catalyst for a specific chemical reaction, often one involving one or more biomolecules as substrates and/or products. Unlike non-biologically derived catalysts, enzymes may recognize a substrate with stereospecificity, i.e., some enzymes are capable of recognizing, and thus catalyzing the chemical reaction of, only one of a pair of L- and D-enantiomers. Epitope: A part of an antigen that interacts specifically with antigen-recognizing components of an animal's immune system. In a polypeptidic antigen, epitopes may correspond to short sequences of contiguous amino acids; the remainder of the antigen is called the carrier. Synonymous with antigenic determinant. Expression vector: An artificial DNA sequence or a naturally-occurring DNA sequence that has been artificially modified, into which foreign or abnormal genes can be inserted for expression thereof in host organisms appropriate for the vector. Foreign or abnormal: Not endogenous to a healthy, wild-type organism. "Foreign or abnormal genes" designates nucleic acid sequences that are not endogenous to an organism's genome, or originally endogenous nucleic acid sequences that have been rearranged, mutated, or otherwise genetically engineered so as to possess properties (i.e., genomic location, regulation of expression, copy number, etc.) not possessed by the endogenous nucleic acid sequences from which they were derived. Gene: A DNA sequence that consists of a structural gene, e.g., a reading frame that encodes a polypeptide sequence, according to the standard genetic code; and expression elements, e.g., promoters, terminators, enhancers, etc., required for transcription of the structural gene. Genetically engineered: Subject to human manipulation intended to introduce genetic change. Hapten: A small molecule which (1) cannot, by itself, induce an immune response in an animal, (2) can, in combination to a carrier to which it is bound, induce an immune response in an animal, and (3) interacts specifically with the antigen-recognizing components of an immune animal's immune system. Host animal: An animal that harbors foreign and or abnormal genes introduced as a result of (1) invasion of cells of the animal by a naturally occurring or genetically engineered intracellular parasite; or (2) introduction into cells of foreign or abnormal genes by human manipulation. Immune animal: An animal which has been presented with an immunizing amount of antigen and has generated a humoral and/or cell-mediated immune response thereto. Mammal: (1) Excludes human beings, individually and collectively, in all stages of development, including embryonic and fetal stages, unless otherwise indicated; and (2) includes all other animals that are members of the vertebrae class Mammalia, including an individual animal in any stage of development, including embryonic and fetal stages, wherein members of the class are distinguished by self-regulating body temperature, hair, and, in the females, milk-producing mammae. Microorganism: A single-celled organism (e.g., a bacterium) or an intracellular parasite (e.g., a rickettsia or a virus); includes both "live" and "attenuated" microorganisms. Polypeptide: A polymer of amino acid residues. Protein: A biomolecule comprising one or more polypeptides arranged into a functional, three- dimensional form. Restriction endonuclease: An endonuclease that cleaves DNA at each occurrence therein of a specific recognition sequence. Synonymous with "restriction enzyme." Transgene: A gene that does not occur naturally in an animal, i.e., a foreign or abnormal gene, introduced into an animal by nonnatural means, i.e., by human manipulation. Transgenic animal: An animal into which has been introduced, by nonnatural means, i.e., by human manipulation, one or more transgenes. Detailed Description of the Preferred Embodiments In its broadest form, the invention comprises two novel mammalian protein members of the InK4 family, known as "InK4c-pl8" (a.k.a. "pl8") and "InK4d-pl9" (a.k.a. "pl9"), that regulate the cell cycle by inhibiting cyclin-dependent kinases such as CDK4; nucleic acid molecules having sequences encoding polypeptide sequences of pl8 and pl9; antibodies specific for pl8 or pl9 polypeptide sequences; transgenic non-human animals with alterations in the gene(s) encoding pi 8, pl9, or both pi 8 and pl9; methods of making plδ and pl9 nucleic acids and polypeptides; methods of making pi 8- or pl9-specifϊc antibodies; methods of making transgenic non-human animals with alterations in the gene(s) encoding pi 8, pi 9, or both pi 8 and pl9; and methods of using the nucleic acids, proteins, antibodies and transgenic animals of the invention to detect pi 8 and pi 9 nucleic acids or proteins in a sample, to diagnose cancers or predispositions thereto, to evaluate compositions for their therapeutic or oncogenic potential, and to prepare therapeutic compositions for the treatment of tumors and cancers. Nucleic Acids and Related Embodiments In one embodiment, the invention comprises nucleic acids having sequences encoding mouse pi 9, human pi 9 and pi 9 polypeptides from other mammals. For example, the invention provides cDNA molecules encoding mouse pl9 (SEQ ID NO:6) and human p!9 (SEQ ID NO:7). The pl9 cDNAs of the invention are in turn used to isolate additional nucleic acids that encode pi 9 polypeptide sequences, such as mouse and human genomic DNA clones. Moreover, because the homology between the nucleotide sequences of mouse and human pl9 genes is quite high, the mouse and human nucleic acids may be used to design probes or degenerate primers for PCR in order to isolate cDNA and genomic clones of pi 9 genes from other mammals. In a parallel embodiment, the invention comprises nucleic acid sequences encoding mouse pi 8 and pi 8 polypeptides from other non-human mammals. For example, the invention provides cDNA molecules encoding mouse pi 8 (SEQ ID NO:4). The pi 8 nucleic acids of the invention are in turn used to isolate additional nucleic acids that encode pi 8 polypeptide sequences, such as mouse genomic DNA clones, and cDNA and genomic clones from other mammals. A nucleic acid encoding human pi 8 has recently been described by Guan et al. (Genes & Develop. 5:2939-2952 (1994)). One skilled in the art can readily adapt the nucleic acid sequences of the invention to any system which is capable of producing nucleic acids to produce the nucleic acids of the invention. The nucleic acids of the invention, which may optionally comprise a detectable label, may be prepared as cDNA clones, genomic clones, RNA transcribed from either cDNA or genomic clones, synthetic oligonucleotides, and/or synthetic amplification products resulting, e.g., from PCR. The nucleic acids of the invention may be prepared in either single- or double-stranded form. Methods of preparing cDNA clones are known in the art (see, for example, Chapter 8 in Sam brook et al., Molecular Cloning: A Laboratory Manual, Vol. 2, 2d. Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1989), pages 8.1-8.86). Methods of analyzing genomic DNA sequences and preparing genomic clones are known in the art (see, for example, Chapter 9 in Sambrook et al., Molecular Cloning: A Laboratory Manual, Vol. 2, 2d. Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1989), pages 9.1-9.62; and Chapter 2 in Current Protocols in Molecular Biology, Vol. 1, Ausubel et al, eds., John Wiley & Sons, Inc., Boston, MA (1994), pages 2.1.1-2.14.8). Genomic DNA sequences, i.e., chromosomal ly-derived nucleic acids, are isolated (see Example 9) from mice and other non-human animals and used for the production of transgenic non-human animals. RNA containing pi 8 or pl9 sequences may be prepared from cells expressing pi 8 or pl9, respectively, according to methods known in the art (see, e.g., Chapter 4 in Current Protocols in Molecular Biology, Vol. 1, Ausubel et al., eds., John Wiley & Sons, Inc., Boston, MA (1994), pages 4.1.1-4.10.11), or may be generated by in vitro transcription using the DNA molecules of the invention (see, e.g., Chapter 10 in Sambrook et al., Molecular Cloning: A Laboratory Manual, Vol. 2, 2d. Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY ( 1989), pages 10.1- 10.70). Synthetic oligonucleotides having pi 8 or pl9 nucleotide sequences can be prepared using the nucleic acid sequences of the invention by known methods (see, e.g., Chapter 1 1 in Sambrook et al, Molecular Cloning: A Laboratory Manual, Vol. 2, 2d. Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1989), pages 1 1.1-11.61). When used as primers in the polymerase chain reaction (PCR), the synthetic oligonucleotides preferably contain from about 15 to about 30 contiguous nucleotides exactly corresponding to the pi 8 or pi 9 of the invention, but may optionally contain additional nucleotides 5' therefrom (Innis, M.A. and Gelfand, D.H., Chapter 1 in PCR Protocols: A Guide to Methods and Applications, Innis et al., eds., Academic Press, Inc., New York (1990), pages 3-12; Saiki, R.K., Chapter 2 in PCR Protocols: A Guide to Methods and Applications, Innis et al, eds., Academic Press, Inc., New York (1990), pages 13-20). Synthetic amplification products are prepared using the synthetic oligonucleotides of the invention in amplification systems such as PCR (see, e.g., U.S. Patent 4,965,188 to Mullis et al. (Oct. 23, 1990); Scharf, S.J., Chapter 11 in PCR Protocols: A Guide to Methods and Applications, Innis et al, eds., Academic Press, Inc., New York (1990), pages 84-98; Chapter 15 in Current Protocols in Molecular Biology, Vol. 2, Ausubel et al, eds., John Wiley & Sons, Inc., Boston, MA ( 1994), pages 15.0.1-15.8.8; and Chapter 14 in Sambrook et al, Molecular Cloning: A Laboratory Manual, Vol. 2, 2d. Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1989), pages 14.1-14.35). Those of skill in the art will appreciate that chemical derivatives of nucleotide structures can be substituted for natural nucleotides in the nucleic acids of the invention. Methods of making proteins: In one aspect of this embodiment of the invention, the nucleic acids of the invention are used to prepare pi 8 or pi 9 proteins, or fusion proteins derived from pi 8 or pi 9, via recombinant DNA technology. By inserting any of the nucleic acids of the invention that encode pi 8 or pi 9 polypeptide sequences into an appropriate expression vector, and introducing the resultant expression vector construct into appropriate host cells, those skilled in the art can produce large quantities of pi 8 or pi 9 polypeptides. There are numerous host/expression vector systems available for the generation of proteins from the isolated nucleic acids of the invention. These include, but are not limited to, bacteria/plasmid systems, bacteria/phage systems, eukaryotic cell/plasmid systems, eukaryotic cell/virus systems, and the like (see, for example, U.S. Patent 4,440,859 to Rutter et al. (Apr. 3, 1984); Chapter 16 in Current Protocols in Molecular Biology, Vol.2, Ausubel et al., eds., John Wiley & Sons, Inc., Boston, MA (1994), pages 16.0.5- 16.20.16; and Sambrook et al, Molecular Cloning: A Laboratory Manual, Vol. 3, 2d. Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1989)). One skilled in the art can readily adapt the nucleic acids of the invention to any host/expression vector system which is capable of propagating and expressing heterologous nucleic acids to produce the proteins or polypeptides of the invention. Preferred host/expression systems include bacteria/plasmid systems and insect cell/baculoviral expression vector systems. Diagnostic methods and kits: In another aspect of this embodiment, pi 8 and pi 9 nucleic acid sequences are used to prepare oligonucleotide probes, or PCR primers, to serve as materials for diagnostic tests for plδ or pl9 expression, mutation, or deletion in samples of cells isolated from mammals. Deletions of the genes encoding pi 5 and pi 6 occur frequently in cancer cells, and the resulting loss of their anti- proliferative functions can contribute to tumorigenesis (Noburi et al, Nature 365:753-756 (1994) Similarly, deletions or other mutations in the genes encoding pi 8 and pl9 are diagnostic of cancer indicative of a predisposition to develop certain types of cancers. Mutations in the human gene for pl9 are detected by any of a variety of methods depending in pa on the nature of the mutation of interest. Deletions and insertions of about 100 base pairs (bp) or more a detected by electrophoretic separation of genomic DNA and hybridization analysis using nucleic acid prob preferably derived from the nucleotide sequence of the human pi 9 coding sequence (SEQ ID NO: 8), or b PCR of genomic DNA using synthetic oligonucleotides derived from the nucleotide sequence of the huma pl9 coding sequence as primers (e.g., SEQ ID NOS:14 and 15). In one aspect, the invention comprises a method of detecting the presence of a nucleic aci polymorphism associated with a predisposition to develop cancer by analyzing DNA or RNA from mammal using nucleic acid molecules containing nucleotide sequences from a pi 9 gene from a mamma such as a mouse or a human, or the reverse complement thereof. In a parallel aspect, the inventio comprises a method of detecting the presence of a DNA polymorphism associated with a predisposition t develop cancer by analyzing DNA or RNA from a non-human mammal using nucleic acid molecul containing nucleotide sequences from a pi 8 gene from a non-human mammal, such as a mouse, or th reverse complement thereof. Both methods are used in conjunction with any procedure which will dete the nucleic acids of the invention. Examples of such procedures include hybridization analysis using th nucleic acids of the invention, i.e., isolation of nucleic acids from the cells of a mammal, followed b restriction digestion, separation by a means such as gel electrophoresis, transfer to nitrocellulose or comparable material, and detection of pi 8 or pi 9 nucleic acid sequences thereon by exposure to detectabl labeled nucleic acid probes which contain nucleotide sequences encoding pi 8 or pl9 polypeptide sequence The detection procedures are chosen such that they are capable of identifying a polymorphism present withi the gene for pi 8 (InK4c) in a non-human mammal, or for a polymorphism pl9, InK4d, in a mammal. I particular, polymoφhisms of human InKAd, located on human chromosome 19, are detected by the metho of the invention. In one embodiment of the present invention, the preferred method of detecting the presence of DNA polymoφhism associated with a predisposition to develop cancer involves RFLP (restriction fragme length polymoφhism) techniques based on amplification of pi 9 sequences via PCR, followed by restrictio digestion and agarose gel electrophoresis. In this method, a biological sample containing nucleated cell preferably leukocytes, is obtained from a human. Suitable biological samples having nucleated cells th may be used in this invention include, but are not limited to, blood and tissue. The method of obtaining th biological sample will vary depending upon the nature of the sample. By the term "nucleated cells" is mea any cell containing a nucleus. Examples of such cells include, but are not limited to, white blood cell epithelial cells, or mesenchymal cells. The cells are then isolated from the sample and the DNA from t nucleated cells is purified using conventional methods known in the art such as phenol-chloroform extraction, lytic enzymes, chemical solutions and centrifugation, or size exclusion chromatography (see, for example, Blin and Stafford, Nucl. Acid Res. 3:2303-2308 (1976); Maniatis, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York (1982)). Following isolation, the DNA sequences of interest are amplified using conventional PCR methods (see, for example, Innis et al, PCR Protocols, Academic Press, NY (1990); Mullis et al, Cold Spring Harbor Symp. Quant. Biol. 57:263-273 (1986); Mullis and Faloona, Methods Enzymol 755:335-350 (1987); and Mullis et al, U.S. Patent 4,965,188 (Oct. 23, 1990)). In one aspect of this embodiment, sequences flanking the coding sequences for pi 9 in InK4daτe utilized as primers for sequence amplification. In this aspect, the 5' primer is preferably from base 239 to base 263 of the human pi 9 DNA sequence (SEQ ID NO: 7) and has the sequence AGCAAGGTGCCAGCCCCAATGTCCA (SEQ ID NO: 14). The 3' primer is preferably the reverse complement of the sequence from base 440 to base 464 of the human pl9 DNA sequence (SEQ ID NO:7) and has the sequence GCGTCCCTGCGATGGAGATCAGATT (SEQ ID NO: 15). In such an embodiment the amplified product is subjected to restriction digestion prior to visualization. Different alleles of Ink4d will yield amplified fragments of differing size after digestion with an appropriate restriction endonuclease. The amplified DNA is then precipitated, and digested with a restriction enzyme, such as BambU, Bglll, Pstl, or EcoRI. Digested DNA fragments are separated according to their molecular weights to form a pattern, typically using agarose gel electrophoresis. Following electrophoresis, the gel is stained with an appropriate agent, such as ethidium bromide, using standard protocols, and photographed under ultraviolet transillumination. Polymoφhisms result in the appearance of additional bands (i.e., bands not found in the wild-type InK4d allele) on the gel. In an alternative aspect of this embodiment, the DNA isolated from the cells' nuclei is digested with a given restriction endonuclease, utilizing PCR amplification. The restriction endonucleases that may be used in this invention include, but are not limited to, BamYR, Bglll, Pstl, or EcoRI. After a digest is obtained, and the DNA is separated by standard technique, for example by agarose gel electrophoresis, the separated bands are probed with a DNA fragment containing sequences encoding human pi 9 polypeptide sequences. In one aspect of this embodiment, the preferred probe of the invention is based on the cDNA or genomic sequence from the gene for human pi 9, InK4d, on human chromosome 19. The use of RFLP technology is only one preferred embodiment of detecting polymoφhisms in the nucleic acids of the invention. Since, ultimately, the use of RFLP depends on polymoφhism in DNA restriction sites along the nucleic acid molecule, other methods of detecting the polymoφhism can also be used. Any method of analysis which allows one skilled in the art to determine the linkage between the polymoφhism detected by the probes and primers of the present invention can be utilized. Techniques such as direct location of the polymoφhism on chromosome 19 by in situ hybridization using radiolabeled, fluorescence-labeled, or enzyme-labeled probes may be employed. Other suitable techniques include, but are not limited to, amplification methods such as the ribonuclease mis-match cleavage assay and direct oligonucleotide hybridization. Any size fragment of the human InK4d gene (SEQ ID NO:7) can be utilized as a probe as long as it is capable of hybridizing to a restriction fragment which displays a polymoφhism within an intron or an exon in the InK4d gene on chromosome 19. The hybridization probes can be labeled by standard labeling techniques such as with a radiolabel, enzyme label, fluorescent label, biotin-avidin label, chemiluminescence, and the like. After hybridization, the probes are visualized using known methods. Comparison of the RFLP or RFLP's for the subject under investigation will quickly reveal the presence or absence of polymoφhisms in the gene encoding human pi 9 linked to a predisposition to cancer. Polymoφhisms that may be detected by the methods of the invention include RFLPs, point mutations, insertions, deletions, inversions, alternately spliced mRNAs, and the like. The materials for use in this aspect of the invention are ideally suited for the preparation of a kit. Specifically, the invention provides a compartmentalized kit to receive in close confinement, one or more containers which comprises: (a) a first container comprising one or more of the probes or amplification primers of the present invention; and (b) one or more other containers comprising one or more of the following: a sample reservoir, wash reagents, reagents capable of detecting presence of bound probe from the first container, or reagents capable of amplifying sequences hybridizing to the amplification primers. In detail, a compartmentalized kit includes any kit in which reagents are contained in separate containers. Such containers include small glass containers, plastic containers or strips of plastic or paper. Such containers allows one to efficiently transfer reagents from one compartment to another compartment such that the samples and reagents are not cross-contaminated and the agents or solutions of each container can be added in a quantitative fashion from one compartment to another. Such containers will include a container which will accept the test sample, a container which contains the probe or primers used in the assay, containers which contain wash reagents (Tris-buffers, etc.), and containers which contain the reagents used to detect the bound probe or amplified product. Types of detection reagents include labeled secondary probes, or in the alternative, if the primary probe is labeled, the enzymatic, or antibody binding reagents which are capable of reacting with the labeled probe. One skilled in the art will readily recognize that the disclosed probes and amplification primers of the present invention can readily be incoφorated into one of the established kit formats which are well known in the art. In one example, a first container may contain a hybridization probe. The second container may contain the restriction enzyme to be used in the digest. Other containers may contain reagents useful in the localization of labeled probes, such as enzyme substrates such as x-gal tagged avidin if a biotinylated probe is utilized. Still other containers may contain buffers, etc. Genetic and antisense oligonucleotide therapy: In another embodiment of this invention, pi 8 or p 19 nucleic acid sequences are used for genetic therapy, i.e., to inhibit, enhance or restore expression of p 18 or pl9 in cells with reduced, altered or no pi 8 or pl9 activity, using the nucleic acid sequences of the invention. 1. In order to enhance or restore plδ and/or pl9 activity to cells in need of growth regulation, pl8, pl9 or pi 8/pl9 expression constructs are prepared. An expression construct consists of nucleic acid sequences encoding a protein having pi 8 polypeptide sequences, nucleic acid sequences encoding a protein having pl9 polypeptide sequences, or both types of nucleic acid sequences, operably linked to nucleic acid sequences required for genetic expression in a cell (such as promoters) in an expression vector. The expression constructs are introduced into cells, wherein they direct expression of proteins having p 18 or p 19 polypeptide sequences, or, in the case of pl8/pl9 expression constructs, both types of proteins or a single protein having polypeptide sequences from both pi 8 and pi 9. The expressed proteins may be fusion proteins that additionally include polypeptide sequences designed to improve the in vivo activity, targeting and/or stability of the gene products expressed by the expression construct. The expressed proteins function to restore or enhance pi 8 and/or pi 9 function in their host cells and thus negatively regulate the progression of the cell through the cell cycle. The disclosure demonstrates that, even in cells genetically engineered to overexpress cyclin D and thus possessing 5-10 fold greater levels of CDKs than corresponding wild-type cells, the constitutive expression of pl9 in a cell results in a Gl phase arrest, i.e., inhibition of DNA replication (see Example 7). Thus, even in cells with runaway cyclin D expression, the introduction of pi 9 function in excess inhibits the progression of the cells through the cell cycle and thus prevents their further growth. 2. In order to inhibit pi 8 or pl9 activity in cells in need of growth stimulation, synthetic antisense oligonucleotides are prepared from the coding sequences for pi 8 or pi 9 found in cDNA or genomic clones. An antisense oligonucleotide consists of nucleic acid sequences corresponding to the reverse complements of plδ or pl9 coding sequences or other sequences required to be present in plδ or pl9 mRNA or DNA molecules for in vivo expression. The antisense oligonucleotides are introduced into cells, wherein they specifically bind to ρl8 or pl9 mRNA molecules (and thus inhibit translation of pi 8 or pl9 gene products), or to double-stranded DNA molecules to form triplexes (see U.S. Patent 5, 190,931 to Inouye (Mar. 2, 1993); Riordan and Martin, Nature 350:442-443 (1991)). Because antisense oligonucleotides bind with high specificity to their targets, selectivity is high and toxic side effects resulting from misdirection of the compounds are minimal, particularly given the present state of the art with regard to the design of, preparation and chemical modification of, and means of delivery to cells for, oligonucleotides (see, e.g., Wagner, R.W., Nature 372:333-335 (1994); Tseng and Brown, Cancer Gene Therapy 7:65-71 (1994); Morishita, R., et al, J. Clin. Invest. 93: 1458-1464 (1994); Stein and Cheng, Science 267:1004-1012 (1993); Lisziewicz, J., et al, Proc. Natl Acad. Sci. (USA) 90:3860-3δ64 (1993); Watson, P.H., et al, Cancer Res. 57:3996-4000 (1991); Han, L., et al, Proc. Natl. Acad. Sci. (USA) 55:4313-4317 (1991); Florini and Ewton, J. Biol. Chem. 265: 13435-13437 (1990); and Uhlmann and Peyman, Chem. Reviews 90:543-583 (1990)). Means for the delivery of oligonucleotides to cells include, but are not limited to, liposomes (see, e.g., Renneisen, K., et al, J. Biol Chem. 265:16337-16342 (1990)) and introduction of expression constructs that direct the transcription of antisense oligoribonucleotides in vivo (see, e.g., Shohat, O., et al, Oncogene 7:277-283 (1987)). Cells in need of growth stimulation may include stem cells, which both self-renew and differentiate in vivo. Stem cells are pluripotent and give rise to a variety of differentiated cell types; for example, a few hematopoietic stem cells can repopulate the entire hematopoietic system (including white blood cells, red blood cells and platelets) of a lethally-irradiated adult mouse. InK4c-pl8 and InK4d-pl9 are expressed at high levels in hematopoietic tissues, i.e., bone marrow and spleen. In principle, pi 8 and/or 19 may likely act to prevent the cycling of hematopoietic stem cells. It is well-known that treatment of cells with FIAU kills cells in cycle but spares hematopoietic stem cells. Therefore, hematopoietic stem cells are, for the most part, non-cycling, and are triggered to enter the cell cycle when new blood cells are needed. A key goal of transplantation therapy is to grow hematopoietic stem cells in vitro, maintaining them in an immature, multipotential state. If these cells are kept out of cycle by CDK inhibitors pi 8 or pl9, then it is possible to move them into the cell cycle by reducing the amount of pl8 or pl9 present in stem cells by treatment with the antisense oliognucleotides of the invention. Polypeptides and Related Embodiments In one embodiment, the invention comprises proteins having amino acid sequences of mouse pi 9 protein, human pi 9 protein and pi 9 polypeptides from other mammals. For example, the invention provides the amino acid sequences of mouse pl9 (SEQ ID NO:2) and human pl9 (SEQ ID NO:9). In a parallel embodiment, the invention comprises proteins having amino acid sequences of mouse plδ protein and plδ polypeptides from other non-human mammals. For example, the invention provides the amino acid sequence of mouse pi 8 (SEQ ID NO:l). One skilled in the art can readily adapt the amino acid sequences of the invention to a variety of known applications. For example, fusion proteins that comprise amino acid sequences from pi 8 or pi 9 and a second polypeptide can be produced by recombinant DNA technology to generate novel proteins having properties of both parent proteins (see Example 2). Similarly, the proteins of the invention can be conjugated to other proteins in order to target the conjugated protein to CDK-cyclin complexes in a cell. Synthetic oligopeptides (a.k.a. "peptides") generally contain from about 5 to about 100 contiguous amino acids exactly corresponding to the polypeptide sequence of pi 8 or pi 9 of the invention, but may optionally contain additional amino acids at the carboxyl terminus, the amino terminus, or both. Moreover, those of skill in the art will appreciate that substitution of endogenous amino acids for chemical derivatives and/or isomers of amino acids will yield peptides with properties that are enhanced relative to the native pl or pi 9 proteins. Properties that may be so altered include, but are not limited to, in vivo stability, affinity for CDK- cyclin complexes, and the like. Therapeutic Embodiments: Another embodiment of the invention includes identifying and producing drugs based on the pi 8 and pi 9 structures that serve as plδ or pi 9 mimetics to inhibit the activity of endogenous CDKs, with the resultant effect that, when cells are treated therewith, the cells are prevented from progressing through the cell cycle, are inhibited from replicating their chromosomal DNAs, and/or undergo reduced or no cellular growth. Therapeutically, this treatment is used for diseases characterized by uncontrolled cell growth such as cancers, carcinomas, tumors, neoplasms and the like. In a related embodiment, the invention includes identifying and producing drugs based on the pi 8 and pl9 structures that serve as pi 8 or pi 9 mimetics to inhibit the activity of endogenous pl or pi 9 proteins, with the resultant effect that the cells are stimulated to advance through the cell cycle, are stimulated to replicate their chromosomal DNAs, and/or undergo enhanced cellular growth. This treatment is used in vitro in order to culture cells or therapeutically to promote healing of endogenous tissues or to stimulate the growth of transplanted tissues. 1. As an example of the first therapeutic (anti-cancer) embodiment, pi 9 is introduced into eukaryotic cells and arrests their progression from Gl to S phases during inteφhase and thus inhibits the growth of the cells, particularly cells undergoing rapid or uncontrolled growth (see Example 7). InK4c-plδ and InK4d-pl9, or derivatives thereof, i.e., fusion polypeptides (Example 2), peptide fragments generated by proteolysis or synthetic oligopeptides containing different portions of the pi δ or p 19 polypeptide sequences, can be assayed for their ability to bind CDK4 and CDK6 kinases by using the assay described in Example 3. In this fashion, the polypeptide sequences comprised within CDK-binding motifs are identified. The structure of these polypeptide motifs is used in turn in computer-assisted rational drug design to generate pi 8 or pi 9 mimetics that are assayed for their ability to bind CDK4 and or CDK6 kinases according to the methods of the invention (Martin, Y.C., Methods in Enzymology 203:587-613 (1991)). As another example, mutant pi 8 or p 19 proteins are prepared that bind more tightly to CDK-cyclin complexes, but which inhibit the catalytic (kinase) activity of the CDK-cyclin complexes to the same or greater degree, than wild-type pi 8 or pi 9 proteins, respectively, using the assays described herein. These "tight-binding" mutant p 18 or p 19 proteins, or peptide fragments, oligopeptides or other derivatives thereof, inhibit the activity of endogenous CDKs when introduced into a cell, with the resultant effect that the cells (1) are prevented from progressing through the cell cycle, (2) are inhibited from replicating their chromosomal DNAs, and/or (3) undergo cellular growth at a decreased rate relative to that of untreated cells. 2. A related embodiment of the invention includes screening for and producing compounds that inhibit the activity of pi 8 or p!9, to be applied, either in vitro or in vivo, to cells in need of stimulation of their progression through the cell cycle, DNA replication, and/or cellular growth. Cells in need of suc stimulation by the compositions and methods of the invention are hemopoietic cells, which reside in viv in the bone marrow and spleen of mammals but which cannot be indefinitely maintained in vitro. As a example, plδ or pl9 mutant proteins are prepared that retain the ability to bind to CDK-cyclin complexe but which have lost the ability to prevent the catalytic (kinase) activity of the CDKs. These "negative dominant" mutant plδ or pl9 proteins, or peptide fragments, oligopeptides or other derivatives thereo competitively inhibit endogenous pi 8 or pl9 proteins when introduced into a cell, with the resultant effec that the cells (1) are advanced through the cell cycle, (2) are stimulated to replicate their chromosoma DNAs, and/or (3) undergo cellular growth at an enhanced rate relative to that of untreated cells. 3. The pi 8 or pl9 proteins, fusion proteins, peptide fragments, synthetic oligopeptides o mimetics derived therefrom according to the above embodiments can be employed in combination wit conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitabl for parenteral application which do not deleteriously react with the active compound. Suitabl pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohol, vegetabl oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters hydroxymethylcellulose, polyvinylpyrrolidone, etc. The pharmaceutical preparations can be sterilized an if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the lik which do not deleteriously react with the active compounds. For parenteral application, particularly suitabl vehicles consist of solutions preferably oily or aqueous solutions, as well as suspensions, emulsions, o implants. Aqueous suspensions may contain substances which increase the viscosity of the suspension an include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspensio may also contain stabilizers. The term "therapeutically effective amount," for the puφoses of the invention, refers to the amoun of plδ or pl9 proteins, fusion proteins, synthetic oligopeptides or mimetics derived therefrom which i effective to achieve its intended puφose. While individual needs vary, determination of optimal ranges fo effective amounts of pl8 or pl9 proteins, fusion proteins, synthetic oligopeptides or mimetics derive therefrom is within the skill of the art. Human doses can be extrapolated from animal studies (Fingle an Woodbury, Chapter 1 in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 5th Ed. MacMillan Publishing Co., New York (1975), pages 1-46). Generally, the dosage required to provide a effective amount of the composition, and which can be adjusted by one of ordinary skill in the art will vary depending on the age, health physical condition, weight, extent of disease of the recipient, frequency o treatment and the nature and scope of the desired effect. The pi 8 or pl9 proteins, fusion proteins, peptide fragments, synthetic oligopeptides or mimetics derived therefrom, can be delivered to mammals via intermittent or continuous intravenous injection of one or more these compositions or of a liposome (Rahman and Schein, in Liposomes as Drug Carriers, Gregoriadis, ed., John Wiley, New York (1988), pages 381-400; Gabizon, A., in Drug Carrier Systems, Vol. 9, Roerdink et al, eds., John Wiley, New York (1989), pages 185-212) or microparticle (Tice et al, U.S. Patent 4,542,025 (Sep. 17, 1985)) formulation comprising one or more of these compositions; via subdermal implantation of drug-polymer conjugates (Duncan, R., Anti-Cancer Drugs 3:175-210 (1992); via microparticle bombardment (Sanford et al, U.S. Patent 4,945,050 (Jul. 31, 1990)); via infusion pumps (Blackshear and Rohde, in Drug Carrier Systems, Vol. 9, Roerdink et al, eds., John Wiley, New York (1989), pages 293-310) or by other appropriate methods known in the art (see, generally, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA (1990)). Of course, the anti-cancer (inhibitory of cell cycle, DNA replication and/or cellular growth) therapeutic compositions of the invention may be used in combination with other anti-cancer compositions known in the art. Similarly, the therapeutic compositions of the invention that stimulate progression through the cell cycle, DNA replication and/or cellular growth may be used in combination with known compositions having like effect. Treatment of cells with pi 8 or pl9 proteins, fusion proteins, peptide fragments, synthetic oligopeptides or mimetics derived therefrom, results in arrest of the affected cells in the Gl phase of the cell cycle (see Example 7). Accordingly, the outcome of treatment with the therapeutic compositions of the invention is a slowing or cessation of growth of malignant cells with a concomitant reduction in size of the tumor and relief from the primary and secondary symptoms associated with the carcinoma or neoplasm. These and other parameters of neoplasms and carcinomas are measured by methods known in the art (see, generally, Mendelesohn, J., and DeVita, V., in Harrison's Principles of Internal Medicine, 11th Ed., Braunwald et al, eds., McGraw-Hill, New York (1987, pages 421-446). Alternatively, at relatively low doses, the treatment of cells with pi 8 or pl9 proteins, fusion proteins, peptide fragments, synthetic oligopeptides or mimetics derived therefrom, results in Gl arrest in non-neoplastic cells. This modality is used to selectively kill neoplastic cells with therapeutic agents that do not affect normal cells in the Gl phase (Crissman tα/., U.S. Patent 5, 185,260 (Feb. 9, 1993)). The plδ and pi 9 proteins or derivatives thereof function in this alternative modality with enhanced selectivity with regard to the Gl kinases (i.e., CDK4, CDK6) and cell types (i.e., hemopoietic and other cells found in the bone marrow and spleen of mammals) that are specifically influenced thereby. Antibodies and Related Embodiments In another embodiment of the invention, pl8 or pl9 proteins, peptide fragments, fusion proteins or oligopeptides derived therefrom, are used to create antibody compositions that specifically recognize (bind) p 18 or p 19 epitopes. Antibodies to p 18 and/or p 19 serve as probes for diagnostic tests for p 18 and or p 19 expression or as diagnostic materials. Methods of generating antibodies using purified proteins or synthetic oligopeptides are known in the art (see Antibodies: A Laboratory Manual, Harlow, E., and Lane, D., Cold Spring Harbor Laboratory, Cold Spring Harbor (1988)). The antibody compositions of the invention may be polyclonal, monospecific or monoclonal. Diagnostic methods and kits: In one aspect of this embodiment, the concentration of p 18 or p 19 protein in a sample of cells from a mammal is determined by contacting the sample with a detectably labeled antibody composition specific to pi 8 or pl9, respectively, qualitatively or quantitatively determining the amount of label bound or not bound in the sample, and calculating therefrom the concentration of pi 8 or pi 9 in the sample. The sample of cells is obtained from a mammal and are washed in an appropriate buffer such as Hank's balanced salt solution. In order to release pi 8 and pl9 proteins, the cells and their nuclei are lysed according to methods known in the art (Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor (1988), pages 446-460). It may be necessary to add protease inhibitors to the samples to stabilize pi 8 and pl9 proteins (Sambrook et al. Molecular Cloning: A Laboratory Manual, 2d. Ed., Cold Spring Harbor Laboratory, Cold Spring Harbor (1989), pages 18.28- 18.41), or to preclear samples to remove proteins that bind immunoglobulins non-specifically (Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor (1988), pages 461-463; Sambrook et al, Molecular Cloning: A Laboratory Manual, 2d. Ed., Cold Spring Harbor Laboratory, Cold Spring Harbor (1989), page 18.43). The samples are incubated with a detectably labeled pi 8- or pl9-specific antibody composition for an appropriate amount of time, and are washed with the buffer a second time to remove unbound antibody. The amount of bound or unbound labeled antibody is then determined by means known in the art. Suitable types of immunoassays for detecting plδ or pl9 include sandwich immunoassay and competition assays, performed using conventional methods (Catty and Raykundalia, in Antibodies: A Practical Approach, Volume II, Catty, ed., IRL Press, Oxford (1989), pages 97-154). Other ligands specific for pl8 or pl9 may be used in lieu of plδ- or pl9-specific antibodies. Alternatively, unlabeled plδ- or pl9-specific antibody compositions, bound or unbound in a sample, are detected using a secondary antibody or protein which is specific for an immunoglobulin, e.g., protein A, protein G, anti-IgM or anti-IgG antibodies. In this alternative embodiment, the secondary (anti- immunoglobulin) antibodies, which may be monoclonal or polyclonal, are detectably labelled and are detected in the course of carrying out the method (Catty and Raykundalia, in Antibodies: A Practical Approach, Volume II, Catty, ed., IRL Press (Oxford) 1989, pages 97-154). Alternatively, pl8 or pl9 levels in a sample of mammalian cells are determined by detecting the level of soluble plδ or pl9, respectively, in a sample of lysed cells. In this aspect, a sample of lysed cells obtained from a mammal is contacted with a plδ- or pl9-specific antibody composition which is immobilized onto a solid matrix, and allowed to incubate so as to form a plδ/plδ-specific antibody or pl9/pl9-specific antibody complex. Following a wash step with suitable buffers to remove the unbound antibody, a detectably labeled molecule which binds to the plδ- or pl9-specific antibody composition is added. The amount of bound label then is detected to determine the concentration of pi 8 or pi 9 present in the sample (Nakamura and Robbins, in Manual of Clinical Laboratory Immunology, 3rd Ed., Rose et al, eds., American Society for Microbiology, Washington, D.C.(1986), pages 116-123). Of course, the specific amounts of pi 8- or pl9-specific antibody compositions and detectably labeled second antibodies, the temperature and time of incubation, as well as other assay conditions may be varied, depending on various factors including the concentration of pi 8 or pl9 in the sample, the nature of the sample, and the like. Those skilled in the art will be able to determine operative and optimal assay conditions for each determination by employing routine experimentation. Other such steps as washing, stirring, shaking, filtering and the like may be added to the assays as is customary or necessary for the particular situation. A variety of means may be used to detectably label antibody compositions for use in the methods of the invention. For example, one means by which pi 8- or pl9-specific antibody compositions, or secondary antibodies, can be detectably labeled is by conjugation to an enzyme. The conjugated enzyme, when later exposed to its substrate, will react with the substrate in such a manner as to produce a chemical moiety which can be detected, for example, by spectrophotometric, fluorometric or by visual means. Enzymes which can be used to detectably label antibody compositions include, but are not limited to, malate dehydrogenase, staphylococcal nuclease, delta-v-steroid isomerase, yeast alcohol dehydrogenase, alpha- glycerophosphate dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, υrease, catalase, glucose- Vl-phosphate dehydrogenase, glucoamylase and acetylcholine esterase. Antibody compositions may also be labeled with a radioactive isotope which can be determined by such means as the use of a gamma counter or a scintillation counter or by autoradiography. It is also possible to label antibody compositions with a fluorescent compound. When fluorescently labeled antibody is exposed to light of the proper wave length, its presence can then be detected due to the fluorescence of the dye. Among the most commonly used fluorescent labeling compounds are fluorescein isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, o-phthaldehyde and fluorescamine. Antibodies can also be detectably labeled using fluorescence emitting metals such as lϊ2 Eu, or others of the lanthanide series. These metals can be attached to pi 8- or pl9-specific antibodies using such metal chelating groups as diethylenetriaminepentaacetic acid (DTP A) or ethylenediaminetetraacetic acid (EDTA). Antibodies also can be detectably labeled by coupling to a chemiluminescent compound. The presence of chemiluminescent-tagged antibodies is then determined by detecting the presence of luminescence that arises during the course of a chemical reaction. Examples of particularly useful chemiluminescent labeling compounds are luminol, isoluminol, theromatic acridium ester, imidazole, acridinium salt and oxalate ester. Likewise, a bioluminescent compound may be used to label antibody compositions for use in the methods of the present invention. Bioluminescence is a type o chemiluminescence found in biological systems in which a catalytic protein increases the efficiency of th chemiluminescent reaction. The presence of a bioluminescent protein is determined by detecting th presence of luminescence. Important bioluminescent compounds for puφoses of labeling are luciferin luciferase and aequorin. Detection of bound or unbound antibodies may be accomplished by a scintillation counter, fo example, if the detectable label is a radioactive gamma emitter, or by a fiυorometer, for example, if the labe is a fluorescent material. In the case of an enzyme label, the detection can be accomplished by colorimetri methods which employ a substrate for the enzyme. Detection may also be accomplished by visua comparison of the extent of enzymatic reaction of a substrate in comparison with similarly prepare standards. In another embodiment of the present invention, kits are provided which contain the necessar reagents to carry out the previously described immunoassays with pi 8- or pl9-specific antibodies, in orde to diagnose certain types of cancers, or to detect a predisposition for certain types of cancers, in a mammal Specifically, the invention provides a compartmentalized kit to receive, in close confinement, on or more containers which comprises: (a) a first container containing a pi 8- or pl9-specific antibody; an (b) one or more other containers containing one or more of the following: wash reagents, and reagent capable of detecting presence of bound or unbound plδ- or pl9-specifιc antibodies. In detail, a compartmentalized kit includes any kit in which reagents are contained in separat containers. Such containers include small glass containers, plastic containers or strips of plastic or paper Such containers allows one to efficiently transfer reagents from one compartment to another compartmen such that the samples and reagents are not cross-contaminated, and the agents or solutions of each containe can be added in a quantitative fashion from one compartment to another. Such containers will include container which will accept the test sample, a container which contains the antibodies used in the assay containers which contain wash reagents (such as phosphate buffered saline, Tris-buffers, etc.), an containers which contain the reagents used to detect the bound antibody. Types of detection reagents include detectably labeled secondary antibodies, or in the alternative if the primary antibody is detectably labeled, the appropriate enzymatic or antibody binding reagents whic are capable of reacting with the labeled antibody. One skilled in the art will readily recognize that th disclosed antibodies of the present invention can readily be incoφorated into any one of the variety o established kit formats which are well known in the art. Transgenic Animals and Related Embodiments In another embodiment of the invention, pl or pi 9 nucleic acid sequences can be used to creat transgenic non-human animals to serve as animal models for plδ or pl9 overexpression (transgeni expression) or mutations such as deletions ("knockouts" or "null alleles") or other mutations which alter on or more pl8 or pl9 activities. For example, transgenic mice having little or no pl9 activity due to mutations in one or both alleles of the gene for pl9 (ink4d) are prone to develop certain types of tumors. Other examples include transgenic mice having little or no pl activity due to mutations in one or both alleles of the gene for plδ (ink4c), and transgenic mice deficient in both pi 8 and pl9 activity. The non-human animals of the invention comprise any animal having a deficiency of pi δ and/or pl9 activity as a result of the transgenic interruption or alteration of the gene(s) encoding pi δ and/or pl9. Such non-human animals include vertebrates such as rodents, non-human primates, sheep, dog, cow, amphibians, reptiles, etc. Preferred non-human animals are selected from non-human mammalian species of animals, most preferably, animals from the rodent family including rats and mice, most preferably mice. The transgenic animals of the invention are animals into which has been introduced by nonnatural means (i.e., by human manipulation), one or more genes that do not occur naturally in the animal, e.g., foreign genes, genetically engineered endogenous genes, etc. The nonnaturally introduced genes, known as transgenes, may be from the same or a different species as the animal but not naturally found in the animal in the configuration and/or at the chromosomal locus conferred by the transgene. Transgenes may comprise foreign DNA sequences, i.e., sequences not normally found in the genome of the host animal. Alternatively or additionally, transgenes may comprise endogenous DNA sequences that are abnormal in that they have been rearranged or mutated in vitro in order to alter the normal in vivo pattern of expression of the gene, or to alter or eliminate the biological activity of an endogenous gene product encoded by the gene. (Watson, J.D., et al, in Recombinant DNA, 2d Ed., W.H. Freeman & Co., New York (1992), pages 255-272; Gordon, J.W., Intl. Rev. Cytol. 775:171-229 (1989); Jaenisch, R., Science 240:1468-1474 (1989); Rossant, J., Neuron 2:323-334 (1990)). Methods of preparing transgenic animals: In one aspect of this embodiment of the invention, the nucleic acids of the invention are used to prepare transgenic constructs to be introduced into non-human animals in order to generate the transgenic animals of the invention. Specifically, pl8 or pl9 sequences derived from the genome of the non-human animal of choice are used to create such transgenic constructs. The transgenic non-human animals of the invention are produced by introducing pi 8 and/or pi 9 transgenic constructs into the germline of the non-human animal. Embryonic target cells at various developmental stages are used to introduce the transgenes of the invention. Different methods are used depending on the stage of development of the embryonic target cell(s). I. Microinjection of zygotes is the preferred method for incoφorating transgenes into animal genomes in the course of practicing the invention. A zygote, a fertilized ovum that has not undergone pronuclei fusion or subsequent cell division, is the preferred target cell for microinjection of transgenic DNA sequences. The murine male pronucleus reaches a size of approximately 20 micrometers in diameter, a feature which allows for the reproducible injection of 1-2 picoliters of a solution containing transgenic DNA sequences. The use of a zygote for introduction of transgenes has the advantage that, in most cases, the injected transgenic DNA sequences will be incoφorated into the host animal's genome before the first cel division (Brinster, et al, Proc. Natl Acad. Sci. (USA) 52:4438-4442 (1985)). As a consequence, all cell of the resultant transgenic animals (founder animals) stably carry an incoφorated transgene at a particula genetic locus, referred to as a transgenic allele. The transgenic allele demonstrates Mendelian inheritance half of the offspring resulting from the cross of a transgenic animal with a non-transgenic animal will inheri the transgenic allele, in accordance with Mendel's rules of random assortment. 2. Viral integration can also be used to introduce the transgenes of the invention into a animal. The developing embryos are cultured in vitro to the developmental stage known as a blastocyte At this time, the blastomeres may be infected with appropriate retroviruses (Jaenich, R., Proc. Natl Sci (USA) 73: 1260- 1264). Infection of the blastomeres is enhanced by enzymatic removal of the zona pellucid (Hogan, et al, in Manipulating the Mouse Embryo, Cold Spring Harbor Press, Cold Spring Harbor, N.Y (1986)). Transgenes are introduced via viral vectors which are typically replication-defective but whic remain competent for integration of viral-associated DNA sequences, including transgenic DNA sequence linked to such viral sequences, into the host animal's genome (Jahner, et al, Proc. Natl Acad. Sci. (USA 52:6927-6931 (1985); Van der Putten, et al, Proc. Natl Acad. Sci. (USA) 52:6148-6152 (1985)) Transfection is easily and efficiently obtained by culture of blastomeres on a mono-layer of cells producin the transgene-containing viral vector (Van der Putten, et al, Proc. Natl Acad. Sci. (USA) 52:6148-615 (1985); Stewart, et al, EMBO Journal 6:383-388 (1987)). Alternatively, infection may be performed at later stage, such as a blastocoele (Jahner, D., et al, Nature 29δ:623-62δ (1982)). In any event, mos transgenic founder animals produced by viral integration will be mosaics for the transgenic allele; that is the transgene is incoφorated into only a subset of all the cells that form the transgenic founder animal Moreover, multiple viral integration events may occur in a single founder animal, generating multipl transgenic alleles which will segregate in future generations of offspring. Introduction of transgenes int germline cells by this method is possible but probably occurs at a low frequency (Jahner, D., et al, Natur 295:623-628 (1982)). However, once a transgene has been introduced into germline cells by this method offspring may be produced in which the transgenic allele is present in all of the animal's cells, i.e., in bot somatic and germline cells. 3. Embryonic stem (ES) cells can also serve as target cells for introduction of the transgene of the invention into animals. ES cells are obtained from pre-implantation embryos that are cultured in vitr (Evans, M.J., et al, Nature 292: 154- 156 (1981); Bradley, M. O., et al, Nature 309:255-258 (1984); Gossler et al, Proc. Nat Acad. Sci. (USA) 53:9065-9069 (1986); Robertson et al, Nature 322:445-448 (1986) Robertson, E.J., in Teratocarcinomas and Embryonic Stem Cells: A Practical Approach, Robertson, E.J. ed., IRL Press, Oxford (1987), pages 71-112). ES cells, which are commercially available (from, e.g. Genome Systems, Inc., St. Louis, MO), can be transformed with one or more transgenes by establishe methods (Lovell-Badge, R.H., in Teratocarcinomas and Embryonic Stem Cells: A Practical Approac Robertson, E.J., ed., IRL Press, Oxford (1987), pages 153-182). Transformed ES cells can be combined with an animal blastocyst, whereafter the ES cells colonize the embryo and contribute to the germline of the resulting animal, which is a chimera (composed of cells derived from two or more animals) (Jaenisch, R., Science 240:1468-1474 (1988); Bradley, A., in Teratocarcinomas and Embryonic Stem Cells: A Practical Approach, Robertson, E.J., ed., IRL Press, Oxford (1987), pages 1 13-151). Again, once a transgene has been introduced into germline cells by this method, offspring may be produced in which the transgenic allele is present in all of the animal's cells, i.e., in both somatic and germline cells. However it occurs, the initial introduction of a transgene is a Lamarckian (non-Mendelian) event. However, the transgenes of the invention may be stably integrated into germ line cells and transmitted to offspring of the transgenic animal as Mendelian loci. Other transgenic techniques result in mosaic transgenic animals, in which some cells carry the transgenes and other cells do not. In mosaic transgenic animals in which germ line cells do not carry the transgenes, transmission of the transgenes to offspring does not occur. Nevertheless, mosaic transgenic animals are capable of demonstrating phenotypes associated with the transgenes. Transgenes may be introduced into animals in order to provide animal models for human diseases. Transgenes that result in such animal models include, e.g., transgenes that encode mutant gene products associated with an inborn error of metabolism in a human genetic disease and transgenes that encode a human factor required to confer susceptibility to a human pathogen (i.e., a bacterium, virus, or other pathogenic microorganism) (Leder et al, U.S. Patent 5,175,383 (Dec. 29, 1992); Kindt et al, U.S. Patent 5,183,949 (Feb. 2, 1993); Small et al, Cell 46:13-18 (1986); Hooper et al, Nature 326:292-295 (1987); Stacey et al, Nature 332:131-136 (1988); Windle et al, Nature 343:665-669 (1990); Katz et al, Cell 74:1089-1100 (1993)). Transgenic animals that are predisposed to a disease may be used to identify compositions that induce the disease and to evaluate the pathogenic potential of compositions known or suspected to induce the disease (Berns, A.J.M., U.S. Patent 5,174,986 (Dec. 29, 1992)). The transgenic animals of the invention are predisposed to develop, and thus serve as animal models for, certain types of carcinomas and neoplasms. Offspring that have inherited the transgenes of the invention are distinguished from littermates that have not inherited transgenes by analysis of genetic material from the offspring for the presence of biomolecules that comprise unique sequences corresponding to sequences of, or encoded by, the transgenes of the invention. For example, biological fluids that contain polypeptides uniquely encoded by the transgenes of the invention may be immunoassayed for the presence of the polypeptides. A more simple and reliable means of identifying transgenic offspring comprises obtaining a tissue sample from an extremity of an animal, e.g., a tail, and analyzing the sample for the presence of nucleic acid sequences corresponding to the DNA sequence of a unique portion or portions of the transgenes of the invention. The presence of such nucleic acid sequences may be determined by, e.g., hybridization ("Southern") analysis with DNA sequences corresponding to unique portions of the transgene, analysis of the products of PCR reactions using DNA sequences in a sample as substrates and oligonucleotides derived from the transgene's DNA sequence, etc. To produce transgenic animals having both plδ and pl9 transgenes, transgenic plδ mice are mated with transgenic pi 9 mice, and the resulting offspring are screened for the presence of both plδ and pi 9 transgenes. Null alleles: A preferred embodiment is a transgenic animal that is homozygous for a null (a.k.a. "knock-out") allele of Ink4c (encodes plδ), or for Ink4d (encodes pl9), or both Ink4c and Ink4d. These animals are predisposed to develop certain types of cancers in a reproducible and thus reliable manner. In order to generate null alleles in Ink4c and Ink4d in embryonic stem cells, the positive-negative selection strategy of Mansour et al. (Nature 336:34δ-352 (1988)) is applied. A positive selectable marker, fo example the hygromycin phosphotransferase cassette (van Deursen and Wieringa, Nucl. Acids Res. 29:3815- 3820 (1992)), is inserted into a 5' portion of an Ink4 gene. This position for the positive selectable marke is chosen to obtain a genuine null mutant allele, i.e., to avoid translation of a truncated polypeptide. In the resulting targeting vector the hygromycin gene is flanked 5' and 3' by several kb of homologous murine genomic sequences. In addition, a negative selectable marker, for example the Heφes Simplex Virus (HSV) thymidine kinase (TK) gene, is placed in a 3' position flanking the region of homologous sequences in order to enable selection against nonhomologous integrants. Both the positive and negative selectable markers are inserted in the antisense orientation with respect to the transcriptional orientation of the Ink4 gene, and are expressed due to the TK promoter and Py F441 Polyoma enhancer. Linearized targeting construct is introduced into ES cells by electroporation or other suitable means and selection with hygromycin and FIAU (l-[2-deoxy, 2-fluoro-β-D-arabinofuranosyl]) is carried out for 7 to 10 days. Resistant colonies are expanded in 24-well plates; half of the cells in each well are cryo-preserved and the other half expanded for genotype analysis. Positive clones are stored in liquid nitrogen and thawed at least 3 days prior to blastocyst injection. Blastocysts are isolated, for example, at day 3.5 postcoitum by flushing the uterine horns o naturally mated C57BL/6 pregnant females with DMEM + 10% FBS. Approximately 10 to 15 ES cells from each homologous recombinant clone with a normal karyotype are microinjected into recipient blastocysts, and about 10 to 20 embryos are transferred into the uterine horns of (C57BL/6 x CBA/Ca)Fl pseudopregnant fosters (Bradley, A., in Teratocarcinomas and Embryonic Stem Cells: A Practica Approach, Robertson, E.J., ed., IRL Press, Oxford (1987), pages 113-151). Chimeric males are mated with C57BL/6 or FVB/J females and germline transmission of the mutant allele is verified by Southern blo analysis of tail DNA from FI offspring with either agouti or gray coat color. F2 offspring from interbred heterozygotes are genotyped by Southern blotting to identify homozygous null mutants. Methods of evaluating the therapeutic or oncogenic potential of compositions: Using th transgenic animals of the invention, it is possible to evaluate a variety of compositions for their therapeuti or oncogenic potential. I. Generally, methods for determining the therapeutic potential of composition to treat cancer comprise the step of administering a known dose of the composition to transgenic animals having a phenotype of reduced or altered plδ and/or pl9 activity, monitoring resulting biological or biochemical parameters correlated with cancer, and comparing the symptoms of treated animals to those of untreated animals. A first method of assessing the therapeutic potential of a composition using the transgenic animals of the invention comprises the steps of: ( 1 ) Administering a known dose of the composition to a first transgenic animal having a phenotype of reduced or altered pi 8 and/or pi 9 activity; (2) Detecting the time of onset of cancer in the first transgenic animal; and (3) Comparing the time of onset of cancer in the first transgenic animal to the time of onset of cancer in a second transgenic animal having a phenotype of reduced or altered pi 8 and/or pi 9 activity, which has not been exposed to the composition, wherein a statistically significant decrease in the time of onset of cancer in the first transgenic animal relative to the time of onset of the symptoms in the second transgenic animal indicates the therapeutic potential of the composition for treating cancer. A second method of assessing the therapeutic potential of a composition using the transgenic animals of the invention comprises the steps of: ( 1 ) Administering a known dose of the composition to a first transgenic animal having a phenotype of reduced or altered pi 8 and/or pl9 activity, at an initial time, to; (2) Determining the extent of cancer in the first transgenic animal at a later time, t,; and (3) Comparing, at t,, the extent of cancer in the first transgenic animal to the extent of cancer in a second transgenic animal having a phenotype of reduced or altered pi 8 and/or pi 9 activity, which has not been exposed to the composition at t o , wherein a statistically significant decrease in the extent of cancer at t, in the first transgenic animal relative to the extent of the symptoms at t, in the second transgenic animal indicates the therapeutic potential of the composition for treating cancer. A third method of assessing the therapeutic potential of a composition using the transgenic animals of the invention comprises the steps of: ( 1 ) Administering a known dose of the composition to a first transgenic animal having a phenotype of reduced or altered p 18 and/or p 19 activity; (2) Measuring the lifespan of the first transgenic animal; and (3) Comparing the lifespan of the first transgenic animal to the lifespan of a second transgenic animal having a phenotype of reduced or altered pi 8 and/or pl9 activity, which has not been exposed to the composition, wherein a statistically significant increase in the lifespan of the first transgenic animal relative to the lifespan of the second transgenic animal indicates the therapeutic potential of the composition for treating cancer. 2. Generally, methods for determining the potential of a composition to cause or exacerbate cancer comprise the step of administering a known dose of the composition to a transgenic animals havin a phenotype of reduced or altered plδ and/or pl9 activity, monitoring resulting biological or biochemical parameters correlated with cancer, and comparing the symptoms of treated animals to those of untreated animals. A first method of assessing the oncogenic potential of a composition using the transgenic animals of the invention comprises the steps of: ( 1 ) Administering a known dose of the composition to a first transgenic animal havin a phenotype of reduced or altered pi 8 and/or pi 9 activity; (2) Detecting the time of onset of cancer in the first transgenic animal; and (3) Comparing the time of onset of cancer in the first transgenic animal to the time o onset of cancer in a second transgenic animal having a phenotype of reduced or altered pi 8 and/o pl9 activity, which has not been exposed to the composition, wherein a statistically significant increase in the time of onset of cancer in the first transgenic animal relative to the time of onset of the symptoms in the second transgenic animal indicates the potential of the composition for causing or exacerbating cancer. A second method of assessing the oncogenic potential of a composition using the transgenic animals of the invention comprises the steps of: ( 1 ) Administering a known dose of the composition to a first transgenic animal having a phenotype of reduced or altered pi 8 and or pl9 activity, at an initial time, to; (2) Determining the extent of cancer in the first transgenic animal at a later time, t,; and (3) Comparing, at t„ the extent of cancer in the first transgenic animal to the extent o neurological symptoms in a second transgenic animal having a phenotype of reduced or altered pi 8 and/or pi 9 activity, which has not been exposed to the composition at to, wherein a statistically significant increase in the extent of cancer at t, in the first transgenic animal relative to the extent of the symptoms at t, in the second transgenic animal indicates the potential of the composition for causing or exacerbating cancer. A third method of assessing the oncogenic potential of a composition using the transgenic animals of the invention comprises the steps of: ( 1 ) Administering a known dose of the composition to a first transgenic animal havin a phenotype of reduced or altered plδ and/or pi 9 activity; (2) Measuring the lifespan of the first transgenic animal; and (3) Comparing the lifespan of the first transgenic animal to the lifespan of a second transgenic animal having a phenotype of reduced or altered plδ and/or pi 9 activity, which has not been exposed to the composition, wherein a statistically significant decrease in the lifespan of the first transgenic animal relative to the lifespan of the second transgenic animal indicates the potential of the composition for causing or exacerbating cancer. 3. In both of the above sets of methods, the composition may comprise a chemical compound administered by circulatory injection or oral ingestion. The composition being evaluated may alternatively comprise a polypeptide administered by circulatory injection of an isolated or recombinant bacterium or virus that is live or attenuated, wherein the polypeptide is present on the surface of the bacterium or virus prior to injection, or a polypeptide administered by circulatory injection of an isolated or recombinant bacterium or virus capable of reproduction within a mouse, and the polypeptide is produced within a mouse by genetic expression of a DNA sequence encoding the polypeptide. Alternatively, the composition being evaluated may comprise one or more nucleic acids, including a gene from the human genome or a processed RNA transcript thereof. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following examples are, therefore, to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. The entire text of all publications cited above and below are hereby incoφorated by reference. Examples Example 1: Cloning of the Mouse pi 8 and pi 9 cDNAs The yeast two-hybrid screen of Bartel et al (In Cellular Interactions in Development: A Practical Approach, Hartley, D.A., ed., Oxford University Press, Oxford UK (1993), pages 153-179) as modified by Durfee et al. (Genes __ Devel. 7:555-569 (1993)) was used to isolate cDNAs from a mouse T cell lymphoma library encoding proteins able to interact with CDK4. A BamHI fragment encoding the entire open reading frame of mouse CDK4 (Matsushime et al, Cell 77:323-334 (1992)) was inserted into the BamWL site of the plasmid, pAS2, which contains the TRP1 and CYH genes conferring auxotrophy to tryptophan and sensitivity to cycloheximide, respectively (Durfee et al, Genes & Devel 7:555-569 (1993)). The resulting "bait" plasmid (pAS2cdk4) drives the expression from the alcohol dehydrogenase promotor of a GAL4- CDK4 fusion protein containing amino terminal GAL4 DNA binding sequences (amino acids 1-147). Screening was performed using yeast strain Y190, which expresses two GAL4-inducible markers, HIS3 and LacZ. Y190 cells containing pAS2-CDK4 were transformed with LEU2 pACT plasmids containing cDNAs (prepared from mouse T lymphoma cells) which were fused 3' to the GAL4 transcriptional activation domain (Clontech, Palo Alto, CA). Transformants were plated and selected for 9 days at 30°C on SD synthetic medium lacking leucine, tryptophan, and histidine and containing 50 mM 3-amino-l,2,4-triazol (3-AT). Of 1.6 X 10 7 transformants, 327 HIS + colonies were obtained, which were transferred to Hybond- nylon filters (Amersham, Arlington Heights, IL), frozen at -70°C for 15 minutes, thawed, and overlaid o Whatman 3M paper containing 60 mM Na 2 HP0 4 , 40 mM NaH 2 P0 4 , 10 mM KCl, 1 mM MgS0 4 , 40 m β-mercaptoethanol, and 0.033% X-gal. After incubation for 20 hrs. at 30°, 158 blue colonies were identifie and streaked on SD synthetic medium lacking leucine and containing 2.5 or 10 ug/ml cycloheximide in orde to segregate pAS2- CDK4, and the surviving colonies were restreaked on medium lacking either leucine o tryptophan to confirm plasmid segregation. Ninety-nine such colonies were mated with yeast strain Yl 8 containing either pAS2-CDK4 or plasmids encoding other transactivating GAL4 fusion proteins (includin the yeast kinase SNFl and human lamin) by coincubation in YPD medium for 15 hr at 30°C, and th progeny were streaked on SD synthetic medium lacking leucine, tryptophan, histidine and containing 50 m 3-AT. Eighty-three library plasmids which activated HIS3 and LacZ only in the presence of GAL4-CDK were isolated from yeast and used to transform Escherichia coli strain HB101. The E. coli transformant were cultivated, and the 83 library-derived plasmids were individually purified therefrom. Positive plasmids were dot-blotted onto Hybond N filters and hybridized for 20 hours at 42 °C wit a 32 P-labeled cyclin D probe (a 1:1:1 mixture of mouse cyclins Dl, D2, and D3) in 3X SSC (IX SSC is 0.1 M NaCl, 0.015 M Na citrate) containing 35% formamide. Filters were washed in IX SSC containing 0.1 sodium dodecyl sulfate (SDS) for 30 minutes at 65°C, yielding 29 cycl in-positive clones. Several of th 54 remaining plasmid DNAs chosen at random were radiolabeled by nick translation and rehybridized t the filters, ultimately describing several families of related sequences. The nucleotide sequences of cDN inserts from representative plasmids of each group were determined using a Sequenase version 2.0 kit (USB Cleveland, OH). Of the 83 isolated library-derived plasmids, 29 contained cDNAs encoding D-type cyclins. Eightee plasmids contained 9 sets of less abundant gene sequences, none of which showed significant homology t known sequences in GenBank. Thirty-six plasmids contained the coding sequences of two novel Ink4 related genes, which are here designated "pl9" (represented by 29 clones) and "pl 8" (represented by clones). The InK4 proteins were initially designated based upon their apparent molecular masses; when th two cDNAs were transcribed and translated in vitro and electrophoretically separated in parallel on denaturing 15% polyacrylamide gel, the pl9 product migrated more slowly than the pl8 product. However the nucleotide sequences of these two mouse InK4 family members predict polypeptides of 166 (p 19) an 168 (pi 8) amino acids with molecular masses of 18,005 and 18,176 daltons, respectively. Based on their predicted amino acid sequences, the two mouse InK4 proteins are approximately 40 identical to one another and share a similar degree of amino acid homology with the previously describe human pl6 ln * and pl5 lnK b polypeptides. Like the latter proteins, pl9 and pi 8 are composed of tande ankyrin motifs, each about 32 amino acids in length (Figure 1 , Panel A). The most highly conserved region of mouse pl9 and plδ include the amino acid sequences comprising repeats 1-3 and half of repeat 4. The most conserved repeats of pl6, pl8, and pl9 can be aligned with one another as well as with those of other InK4 family members (Figure 1, Panel B). After completion of this work, the cloning and sequencing of a cDNA molecule encoding human pi 8 was reported (Guan et al, Genes & Devel. 5:2939-2952 (1994)). The human and mouse plδ polypeptides, each 168 amino acids in length, are identical over 153 residues. Mouse pl9 and pl8 exhibit only about 40% amino acid identity to one another, and both show a similarly limited degree of homology to human pl6 taK ϊ and pl5 InK4b . In contrast, mouse pl9 and pl8 exhibit >90% amino acid identity with their human counteφarts. Human pi 6 and pi 5 map in tandem on the short arm of human chromosome 9 (Kamb et al, Science 264:436-440 (1994)). The gene for human pi 8 has been assigned to chromosome 1 (Guan et al, Genes & Devel 5:2939-2952 (1994)), indicating that the InK4 family includes a minimum of four distinct genes. We therefore suggest that the pl8 and pl9 genes be designated Ink4c and Ink4d, respectively. Example 2: Production of Mouse pi 8 and pi 9 Fusion Proteins Fragments containing the entire coding sequences for pi 9 were amplified by PCR using the following oligonucleotide primers: CCGGATCCATGCTTCTGGAAGAAGT (5' primer) (SEQ ID NO: 12); and CCGAATTCTCACATTGGGATCATCA (3 ' primer) (SEQ ID NO: 13). Fragments containing the entire coding sequences for plδ were amplified by PCR using the following oligonucleotide primers: CCGGATCCATGGCCGAGCCTTGGGG (5' primer) (SEQ ID NO:10); and CCGAATTCTCACTGCAGGCTTGTGG (3 ' primer) (SEQ ID NO: 11 ). T e underlined ATGs in the sense strand oligonucleotides correspond to the pl9 and pi 8 initiator codons, which were preceded by BamHI sites to enable subsequent cloning. Products digested with BamHI and 7-coRI were inserted into pGEX-3X (Pharmacia, Uppsala, Sweden) in frame with GST. pGST-MAD3, a plasmid encoding mouse IκB, and pGST-ANK6, which encodes the MAD3 subdomain containing only the five ankyrin repeats (amino acids 73-242), were kindly provided by Dr. Lawrence Kerr (Vanderbilt University, Nashville, TN). Overnight cultures of bacteria transformed with plasmids encoding the GST fusion proteins were diluted 10-fold with fresh media and cultured for 2-4 hours at 37°C. Recombinant proteins were induced with 1 mM isopropyl-β-D-thiogalactoside (IPTG) for 1 hour at 37°C, and the harvested cells were lysed by sonication in phosphate-buffered saline (PBS) containing 1% Triton X-100 and clarified by centrifugation. GST fusion proteins were adsorbed to glutathione-Sepharose beads (Pharmacia), washed with 50 mM Tris HCl (pH 7.5), and eluted in the same buffer containing 5 mM reduced glutathione (Sigma, St Louis, MO). Proteins were dialyzed against 50 mM Hepes (pH 7.5), 150 mM NaCl, and 1 mM EDTA and quantitate with a bicinchoninic acid assay kit (Pierce, Rockford, IL) using bovine serum albumin (BSA) as a protei standard. Example 3: Mouse InK4 Proteins Specifically Bind to and Inhibit CDK4 and CDK6 Kinases CDK Binding Assays Human InK4 polypeptides specifically bind to the cyclin D-dependent catalytic subunits, CDK4 an CDK6 (5,18,45). To study the interactions of mouse pl9 and pi 8 with CDKs, cDNAs encoding CDC (CDK1) and CDKs 2-6 were transcribed and translated in vitro, and the radiolabeled products were mixe with GST-tagged pi 9 and pi 8 fusion proteins adsorbed to glutathione-Sepharose beads or to GST-Sepharos beads as a control. Plasmids derived from pBluescript and containing the entire coding sequences of the mouse cdk2 cdk4, cdk5, or cdkό genes (Matsuoka et al, Mol. Cell. Biol 74:7265-7275 (1994); Matsushime et al, Cel 77:323-334 (1992)) or human cdc2/cdkl or cdk3 genes (provided by Drs. Matthew Meyerson and Edwar Harlow (MGH Cancer Center, Cambridge, MA)) were transcribed and translated in vitro (Matsuoka et al Mol. Cell. Biol. 74:7265-7275 (1994)). Mouse cdkό cDNA was cloned from a mouse macrophage librar (Stratagene, La Jolla, CA) by screening with a full-length human cdkό clone (also provided by M. Meyerso and E. Harlow). Following transcription and translation, rabbit reticulocyte lysates containin 33 S-methionine labeled CDKs (20-40 ul) were diluted to 0.5 ml in IP kinase buffer (50 mM Hepes, pH 7.5 containing 150 mM NaCl, 1 mM EDTA, 1 mM DTT, 0.1 % Tween-20) containing 10 mg/ml BSA and mixe with 1 ug of purified GST or GST-pl9 immobilized on glutathione-Sepharose beads. After 2 hours o incubation at 4°C, beads were collected by centrifugation, washed 4 times in IP kinase buffer, and the boun proteins were denatured and analyzed by electrophoresis on 12.5% polyacrylamide gels containing SD (Anderson, S.J., et al, J. Virol. 57:730-741 (1984)). As reported previously (Matsuoka et al, Mol. Cell. Biol. 74:7265-7275 (1994)), several cd translation products were produced from each template, with major radiolabeled species in the 34 kDa rang being obtained with the cdc2, cdk2, cdk4, and cdk5 cDNAs (Figure 2, Panel A, lanes 1, 2, 4, and 5). Th predominant CDK6 species was about 38 kDa (lane 6) as predicted from its nucleotide sequence (Bate et al, Oncogene 9:71-79 (1994); Meyerson et al, EMBOJ. 77:2909-2917 (1992)), but cdk3 products wer significantly larger than expected, due to improper translational termination (lane 3) (Matsuoka et al , Mo Cell Biol 74:7265-7275 (1994)). None of the radiolabeled translation products bound to contro glutathione-Sepharose beads (Figure 2, Panel A, lanes 7-12), and only the CDK4 and CDK6 protein efficiently bound to beads containing the GST-pl9 fusion protein (lanes 16 and 18). In the same assay, D type cyclins were unable to interact with GST-pl9 beads (Figure 2, Panel B). Virtually identical result were obtained using GST-pl 8. CDK Inhibition Assays To determine whether their binding could inhibit CDK4 and CDK6 activity, bacterially-produced pi 9 and pi 8 fusion proteins were mixed at different concentrations with extracts containing enzymatically active complexes of CDK4-cyclin D2 and CDK6-cyclin D2 produced in baculovirus vector-infected insect cells, and the enzymes were assayed for pRb kinase activity (Kato et al, Genes & Devel. 7:331-342 (1993)). Figure 3 shows that addition of the GST-pl9 fusion protein reduced the pRb kinase activity of the CDK4- cyclin D2 (Panel A) and CDK6-cyclin D2 (Panel B) holoenzymes (lanes 2-7) to background levels equal to those observed with extracts of cells infected with a control, wild-type baculovirus (lanes 1). GST-pl9 was as potent as human pi 6 in inhibiting the pRb kinase activity of either CDK4-cyclin D or CDK6-cyclin D (Panels A and B, lanes 9-11). However, addition of up to 1 ug of a control GST protein had no effect on either enzyme (lanes 8). Although human pi 8 has been reported to have greater affinity for CDK6 than for CDK4 (Guan et al, Genes & Devel 5:2939-2952 (1994)), the murine GST-pl8 fusion protein is as potent as GST-pl9 in inhibiting both kinases in vitro (Figure 3, panels C and D, lanes 2-7). However, not all proteins containing repeated ankyrin motifs can effectively inhibit these enzymes. Mouse IκB (MAD3), for example, (Figure 3, Panels C and D, lanes 9 and 10) or a subdomain of the protein containing only the ankyrin repeats (lanes 11 and 12) were at least 30-fold less efficient in extinguishing CDK4 and CDK6 activity than were the pl9 and pl8 fusion proteins. Moreover, although combinations of CDK4 with any of the D-type cyclins proved to be effective substrates for pl9-mediated inhibition (Figure 4, Panel A, lanes 1-10), pi 9 neither attenuated the pRb kinase activity of CDK2-cyclin E (Figure 4, Panel A, lanes 11-13) nor affected the his- tone HI kinase activity of CDK2-cyclin E, CDK2-cyclin A, or CDC2-cyclin B (Figure 4, Panel B). Similar data were obtained with mouse pi 8. Therefore, both pl9 and pi 8 interact specifically with CDK4 and CDK6 to inhibit their pRb kinase activities in complexes with D-type cyclins. Example 4: Mouse pi 9 Protein does Not Displace Cyclin D from Complexes with CDK4 Spodoptera frugiperda (Sf9) cell lysates (2.5 to 5 ul, corresponding to 5 X 10 4 cells) containing CDKs and cyclins (Kato et al., Genes & Devel. 7:331-342 (1993)) were mixed with purified, soluble GST or the indicated GST fusion proteins in 10 ul of 50 mM Hepes buffer, pH 7.5, containing 10 mM MgCl 2 , and 1 mM DTT, and incubated for 2 hours at 4°C. Kinase activity was assayed in a 25 ul reaction mixture at 30°C for 20 minutes in the same buffer to which 2.5 mM EGTA, 10 mM β-glycerophosphate, 0.1 mM Na orthovanadate, 1 mM NaF, 20 μM ATP, 5 μCi γ- 32 P-ATP (6000 Ci/mmol; Amersham) were added. Either 0.2 ug soluble GST-pRb (Ewen et al, Cell 73:487-497 (1993); Kato et al, Genes & Devel. 7:331-342 (1993)) or 1 ug histone HI (Boehringer Mannheim) were used as substrates. The reaction products were electrophoretically separated on denaturing gels, and phosphorylated proteins were detected by autoradiography. For preparation of radiolabeled Sf9 lysates, cells infected with recombinant baculovirus vectors encoding cyclin D2 and CDK4 were metabolically labeled 40 hours after infection for 8 hours with 200 μCi/ml 35 S-methionine (specific activity 1000 Ci/mmol; ICN, Irvine, CA) and harvested as described (Kato et al, Genes & Devel 7:331-342 (1993)). Portions of the lysate (7.5 ul) were diluted with 0.5 ml of IP kinase buffer containing 10 mg ml BSA, and GST-pl9 (0.3 ug) was added as indicated prior to incubation for 2 hours at 4°C. Complexes containing cyclin D2 and CDK4 were precipitated either with rabbit antiser¬ um to intact recombinant cyclin D2 (serum R τ ) or to the C-terminus of CDK4 (serum R z ) preadsorbed to protein A-Sepharose beads (Matsushime et al, Mol. Cell. Biol 74:2066-2076 (1994)). For detection of kinase activity in the immune complexes, the beads were washed twice in IP buffer and twice in kinase buffer without protease inhibitors, suspended in 25 ul kinase reaction mixture, and assayed as described above. Phosphorylated GST-pRb and metabolically labeled cyclin D2 and cdk4 were resolved by electro¬ phoresis on 12.5% polyacrylamide gels and detected by autoradiography. In cells that fail to express a functional pRb protein, pl6 InK4* ' has been reported to be found in a com¬ plex with CDK4 at the expense of cyclin D (Bates et al, Oncogene 9:1633-1640 (1994); Serrano et al, Nature 366:704-707 (1993)). Therefore, plό* 1 * 4 * might compete with cyclin D for binding sites on CDK4, extinguishing its activity by displacing the positive regulator. When metabolically labeled lysates from baculovirus-infected Sf9 cells containing cyclin D2 and CDK4 were immunoprecipitated with antibodies to the individual subunits, antibodies to either subunit coprecipitated the other (Figure 5, lanes 3 and 4). Two forms of CDK4 are produced in this system (Kato et al, Genes & Devel. 7:331-342 (1993)), the faster migrating form (designated at the right margin) being equivalent in mass to that detected in mammalian cells. In the experiment shown, lysates from coinfected Sf9 cells contained much more cyclin D2 (lane 3) than CDK4 (lane 4), so that all of the CDK4 coprecipitated with cyclin D under these conditions (compare the CDK4 signal in lanes 3 and 4). Consistent with these data, the washed immune complexes recovered after precipitation with either antiserum contained similar amounts of pRb kinase activity (lanes 7 and 8). When pl9 was added to these lysates prior to immunoprecipitation, pRb kinase activity in recovered immune complexes was reduced to background levels (compare lanes 9 and 10 to lane 6), but the amount of cyclin D in the complexes was not significantly reduced (lane 10 versus lane 4). Under these conditions, similar amounts of pl9 were recovered in immune complexes generated with antisera to cyclin D2 or CDK4 even though cyclin D does not interact with pl9 directly. Therefore, pl9 can bind to the CDK4-cyclin D holoenzyme and directly inhibit its activity without disrupting the interaction between cyclin D and CDK4. Discussion. Both pl9 and pi 8 share the cardinal structural and biochemical properties of previously described human Ink4 gene products, pl6 lnK4 * and pl5 InK4b . They are composed of repeated ankyrin motifs, bind to CDK4 and CDK6, and specifically inhibit the pRb kinase activities of CDK4-cyclin D and CDK6- cyclin D complexes. InK4d-pl9 can bind to binary CDK4-cyclin D complexes and inhibit their activity in vitro without displacing cyclin D. However, while antibodies to p!9 coprecipitated CDK4 and CDK6 from lysates of proliferating mammalian cells, cyclin D was not detected in these complexes, suggesting that pi 9 might preferentially interact with the non-cyclin D-complexed forms of these CDKs in vivo. Interactions with CDK4 and CDK6 appear quite specific to the InK4 subfamily of ankyrin repeat proteins in the sense that other proteins containing these motifs, such as IκB, bind only weakly to these CDKs and inhibit their activities in vitro only if added in quantities at least 30-fold in excess of those of the InK4 polypeptides. The fact that cDNAs encoding pl9 were as frequently isolated as the D-type cyclins from the yeast two hybrid screen, whereas other ankyrin repeat proteins (apart from pi 8) were not identified among the remain¬ ing interacting clones, provides additional confidence in the specificity of its association with CDK4. In turn, the InK4 proteins as a group fail to inhibit other CDK-cyclin complexes, including CDK2-cyclin E, CDK2-cyclin A, and CDC2-cyclin B, and they do not bind to CDC2, CDK2, CDK3, or CDK5 in vitro. This evidence supports the position that these proteins play physiologic roles as specific regulators of CDK4 and CDK6 activity in vivo. Example 5: Expression of pi 8 and pi 9 in Mice InK4c-pl8 and InK4d-pl9 are Expressed in Many Tissues in Mice A single class of pi 9 mRNA transcripts 1.3 kb in length was detected in a variety of mouse cell lines, as well as in many mouse tissues, when pi 9 cDNA was used as a probe in hybridization studies (Figure 6). The pl9 cDNA was originally isolated from thymic lymphoma cells, and relatively high levels of pi 9 mRNA were detected in hematopoietic organs, such as bone marrow and spleen (Figure 6, Panel B), as well as in blood cell lines including MEL (erythroid), 32D, DA-3 and FDC-P1 (immature myeloid), BAC1.2F5 (macrophages), and CTLL-2 (T cells) (Figure 6, Panel A). As reported for its human cognate (Guan etal., Genes __ Devel. 5:2939-2952 (1994)), the patterns of expression of pi 8 were more complex. First, at least three forms of mRNA were observed, and these were differentially expressed in various tissues. Note, for example, that skin and lung primarily express a pi 8 transcript of 1.1 kb, whereas the predominant mRNA in bone marrow and spleen is considerably larger (1.9 kb). Unlike the human InK4a and InK4b genes, which are expressed at very low levels in many tissues and are deleted in a high percentage of established cell lines, both pl9 and pi 8 expression can be readily detected. Expression of pi 9 During the Macrophage Cell Cycle Murine BAC1.2F5 macrophages were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 15% fetal bovine serum, 2 mM glutamine, 100 U/ml penicillin, 100 ug/ml streptomycin, and 25% L cell-conditioned medium as a source of colony-stimulating factor- 1 (CSF-1) (Stanley, Methods Enzymol 776:564-587 (1986)). The cells were arrested in early Gl phase by CSF-1 starvation for 18 hours, after which they were restimulated with CSF-1 to reenter the cycle synchronously (Matsushime et al, Cell 65:701-713 (1991); Tushinski and Stanley, J. Cell. Physiol. 722:221-228 (1985)). Cells (2 X 10 7 per data point) were harvested at indicated intervals thereafter, and the DNA content of representative aliquots was measured by flow cytometric analysis of propidium iodide stained nuclei (Matsushime et al, Cell 65:701-713 (1991)). For preparation of RNA, washed cells were scraped into 4.2 M guanidine thiocyanate, 0.1 M Na acetate (pH 5), 5 mM EDTA and layered over 2M CsCl 2 , 0.1 M Na acetate, 5 mM EDTA in a Beckman SW41 centrifuge tube. Following centrifugation at 33,000 φm overnight, the pelleted RNA was suspended in 10 mM Tris HCl, pH 7.5, 10 mM EDTA, and 0.5% SDS, extracted twice with phenol and twice with chloroform, and precipitated with 2.5 volumes of ethanol at -20°C. RNA was separated electropho- retically in 1% agarose, blotted to nitrocellulose, and hybridized with the indicated cDNA probes at 42 °C for20 hours in 5X SSPE buffer (lX SSPE is 0.15 M NaCl, 10 mM NaH 2 PO 4 , 1 mM EDTA) containing 50% formamide (Dean et al, Oncogene Res. 7:279-296 (1987)). Filters were washed with 2X SSC containing 0.1% SDS first at 42°C and then at 65°C. Asynchronously proliferating macrophages or synchronized cells prepared as described above (1 X 10 6 cells per time point) were metabolically labeled for 1 hr. with 200 μCi/ml 35 S-methionine, and pl9 immunoprecipitated from the cell lysates was resolved on denaturing polyacrylamide gels and detected by autoradiography using previously described methods (Matsushime et al. , Cell 65: 701 -713 ( 1991 )). In some experiments, immunoprecipitated pl9 resolved on gels was transferred to nitrocellulose and immunoblotted with antiserum to CDK4; sites of antibody binding were detected using l25 I-labeled S. aureus protein A (Downing et al, Mol. Cell. Biol. 5: 1795-1799 (198δ)). Because both pi 9 and plδ are expressed in bone marrow-derived macrophages, we were able to study their regulation throughout the cell cycle. BAC1.2F5 macrophages arrest in early Gl phase when deprived of CSF-1 for 18-22 hrs and can be induced to reenter the cell cycle synchronously by readdition of the growth factor (Matsushime et al. , Cell 65: 701 -713 ( 1991 ); Tushinski and Stanley, J. Cell Physiol 722:221-228 (1985)). Figure 7 shows that pl9 mRNA could be detected in starved, quiescent cells (time 0) but decreased in abundance as cells entered Gl phase. However, as cells approached the Gl/S transition (about 10 hrs.), pl9 mRNA synthesis was abruptly reinitiated and increased as the cells progressed through the remainder of the cycle. Maximal cell division occurred at 18-20 hrs. Although the cells rapidly lost synchrony in the second cycle, and the second G 1 phase was shorter than the first (Matsushime et al , Cell 65:701-713 (1991)), pl9 levels again fell during Gl (about 22-28 hrs.) but increased in S phase (32-36 hrs). The relative abundance of pl9 mRNA, determined by scanning the Northern blots with a phosphoimager, is summarized graphically at the bottom of Figure 7. Virtually identical results were obtained using NIH- 3T3 cells induced to reenter the cell cycle from quiescence by serum readdition. During reentry into the cell cycle, pl8 mRNA was induced with kinetics similar to that of pl9. However, CSF-1 -starved macrophages expressed the 1.1 kb plδ mRNA species, whereas only the 1.9 kb form was induced at the Gl/S transition and remained elevated until cells reentered another cycle. The kinetics of induction of the pi 9 and plδ mRNAs in the first cycle were similar to that of cyclin A, which is also induced near the Gl/S boundary (Pines and Hunter, Nature 346:760-763 (1990)), but are readily distinguished from those of cyclin Dl mRNAs, which are induced early in Gl phase and oscillate only mod- estly as cells continue to proliferate (Matsushime et al, Cell 65:701-713 (1991)). The expression of a "housekeeping" gene, glucose 6-phosphate dehydrogenase (G6PD), showed minimal oscillation throughout the cycle, although its mRNA was somewhat less abundant in growth factor deprived cells. Expression of plδ InK4c and pl9 taK4d mRNAs can be readily detected in mouse tissues and cell lines where they appear to oscillate throughout the cell cycle. Several forms of pi 8 mRNA were observed which were differentially regulated in various tissues, whereas the pattern of pl9 expression was less complex, with only a single 1.3 kb mRNA observed. In synchronized macrophages, the abundance of pl9 mRNA temporally correlated with the rates of pi 9 protein synthesis observed throughout the cell cycle, with the levels of mRNA and protein reaching a nadir in Gl phase, abruptly increasing as cells entered S phase, and declining again as cells completed mitosis and reentered Gl . Example 6: Antibodies to pi 8 and pi 9 Polyclonal Antibodies A polyclonal antibody composition is produced by immunizing an animal with purified pi 8 or pi 9 protein produced, for example, by expression of nucleic acid sequences encoding pi 8 or pl9 in an appropriate host/vector system (see Example 2), and preparing serum from the immunized animal (Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor (1989), pages 53-137). Monospecific Antibodies A synthetic peptide corresponding to the eight C-terminal amino acids of mouse pl9 was conjugated to keyhole limpet hemocyanin and used to immunize rabbits (Downing et al, Mol. Cell. Biol 77:24δ9-2495 (1991)). The antiserum precipitated radiolabeled mouse pi 9 produced by translation in vitro, but did not crossreact with mouse plδ or human pl6 produced in parallel. An anti-peptide (monospecific) serum directed to the pi 9 carboxyl terminus was used to immunoprecipitate the metabolically labeled protein from proliferating mouse cells (Figure δ, Panel A, lanes 1 and 4). The immunoprecipitated 19 kDa protein could be competed with the cognate peptide (lanes 2 and 5) but not with an unrelated peptide based on the CDK2 C-terminus (lane 3). InK4d-pl9 immuno- precipitates also contained CDK4 (Figure 8, Panel B, lane 2) but did not contain detectable levels of cyclin Dl . Similar results were obtained with cell lines expressing CDK6. Thus, although pi 9 can bind to CDK4- cyclin D complexes in vitro (Figure 5), like other InK4 proteins, it may preferentially interact with unbound CDK4 and CDK6 in vivo. Consistent with the kinetics of pi 9 mRNA expression in synchronized macro¬ phages (Figure 7), synthesis of pi 9 protein was first detected near the Gl/S boundary, decreased as cells divided and re-entered a second Gl phase, and increased again during the following S phase (Figure 8, Panel C). Hence, pi 9 mRNA and protein synthesis are periodic with relative nadirs during Gl phase. Monoclonal A ntibodies For preparation of monoclonal antibodies, spleen cells from the animals immunized with pi 8 or pi proteins, or with synthetic pi 8 or pi 9 oligopeptides are removed, fused with myeloma cells, such as SP2/ AG14 myeloma cells, and allowed to become monoclonal antibody producing hybridoma cells (Harlow a Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor ( 19δ9), pag 139-281). Any one of a number of methods well known in the art can be used to identify the hybridoma c which produces an antibody with the desired characteristics. These include screening the hybridomas wi an ELISA assay, western blot analysis, or radioimmunoassay (Lutz et al, Exp. Cell Res. 775:109-1 (1988)). Hybridomas secreting the desired plδ- or pl9-specific antibodies are cloned and the class a subclass is determined using procedures known in the art (Campbell, A.M., Monoclonal Antibo Technology: Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishe Amsterdam, The Netherlands ( 1984)). Monoclonal antibodies are purified using methods known in the a (Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harb (1989), pages 283-318; Grandics, Biotechnology Laboratory, May issue, pages 58-62 (1994); Grandic Biotechnology Laboratory, June issue, pages 12-14 (1994); Grandics, Biotechnology Laboratory, July issu pages 16-18 (1994)). Example 7: InK4d-pl9-Mediated Arrest of Gl Enforced Expression ofpl9 in Mammalian Fibroblasts The BamH -EcoiRl fragment encoding pi 9 and a Hind ϊ -BamHl fragment containing the enti coding sequence of mouse CD8 (Zamoyska et al, Cell 43:153-163 (1985)) were both subcloned into t pSRα-MSV-TK retrovirus vector (Muller et al, Mol. Cell. Biol. 77:1785-1792 (1994)) provided by Charles Sawyers (UCLA Medical Center, Los Angeles, CA). In this construct, pl9 is expressed under t control of viral LTR sequences, whereas CD8 expression is controlled by an internal thymidine kina promoter. The plasmid was transfected into NIH-3T3 cells (Chen and Okayama, Mol. Cell. Bi 7:2745-2752 (1987)), and 48 hours later, transfected cells were immunostained with anti-CD8, counte stained with propidium iodide, and analyzed by flow cytometry to determine the DNA content of gat CD8-positive and CD8-negative cells (Look et al, J. Clin. Invest. 73:1617-1628 (1984)). For virus production and infection, the same plasmid was cotransfected into 293T cells (Pear et a Proc. Natl. Acad. Sci. (USA) 90:8392-8396 (1993)) together with a plasmid encoding an ecotropic help virus containing a defective virion packaging (ψ2) sequence (Muller et al, Mol Cell. Biol 77:1785-17 (1994)). Culture supernatants containing retroviruses harvested 48-72 hours after transfection were us to infect proliferating NIH-3T3 fibroblasts. Infected cells were analyzed 48 hours later by flow cytomet as described above or were lysed in IP kinase buffer, and CDK4-cyclin D complexes were immunoprecipit ted and assayed for Rb kinase activity (Matsushime et al, Mol. Cell. Biol 74:2066-2076 (1994)). InK4d-pl 9 Arrests Gl Progression Expression of pi 9 is extinguished during Gl phase as CDK4-cyclin D or CDK6-cyclin D executes its critical functions. To determine whetiher constitutive expression of pi 9 would specifically arrest the cell cycle in Gl phase, pl9 cDNA was inserted into a retroviral expression vector that also encodes the CD8 cell surface antigen. Asynchronously proliferating mouse NIH-3T3 fibroblasts were transfected with CD8 vectors lacking or containing pi 9 cDNA, and 48 hours later, the transfected cells were analyzed for both CD8 expression and DNA content by two color flow cytometry. Cells transfected with the vector encoding both CDδ and pl9 yielded a proportion of untransfected recipients that exhibited background CDδ fluores¬ cence and were distributed throughout the cell cycle (delimited by box Rl in Figure 9, Panels A and B). By contrast, 85% of those cells that expressed high levels of CD8 antigen (gated in box R2) exhibited a 2N DNA content characteristic of those in Gl phase (Figure 9, Panels A and B). Cells transfected with the control CD8 expression vector, whether CDδ-positive or not, were distributed throughout the cell cycle in a manner indistinguishable from those of untransfected cells (Gl = 54.6% ± 4.9; S = 36.5% ± 3.1; and remainder G2/M) indicating that transfection per se was not toxic and did not induce cell cycle arrest. In five independent experiments, transfection with the CDδ vector coexpressing pi 9 increased the proportion of cells in Gl by 22% ± 12, whereas transfection with the control CD8 vector had no effect. By cotransfecting the pi 9 vector plasmid together with a second plasmid providing retroviral helper functions into SV40 T antigen-positive 293T cells, virions were produced that were capable of efficiently infecting NIH-3T3 cells. Within 48 hours of infection, the majority of such cells became CD8-positive and exhibited a concomitant (18% ± 3%) increase in their Gl fraction as compared to cells infected with the control CD8 vector lacking pl9 cDNA. Cells harvested upon completion of the experiment, unlike prolif¬ erating NIH-3T3 cells, lacked detectable cyclin D-dependent kinase activity (Figure 9, Panel B, lanes 9-11). Even using cells engineered to overexpress cyclin D (Quelle et al, Genes & Devel. 7:1559-1571 (1993)), where the levels of cyclin D-dependent kinase are elevated 5-10 fold (Matsushime et al, Mol. Cell Biol. 74:2066-2076 ( 1994)), infection with the p 19 vector almost completely inhibited cyclin D-dependent kinase (or cdk4 kinase) activity (Figure 9, Panel B, lanes 1-8). Therefore, Gl phase arrest induced by constitutive pi 9 expression is accompanied by inhibition of cyclin D-dependent kinase activity in vivo. Introduction of a vector encoding pi 9 into NIH-3T3 fibroblasts led to Gl phase arrest, indicating that pi 9 synthesis during the Gl interval, but apparently not during later phases, can halt cell cycle progression. Cyclin Dl -dependent (CDK4) kinase activity was markedly reduced in cells engineered to ectopically express pi 9, including those that were engineered to overexpress cyclin Dl, demonstrating that pi 9 has potent CDK4 inhibitory activity in vivo. The simplest inteφretation is that pl9-mediated inhibition of CDK4 kinase activity renders such cells unable to transit a cyclin D-dependent Gl phase checkpoint. Example 8: Cloning of Human pi 9 cDNA Sequences To obtain a human cDNA encoding InK4d-pl9, a ~300-bp Spel-Hincll fragment of the murine pi cDNA was isolated, labeled with α 32 P-dCTP (DuPont-NEN, Boston, MA) by use of random hexamers an the Klenow fragment of DNA polymerase (Boehringer Mannheim, Indianapolis, IN) (Feinberg an Vogelstein, Anal. Biochem. 732:6-13 (1983)), and was used to screen a lambda gt-10 cDNA library prepare from human bone marrow (Clontech Laboratories, Palo Alto, CA). This library was chosen based on th preliminary observation that the message of the Ink4d gene was highly expressed in hematopoietic tissue as demonstrated in Northern blots of tissues from mouse organs (Example 5). Colony lifts on nylo membrane filters (Amersham, Arlington Heights, IL) were hybridized with 1 x 10 6 cpm of probe per ml i 3 x SSC, 1 x Denhardt, 40 ug/ml denatured salmon testis DNA and 35% formamide at 42°C overnight Filters were washed in 1 x SSC, 0.1% SDS at 42 °C followed by autoradiography. The conditions fo hybridization and washing were predetermined by Southern blot analysis using the mouse probe o fractionated human genomic DNA. Candidate clones were plaque purified, and cDNA inserts wer subcloned into pBluescript (Stratagene, La Jolla, CA) plasmid vector and subjected to restriction enzym mapping by standard methods (Sambrook et al, Molecular Cloning: A Laboratory Manual, 2nd Ed., Col Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1989), pages 5.28-5.32) and to sequencin analysis by the dideoxynucleotide chain-termination method (Sanger et al, Proc. Natl. Acad. Sci. (USA 74:5463-5467 (1977)) modified for use with double-stranded DNA templates (United Stated Biochemical Cleveland, OH). To obtain human cDNA for InK4d-pl9, one million plaques from a human bone marrow cDN library were screened. Three independent human pl9 cDNA clones were isolated, including a 1.4-kb cDN clone (clone 19-4) and two smaller, presumed partial cDNA clones (clones 19-1 and 19-3). Given the siz of mRNA transcripts detected in Northern blot analysis (~1.4-kb; see Example 10), it is likely that clone 19 4 contains a full-length cDNA. Sequence analysis of the three clones revealed an open reading frame of 49 bp that encodes a 166 amino acid polypeptide having a predicted molecular weight of 17.7 kilodaltons (kDa (Figure 10A). As described in Example 1, the mouse Ink4d gene product comprises four repeats of a ankyrin motif, and belongs to the InK4 gene family. The sequence of the human InK4d-pl9 polypeptid is 86% identical at the amino acid level to that of the murine InK4d-pl9 clone and 44% identical to huma lnK4c-pl 8, its most closely related InK family member (Figure 10B). Example 9: Analysis and Cloning of Human pl9 Genomic DNA Sequences Southern Blot Analysis High molecular weight genomic DNA was isolated by standard techniques from Epstein-Barr virus (EBV) transformed lymphoblastoid cell lines established from peripheral blood of healthy volunteers. The isolated DNA was digested with restriction endonuclease EcoRI, Bglll or Hindϊll, size fractionated by electrophoresis through a 0.9% agarose gel, transferred to a nylon membrane (HyBond-N, Amersham), and hybridized with a 32 P- labeled 1.4-kb human InK4d-pl9 cDNA (clone 19-4). After high stringency washing in 0.1 x SSC and 0.1% SDS at 65 °C, the filters were exposed to XAR-5 film (Kodak, Rochester, NY) with intensifying screens at -70°C. Results of this analysis demonstrate a single InK4d-pl9 hybridizing restriction fragment following digestion with EcoRI (-23 kb), Bglll (-22 kb), and Hwidlll (-9 kb), consistent with InK4d-pl9 being encoded by a single copy gene. The estimated size of the genomic locus for the human Ink4d gene is <20 kb. Isolation of a PI Phage Clone for the Human pi 9 Locus A human genomic PI -phage library (Genome Systems, St. Louis, MO) was screened by the polymerase chain reaction (PCR) using a pair of oligonucleotide primers, the sequences of which are derived from the cloned human pl9 cDNA nucleotide sequence: AGC AAGGTGCCAGCCCC AATGTCCA (5 ' primer) (SΕQ ID NO: 14); and GCGTCCCTGCGATGGAGATCAGATT (3' primer) (SΕQ ID NO: 15). The primers were designed to amplify a 225 bp fragment within putative exon 2 of the gene, as predicted by comparing the pl9 sequence with the genomic organization of InK4a-pl6 genes (Serrano et al, Nature 366:704-707 (1993); Kamb et al, Science 264:436-440 (1994); Noburi et al, Nature 365:753-756 (1994)). The predicted genomic organization was verified by amplification reactions that yielded a product of expected size from human genomic DNA. PCR amplification conditions were optimized prior to screening the library. Three partially overlapping PI -phage clones (#3857, #3858, #3859) yielded the expected sized InK4d-pl9 PCR amplification fragment. Southern blot analysis of DNA isolated from these clones revealed identical sized InK4d-pl9 hybridizing EcoRI, BgHl, and Hindlll restriction fragments compared to those seen with total human genomic DNA (i.e., -23 kb, -22 kb and -9 kb, respectively), demonstrating that the Pl-phage clones contained the entire InK4d-pl9 genomic locus. Clone #3857 was used as a probe for fluorescence in situ hybridization analysis (see Example 11). Example 10: Expression of pi 9 in Human Cells Cell Culture, Cell Cycle Fractionation and Induction ofApoptosis HeLa and CEM-C7 (a human immature T-cell line) cells were cultured under standard condition (Zieve et al, Exp. Cell Res. 726:397-405 (1980); Lahti et al, Mol. Cell Biol. 75:1-111 (1995)). For cel cycle fractionation, HeLa cells were arrested at mitosis as described by Zieve et al. by sequential treatmen with 5 mM thymidine and 0.4 ug ml of nocadazole for 8 hours and 12 hours, respectively. Mitotic cell were then harvested by mechanical release from the culture dish. After releasing from nocadazole bloc by washing with phosphate buffer and putting back the cells into complete culture media, the cells enterin cell cycle were sequentially harvested for RNA isolation at every 2 hours for 24 hours, and DNA conten of aliquots at each time point was measured by flow cytometric analysis of propidium iodide stained nucle (see Example 5). Apoptosis was induced by treated CEM-C7 cells with a FAS monoclonal antibod (Upstate Biotechnology, Inc.) at 100 ng/ml, and cells were collected at various time points for RNA an DNA analysis. Programmed cell death was confirmed by moφhological analysis of nuclei and DN analysis by fractionation in a 0.9% agarose gel followed by ethidium bromide staining (Lahti et al, Mo Cell Biol 75:1-11 (1995)). Northern Blot Analysis Total cellular RNA and poly(A)+ RNA were isolated from murine and human cell lines by standar methods (Sambrook et al, Molecular Cloning: A Laboratory Manual, 2nd Ed., Cold Spring Harbo Laboratory Press, Cold Spring Harbor, NY (1989), pages 7.39-7.52). Approximately 20 ug of total cellula RNA or 4 ug of poly(A)+ RNA were fractionated on 1.0% agarose-formaldehyde gels by electrophoresi and blotted to nitrocellulose or nylon membrane filters. Northern blots containing poly(A)+ RNA fro various human adult or fetal tissues were purchased (Clontech). Filters were hybridized with a cDNA prob for human InK4d-pl9 or chicken or human cDNAs for β-actin. Final wash of the filters was in 0.1 x SSC 0.1% SDS at 60°C. Northern blot analysis of various human adult and fetal organs was used to assess the tissu distribution of human InK4d (pi 9) expression. A 1.4 kb transcript was expressed ubiquitously with hig levels in brain, thymus, spleen, peripheral blood leukocyte and fetal liver as shown in Figure 1 1. Becaus the expression levels of mouse pi 9 mRNA oscillate during the cell cycle in mouse macrophages (Exampl 5), the pattern of expression of human pl9 was examined as a function of the cell cycle in the huma cervical carcinoma cell line LeLa. Similar to the results shown in Figure 7, Human InK4d mRNA wa present in cells synchronized at mitosis with nocadazole block, and the mRNA level declined graduall according to the Gl progression after release from the drug. When approximately 50% of the cells bega to enter S phase (12 hours after the release), the pi 9 mRNA signal began to rise and reached maximu expression at a point which corresponds to the entry from mid to late S phase for the majority of the cell (18-20 hours after the release) (Figure 12). Several of the organs where human pi 9 gene is highly expressed are known to contain cells that are undergoing apoptosis. Accordingly, pi 9 expression during FAS-induced apoptosis was analyzed. As shown in Figure 13, the immature T-cell line CEM-C7 undergoes apoptotic cell death with 1-2 hrs after treatment of FAS antibody. In this system, the pl9 gene is rapidly (within 60 min.) down regulated by this treatment. In contrast, expression levels of other members of the InK4 gene family, InK4a-pl6 and InK4b-pl 8, were maintained at a constant level for up to 6 hrs following FAS treatment (data not shown). Example 11: Chromosomal Assignment of the Human pi 9 Gene Fluorescence in situ hybridization (FISH) was used to define the chromosomal location of the gene for human pl9 (Selleri et al, Proc. Natl. Acad. Sci. (USA) 5S:8δ7-δ91 (1991); Tkachuk et al. Science 250:559-562 (1990)). Bromodeoxyuridine-synchronized, phytohemagglutinin-stimulated peripheral blood lymphocytes from a normal male donor were used as a source of metaphase chromosomes. DNA from the human pl9-containing PI -phage clone #3857 (Example 9) was nick-translated with digoxigenin-11-UTP (Boehringer Mannheim) and hybridized overnight at 37°C to fixed metaphase chromosomes as described (Okuda et al, Genomics 27:217-821 (1994)). As a control probe to indicate the human chromosome 19 band ql3, a cosmid clone for human D-site-binding protein gene (DBP) (Khatib et al, Genomics 23:344-351 (1994)) was labeled with biotin-11-dUTP (Gibco-BRL, Gaithersburg, MD) and included in the incubation mixture. Specific hybridization signals were detected by applying the fluorescein-conjugated sheep antibodies to digoxigenin (Boehinger Mannheim), and avidin Texas red (Vector Laboratories Inc., Burlingame, CA) to biotin, followed by counter staining in propidium iodide (Sigma Chemicals, St. Louis, MO). Fluorescein microscopy was performed with a Zeiss standard microscope equipped with fluorescence filters to detect green signals (fluorescein- labeled pi 9) in comparison with red signals (Texas-red-labeled DBP on l9ql3). Analysis of metaphase preparations demonstrated the localization of pl9 hybridizing sequences to a telomeric region on the short arm of chromosome 19 (Figure 14). The identity of chromosome 19 was confirmed by the co-localization of the signal for the human DBP gene in the short arm of this chromosome in two-color analysis. On the basis of the distance of the signal from centromere relative to the entire length of the short arm, Ink4d, the gene for human pi 9, was assigned to band 19pl3. Chromosome 19 band pl3 is involved in non-random translocation t(l;19Xq23;pl3), which is primarily observed in pediatric patients with acute lymphoblastic leukemia having a pre-B cell immunophenotype. Using the nucleic acids of the inventions as a probe, Southern blots were prepared on 3 pediatric ALL patients whose leukemic blasts contained a t( 1 ; 19) translocation. No evidence of a rearrangement in, or either hemizygous or homozygous loss of, InK4d-pl9 was observed in these cases, suggesting that the InK4d gene was not involved in these particular translocations. The nucleic acids of the invention are useful as probes in hybridization analyses or, in the case of the oligonucleotides of the invention, as pl9-specific primers for amplification and analysis of genomic DNA by PCR (Bos, J., in PCR Technology: Principles and Applications for DNA Amplification, Erlich, ed., Stockton Press, New York (1989), pages 225-233), in further studies of chromosomal structur in additional cases and types of carcinomas and neoplasms. Deposits A cDNA clone having coding sequences derived from the InK4c (pi 8) gene from mouse contained in plasmid pSKpl 8 lnk4c < 0UM >. A cDNA clone having coding sequences derived from the InK (pl9) gene from mouse is contained in plasmid pSKpl9 ln 4d< ouje) . A cDNA clone having coding sequenc derived from the InK4d (pl9) gene from human is contained in plasmid pl9-4B. Plasmids pSKpl ω[ c<π,ou and pSKpl9 ta 4i<mo,,i ) were deposited under the Budapest Treaty with the American Type Culture Collecti (A.T.C.C), 12301 Parklawn Drive, Rockville, Maryland, 20852, U.S.A. on February 6, 1995, and assign the accession numbers 97045 and 97044, respectively. Plasmid pl9-4B was deposited under the Budape Treaty with the American Type Culture Collection (A.T.C.C), 12301 Parklawn Drive, Rockville, Marylan 20852, U.S.A. on February 6, 1995, and assigned the accession number 97043. After issuance of a pate on this application, the A.T.C.C. will make the plasmids available to requestors in accordance with t Budapest Treaty and applicable U.S. patent laws and regulations. These deposits are not a license to practi the invention, and no admission is intended to be made that the deposits were necessary to satisfy the pate laws of the United States or any other country. Utility of the Invention The embodiments of the invention described above can be used for such puφoses as listed belo alone or in combination with each other or other complementary methods and/or compositions. ( 1 ) The nucleic acids of the invention, which include sequences encoding the polypeptide sequenc of a plδ protein from a non-human mammal or a pl9 protein from mice, humans and other mammals, a useful for producing plδ or pl9 proteins, or fusion proteins derived therefrom, using recombinant DN technology (see Example 2). (2) Methods for detecting one or more nucleic acids encoding plδ or pl9 polypeptide sequence or alterations in such nucleic acids, are useful to diagnose certain types of cancers or to identi predispositions to certain types of cancers. The methods of the invention utilize one or more nucleic aci encoding pi δ or pi 9 polypeptide sequences in hybridization and/or amplification assays specific for pi or pl9 genetic sequences. Genetic alterations in pi 8 or pi 9 nucleic acids that correlate with cancer and a detected by the methods of the invention include RFLPs, deletions, insertions, inversions, point mutation altered mRNA splicing products, and the like. The methods for detecting pi 8 or pl9 nucleic acids are als useful for isolating pi 8 or pi 9 nucleic acids from other mammals such as cats, dogs, horses, pigs, cows, et (see Example 8). (3) The nucleic acids of the invention are also useful in methods of gene therapy in order to enhan or restore pi 8 or p!9 activity in mammalian cells by, for example, directing the constitutive expression a protein containing pi 8 or pl9 polypeptide sequences in cells in need of regulation of cellular growth, the cell cycle, or DNA replication (see Example 7). (4) One subset of the nucleic acids of the invention, antisense oligonucleotides that bind to mRNA molecules encoding pl8 or pl9, are useful for inhibiting plδ and/or pl9 activity in mammalian cells in need of stimulation of cellular growth, the cell cycle, or DNA replication. In particular, cells in need of growth stimulation include hematopoietic stem cells. InK4c-pl 8 and InK4d-pl 9 are expressed at high levels in hematopoietic tissues, i.e., bone marrow and spleen, and may likely act to prevent the cycling of hematopoietic stem cells. A key goal of transplantation therapy is to grow hematopoietic stem cells in vitro, maintaining them in an immature, multipotential state. To the extent that these cells are kept out of cycle by CDK inhibitors pi 8 or pl9, it is possible to move them into the cell cycle and grow them in vitro by reducing the amount of pi 8 or pi 9 present in stem cells by treatment with the antisense oliognucleotides of the invention. (5) The nucleic acids of the invention are useful for making transgenic non-human animals that have a genetical ly engineered alteration in one or more nucleic acids encoding p 18, p 19 or both p 18 and p 19. In particular, the genomic DNA sequences of pi 8 and pl9 from mice are used to generate transgenic mice that are homozygous for a pi 8 null allele, a pl9 null allele, or for both pi 8 and pi 9 null alleles. Transgenic mice with reduced or absent pi 8 and/or pi 9 activity develop certain types of carcinomas and neoplasms in a reproducible and thus predictable manner, and serve as useful animal models for human cancers. (6) Purified pi 8 or pl9 proteins, peptide fragments and oligopeptides, or fusion proteins derived from the joining of a pl8 or pl9 polypeptide sequence with a second polypeptide sequence, inhibit mammalian cells from proceeding past the Gl phase of the cell cycle, i.e., prevent cells from initiating the replication of chromosomal DNA molecules. Purified plδ or pi 9 proteins or fusion proteins derived therefrom are useful for treating diseases characterized by uncontrolled cell growth such as cancers, carcinomas, tumors, neoplasms and the like. The pi 8 or pi 9 proteins, fusion proteins, peptide fragments or synthetic oligopeptides derived therefrom, can be introduced into eukaryotic cells to arrest their progression from Gl to S phases during inteφhase and thus inhibit growth of the cells, particularly cells undergoing rapid or uncontrolled growth (see Example 7). (7) Methods are known in the art for using non-polypeptide Gl kinase inhibitors to distinguish and selectively kill transformed (neoplastic) cells and have been described by, e.g., Crissman et al. (U.S. Patent 5,185,260 (Feb. 9, 1993)). Such methods reflect the fact that, at low doses, Gl kinase inhibitors selectively and reversibly arrest normal cells without arresting neoplastic cells; the latter may be selectively killed by therapeutic agents that do not affect normal cells in the Gl phase. The polypeptide Gl kinase inhibitors of the invention (i.e., pi 8 and pi 9 proteins or fusion proteins or oligopeptides derived therefrom) function in these methods with enhanced selectivity with regard to the Gl kinases (i.e., CDK4, CDK6) that are specifically inhibited thereby, and may be used in conjunction with chemotherapeutic agents known i the art to kill neoplastic cells. (8) The methods and compositions of the invention are useful for the identification and desig of synthetic compositions that inhibit pl8 or pl9 activities in vivo. For example, fusion polypeptides (se Example 2), peptide fragments generated by proteolysis or synthetic oligopeptides containing differen portions of the plδ or pl9 polypeptide sequences can be assayed for their ability to bind CDK4 and CDK kinases by using the assay described herein (see Example 3). In this fashion, the polypeptide sequence comprised within CDK-binding motifs are identified. The structure of these polypeptide motifs is used i turn in computer-assisted rational drug design to generate plδ or pi 9 mimetics that are assayed for thei ability to bind CDK4 and/or CDK6 kinases according to the methods of the invention (Martin, Y.C. Methods in Enzymology 203:5δ7-613 (1991)). The pi δ or pl9 mimetics can be introduced into eukaryoti cells to arrest their progression from Gl to S phases during inteφhase and thus inhibit growth of the cell (see Example 7). (9) The proteins and polypeptide sequences of the invention are also useful as antigens in order t generate antibodies that specifically bind p 18 or p 19 epitopes. Specifically, p 18 or p 19 proteins, or fusio proteins derived therefrom, are produced by recombinant DNA technology and used to immunize animals Alternatively, synthetic oligopeptides having polypeptide sequences derived from a pi 8 or p 19 protein ar prepared and used to immunize animals (see Example 6). (10) Antibodies that specifically bind proteins having pi 8 or pi 9 polypeptide sequences (se Example 6) are useful in assays to detect various forms of, quantitate the levels of, or to determine th presence (or absence) and distribution of, pi 8 or pl9 protein in cells from a mammal. Alterations in pi or pl9 polypeptides that correlate with cancer and are detected by the methods of the invention include, fo example, truncated proteins resulting from aborted translation. Antibodies to pi 8 or pi 9 polypeptides ar also used to isolate pi 8 or pi 9 proteins from other mammals such as cats, dogs, horses, pigs, cows, etc. SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: St. Jude Children's Research Hospital (ii) TITLE OF INVENTION: InK4c-pl8 and InK4d-P19, Inhibitors of Cyclin Dependent Kinases CDK4 and CDK6, and Uses Thereof (iii) NUMBER OF SEQUENCES: 15 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: STERNE, KESSLER, GOLDSTEIN & FOX, P.L.L.C. (B) STREET: 1100 New York Ave. , N.W. (C) CITY: Washington (D) STATE: D.C. (E) COUNTRY: USA (F) ZIP: 20005 (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: to be assigned herewith (B) FILING DATE: 06-FEB-1996 (C) CLASSIFICATION: (vii) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: 08/384,106 (B) FILING DATE: 06-FEB-1995 (C) CLASSIFICATION: (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: Fox, Samuel L. (B) REGISTRATION NUMBER: 30,353 (C) REFERENCE/DOCKET NUMBER: 0656.050PC01 (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: 202-371-2600 (B) TELEFAX: 202-371-2540 (2) INFORMATION FOR SEQ ID Nθ:l: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 168 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (vi) ORIGINAL SOURCE: (A) ORGANISM: Mus musculus (B) STRAIN: C57 Black Kaplan (H) CELL LINE: V13 (viii) POSITION IN GENOME: (A) CHROMOSOME/SEGMENT: pl8 (xi) SEQUENCE DESCRIPTION: SEQ ID Nθ:l: Met Ala Glu Pro Trp Gly Asn Glu Leu Ala Ser Ala Ala Ala Arg Gly 1 5 10 15 Asp Leu Glu Gin Leu Thr Ser Leu Leu Gin Asn Asn Val Asn Val Asn 20 25 30 Ala Gin Asn Gly Phe Gly Arg Thr Ala Leu Gin Val Met Lys Leu Gly 35 40 45 Asn Pro Glu lie Ala Arg Arg Leu Leu Leu Arg Gly Ala Asn Pro Asn 50 55 60 Leu Lys Asp Gly Thr Gly Phe Ala Val lie His Asp Ala Ala Arg Ala 65 70 75 80 Gly Phe Leu Asp Thr Val Gin Ala Leu Leu Glu Phe Gin Ala Asp Val 85 90 95 Asn He Glu Asp Asn Glu Gly Asn Leu Pro Leu His Leu Ala Ala Lys 100 105 110 Glu Gly His Leu Pro Val Val Glu Phe Leu Met Lys His Thr Ala Cys 115 120 125 Asn Val Gly His Arg Asn His Lys Gly Asp Thr Ala Phe Asp Leu Ala 130 135 140 Arg Pne Tyr Gly Arg Asn Glu Val He Ser Leu Met Glu Ala Asn Gly 145 150 155 _60 Val Gly Gly Ala Thr Ser Leu Gin 165 INFORMATION FOR SEQ ID NO:2: (I) SEQUENCE CHARACTERISTICS: (A) LENGTH: 166 amino acids (B) TYPE: amino ac d (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (vi) ORIGINAL SOURCE: (A) ORGANISM: Mus musculus (B) STRAIN: C57 Black Kaplan (H) CELL LINE: VI3 in) POSITION IN GENOME: (A) CHROMOSOME/SEGMENT: pl9 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: Met Leu Leu Glu Glu Val Cys Val Gly Asp Arg Leu Ser Gly Ala Arg 1 5 10 15 Ala Arg Gly Asp Val Gin Glu Val Arg Arg Leu Leu H s Arg Glu Leu 20 25 30 Val His Pro Asp Ala Leu Asn Arg Phe Gly Lys Thr Ala Leu Gin Val 35 40 45 Met Met Phe Gly Ser Pro Ala Val Ala Leu Glu Leu Leu Lys Gin Gly 50 55 60 Ala Ser Pro Asn Val Gin Asp Ala Ser Gly Thr Ser Pro Val His Asp 65 70 75 80 Ala Ala Arg Thr Gly Phe Leu Asp Thr Leu Lys Val Leu Val Glu His 85 90 95 Gly Ala Asp Val Asn Ala Leu Asp Ser Thr Gly Ser Leu Pro He His 100 105 no Leu Ala He Arg Glu Gly His Ser Ser Val Val Ser Phe Leu Ala Pro 115 120 125 Glu Ser Asp Leu His His Arg Asp Ala Ser Gly Leu Tnr Pro Leu Glu 130 135 140 Leu Ala Arg Gin Arg Gly Ala Gin Asn Leu Met Asp He Leu Gin Gly 145 150 155 160 His Met Met He Pro Met 165 INFORMATION FOR SEQ ID NO:3: (I) SEQUENCE CHARACTERISTICS: (A) LENGTH: 507 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear ii) MOLECULE TYPE: cDNA vi) ORIGINAL SOURCE: (A) ORGANISM: Mus musculus (B) STRAIN: C57 Black Kaplan (K) CELL LINE: VI3 ll) POSITION IN GENOME: (A) CHROMOSOME/SEGMENT: pi8 1X1) SEQUENCE DESCRIPTION: SEQ ID Nθ:3: -CGAGC CTTGGGGGAA CGAGTTGGCG TCCGCAGCTG CCAGGGGGGA CCTAGAGCAA 60 -TAGTT TGTTGCAAAA TAATGTAAAC GTCAACGCTC AAAATGGATT TGGGAGAACT 120 TGCAGG TTATGAAACT TGGAAATCCG GAGATTGCCA GGAGGCTTCT CTCAGAGGT 180 V-CCCA ATTTGAAAGA TGGAACTGGT TTTGCTGTCA TTCATGATGC TGCCAGAGCA 24C GGTTTCCTGG ACACTGTACA GGCTTTGCTG GAGTTCCAGG CTGATGTTAA CATTGAAGAT 300 AATGAAGGGA ACCTGCCCTT GCACTTGGCT GCCAAAGAAG GCCACCTCCC TGTGGTGGAG 360 TTCCTTATGA AGCACACAGC CTGCAATGTG GGGCATCGGA ACCATAAGGG GGACACCGCC 420 TTCGACTTGG CCAGGTTCTA TGGAAGAAAT GAGGTCATTA GCCTGATGGA GGCAAATGGG 480 GTTGGGGGAG CCACAAGCCT GCAGTGA 507 (2) INFORMATION FOR SEQ ID NO:4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 694 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (vi) ORIGINAL SOURCE: (A) ORGANISM: Mus musculus (B) STRAIN: C57 Black Kaplan (H) CELL LINE: V13 (viii) POSITION IN GENOME: (A) CHROMOSOME/SEGMENT: plB ( i) SEQUENCE DESCRIPTION: SEQ ID NO:4: CCTCGAGATT TACCCTGCGA AGGACCTGAC TCTGAAATTC TGCCTCAAAT CACCACTGTG 60 AACAAGGGAC CCTAAAGAAT GGCCGAGCCT TGGGGGAACG AGTTGGCGTC CGCAGCTGCC 120 AGGGGGGACC TAGAGCAACT TACTAGTTTG TTGCAAAATA ATGTAAACGT CAACGCTCAA 180 AATGGATTTG GGAGAACTGC GCTGCAGGTT ATGAAACTTG GAAATCCGGA GATTGCCAGG 240 AGGCTTCTCC TCAGAGGTGC TAATCCCAAT TTGAAAGATG GAACTGGTTT TGCTGTCATT 300 CATGATGCTG CCAGAGCAGG TTTCCTGGAC ACTGTACAGG CTTTGCTGGA GTTCCAGGCT 360 GATGTTAACA TTGAAGATAA TGAAGGGAAC CTGCCCTTGC ACTTGGCTGC CAAAGAAGGC 420 CACCTCCCTG TGGTGGAGTT CCTTATGAAG CACACAGCCT GCAATGTGGG GCATCGGAAC 480 CATAAGGGGG ACACCGCCTT CGACTTGGCC AGGTTCTATG GAAGAAATGA GGTCATTAGC 540 CTGATGGAGG CAAATGGGGT TGGGGGAGCC ACAAGCCTGC AGTGAATGTG TAGAGGTCTC 600 TCTCACTGAC CTCACACTGT CCGTTAGTTG GTTGGCTGTC CGTTTCACTA TCACTTATTA 660 AAATATAGGG TTTCTTCGCT TTGTTTTAAA ATAT 694 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 501 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (vi) ORIGINAL SOURCE: (A) ORGANISM: Mus musculus (B) STRAIN: C57 Black Kaplan (H) CELL LINE: V13 (viii) POSITION IN GENOME: (A) CHROMOSOME/SEGMENT: pi9 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: ATGCTTCTGG AAGAAGTCTG CGTCGGCGAC CGGTTGAGTG GCGCACGGGC CCGTGGCGAC 60 GTGCAAGAGG TCCGCCGCCT TCTTCACCGG GAGCTGGTGC ATCCTGACGC CCTGAACCGC 120 TTTGGCAAGA CGGCCTTGCA GGTCATGATG TTTGGAAGTC CAGCAGTTGC TTTGGAGCTC 180 CTGAAGCAAG GTGCCAGCCC CAATGTCCAA GATGCCTCCG GTACTAGTCC TGTGCATGAT 240 GCGGCTCGCA CCGGGTTCCT GGACACCCTG AAGGTTCTGG TGGAGCATGG TGCTGATGTC 300 AATGCCCTGG ACAGCACTGG GTCGCTCCCC ATCCATCTGG CGATAAGAGA GGGCCATAGC 360 TCCGTGGTCA GCTTCCTAGC TCCTGAATCT GATCTCCACC ACAGGGACGC TTCCGGTCTC 420 ACTCCCCTGG AGTTGGCTCG GCAGAGAGGG GCTCAGAACC TCATGGACAT TCTGCAGGGG 480 CACATGATGA TCCCAATGTG A 501 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 941 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (vi) ORIGINAL SOURCE: (A) ORGANISM: Mus musculus (B) STRAIN: C57 Black Kaplan (H) CELL LINE: V13 (viii) POSITION IN GENOME: (A) CHROMOSOME/SEGMENT: pl9 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6: CGAATTCGGC ACGAGAGTTG GCCCTGGTGG CACCGCAGTC CCTAGAGTTC TGATCCAGCT 60 CTTGCTGGTT CCCCAGCCCT GACCTTAACT GGGCTTGGGG CTGGGTGGGT TTCACAGTCC 120 ACCGGTATCC ACTATGCTTC TGGAAGAAGT CTGCGTCGGC GACCGGTTGA GTGGCGCACG 180 GGCCCGTGGC GACGTGCAAG AGGTCCGCCG CCTTCTTCAC CGGGAGCTGG TGCATCCTGA 240 CGCCCTGAAC CGCTTTGGCA AGACGGCCTT GCAGGTCATG ATGTTTGGAA GTCCAGCAGT 300 TGCTTTGGAG CTCCTGAAGC AAGGTGCCAG CCCCAATGTC CAAGATGCCT CCGGTACTAG 360 TCCTGTGCAT GATGCGGCTC GCACCGGGTT CCTGGACACC CTGAAGGTTC TGGTGGAGCA 420 TGGTGCTGAT GTCAATGCCC TGGACAGCAC TGGGTCGCTC CCCATCCATC TGGCGATAAG 480 AGAGGGCCAT AGCTCCGTGG TCAGCTTCCT AGCTCCTGAA TCTGATCTCC ACCACAGGGA 540 CGCTTCCGGT CTCACTCCCC TGGAGTTGGC TCGGCAGAGA GGGGCTCAGA ACCTCATGGA 600 CATTCTGCAG GGGCACATGA TGATCCCAAT GTGACCCAAG GCCACTGTCT CCAGCCTTAC 660 TGGGTTACTT GTCAACAAAA GAGGAAAGAA ACTTTCTCTT TTCACACCTG TCCATTGAAG 720 AAGGGAGTGG GAGGAGCAGT TTGTGGTTTA TTGGTGTTGA TTTCTTGAGT GTGTGTGTTT 780 GGGGGGTGTT TCTCATTTGT TTTTCCTCAC CCCTTTTGGT GTGTTGGAAA AGAAGGGTCC 840 TACAGGCAAC AGATCTAAAT GGTTCAGTTT CCTCTGCACT GGGGCTGCAC CAGGGCAGGG 900 GTTAAAGCCC TAGCCTCAGA GTGAGGTCAT CACTTCCCGG G 941 (2) INFORMATION FOR SEQ ID NO: 7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: S55 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (vi) ORIGINAL SOURCE: (A) ORGANISM: Homo sapiens (viii) POSITION IN GENOME: (A) CHROMOSOME/SEGMENT: pi9 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7: TGACAGCGCC GGGCTGGGGC GGGGCGGGGG GCTTTGCAGG CCGCCAGTGT CGACATGCTG 60 CTGGAGGAGG TTCGCGCCGG CGACCGGCTG AGTGGGGCGG CGGCCCGGGG CGACGTGCAG 120 GAGGTGCGCC GCCTTCTGCA CCGCGAGCTG GTGCATCCCG ACGCCCTCAA CCGCTTCGGC 180 AAGACGGCGC TGCAGGTCAT GATGTTTGGC AGCACCGCCA TCGCCCTGGA GCTGCTGAAG 240 CAAGGTGCCA GCCCCAATGT CCAGGACACC TCCGGTACCA GTCCAGTCCA TGACGCAGCC 300 CGCACTGGAT TCCTGGACAC CCTGAAGGTC CTAGTGGAGC ACGGGGCTGA TGTCAACGTG 360 CCTGATGGCA CCGGGGCACT TCCAATCCAT CTGGCAGTTC AAGAGGGTCA CACTGCTGTG 420 GTCAGCTTTC TGGCAGCTGA ATCTGATCTC CATCGCAGGG ACGCCAGGGG TCTCACACCC 480 TTGGAGCTGG CACTGCAGAG AGGGGCTCAG GACCTCGTGG ACATCCTGCA GGGCCACATG 540 GTGGCCCCGC TGTGA 555 (2) INFORMATION FOR SEQ ID NO: 8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 501 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (vi) ORIGINAL SOURCE: (A) ORGANISM: Homo sapiens (viii) POSITION IN GENOME: (A) CHROMOSOME/SEGMEN : pl9 (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..501 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8: ATG CTG CTG GAG GAG GTT CGC GCC GGC GAC CGG CTG AGT GGG GCG GCG 48 Met Leu Leu Glu Glu Val Arg Ala Gly Asp Arg Leu Ser Gly Ala Ala 1 5 10 15 GCC CGG GGC GAC GTG CAG GAG GTG CGC CGC CTT CTG CAC CGC GAG CTG 96 Ala Arg Gly Asp Val Gin Glu Val Arg Arg Leu Leu His Arg Glu Leu 20 25 30 GTG CAT CCC GAC GCC CTC AAC CGC TTC GGC AAG ACG GCG CTG CAG GTC 144 Val His Pro Asp Ala Leu Asn Arg Phe Gly Lys Thr Ala Leu Gin Val 35 40 45 ATG ATG TTT GGC AGC ACC GCC ATC GCC CTG GAG CTG CTG AAG CAA GGT 192 Met Met Phe Gly Ser Thr Ala He Ala Leu Glu Leu Leu Lys Gin Gly 50 55 60 GCC AGC CCC AAT GTC CAG GAC ACC TCC GGT ACC AGT CCA GTC CAT GAC 240 Ala Ser Pro Asn Val Gin Asp Thr Ser Gly Thr Ser Pro Val His Asp 65 70 75 80 GCA GCC CGC ACT GGA TTC CTG GAC ACC CTG AAG GTC CTA GTG GAG CAC 288 Ala Ala Arg Thr Gly Phe Leu Asp Thr Leu Lys Val Leu Val Glu His 85 90 95 GGG GCT GAT GTC AAC GTG CCT GAT GGC ACC GGG GCA CTT CCA ATC CAT 336 Gly Ala Asp Val Asn Val Pro Asp Gly Thr Gly Ala Leu Pro He His 100 105 110 CTG GCA GTT CAA GAG GGT CAC ACT GCT GTG GTC AGC TTT CTG GCA GCT 384 Leu Ala Val Gin Glu Gly His Thr Ala Val Val Ser Phe Leu Ala Ala 115 120 125 GAA TCT GAT CTC CAT CGC AGG GAC GCC AGG GGT CTC ACA CCC TTG GAG 432 Glu Ser Asp Leu His Arg Arg Asp Ala Arg Gly Leu Thr Pro Leu Glu 130 135 140 CTG GCA CTG CAG AGA GGG GCT CAG GAC CTC GTG GAC ATC CTG CAG GGC 480 Leu Ala Leu Gin Arg Gly Ala Gin Asp Leu Val Asp He Leu Gin Gly 145 150 155 160 CAC ATG GTG GCC CCG CTG TGA 501 His Met Val Ala Pro Leu * 165 (2) INFORMATION FOR SEQ ID NO:9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 167 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: Met Leu Leu Glu Glu Val Arg Ala Gly Asp Arg Leu Ser Gly Ala Ala 1 5 10 15 Ala Arg Gly Asp Val Gin Glu Val Arg Arg Leu Leu His Arg Glu Leu 20 25 30 Val His Pro Asp Ala Leu Asn Arg Phe Gly Lys Thr Ala Leu Gin Val 35 40 45 Met Met Phe Gly Ser Thr Ala He Ala Leu Glu Leu Leu Lys Gin Gly 50 55 60 Ala Ser Pro Asn Val Gin Asp Thr Ser Gly Thr Ser Pro Val His Asp 65 70 75 80 Ala Ala Arg Thr Gly Phe Leu Asp Thr Leu Lys Val Leu Val Glu His 85 90 95 Gly Ala Asp Val Asn Val Pro Asp Gly Thr Gly Ala Leu Pro He His 100 105 110 Leu Ala Val Gin Glu Gly His Thr Ala Val Val Ser Phe Leu Ala Ala 115 120 125 Glu Ser Asp Leu His Arg Arg Asp Ala Arg Gly Leu Thr Pro Leu Glu 130 135 140 Leu Ala Leu Gin Arg Gly Ala Gin Asp Leu Val Asp He Leu Gin Gly 145 150 155 160 His Met Val Ala Pro Leu * 165 (2) INFORMATION FOR SEQ ID NO:10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iv) ANTI-SENSE: NO (vi) ORIGINAL SOURCE: (A) ORGANISM: Mus musculus (B) STRAIN: C57 Black Kaplan (viii) POSITION IN GENOME: (A) CHROMOSOME/SEGMENT: pi8 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10: CCGGATCCAT GGCCGAGCCT TGGGG 25 (2) INFORMATION FOR SEQ ID NO-.11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iv) ANTI-SENSE: YES (vi) ORIGINAL SOURCE: (A) ORGANISM: Mus musculus (B) STRAIN: C57 Black Kaplan (viii) POSITION IN GENOME: (A) CHROMOSOME/SEGMENT: plβ (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11: CCGAATTCTC ACTGCAGGCT TGTGG 25 (2) INFORMATION FOR SEQ ID NO:12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iv) ANTI-SENSE: NO (vi) ORIGINAL SOURCE: (A) ORGANISM: Mus musculus (B) STRAIN: C57 Black Kaplan (viii) POSITION IN GENOME: (A) CHROMOSOME/SEGMENT: pi9 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12: CCGGATCCAT GCTTCTGGAA GAAGT 25 (2) INFORMATION FOR SEQ ID NO: 13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iv) ANTI-SENSE: YES (vi) ORIGINAL SOURCE: (A) ORGANISM: Mus musculus (B) STRAIN: C57 Black Kaplan (viii) POSITION IN GENOME: (A) CHROMOSOME/SEGMENT: pl9 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13: CCGAATTCTC ACATTGGGAT CATCA 25 (2) INFORMATION FOR SEQ ID NO:14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iv) ANTI-SENSE: NO (vi) ORIGINAL SOURCE: (A) ORGANISM: Homo sapiens (viii) POSITION IN GENOME: (A) CHROMOSOME/SEGMENT: pi9 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: AGCAAGGTGC CAGCCCCAAT GTCCA 25 (2) INFORMATION FOR SEQ ID NO:15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iv) ANTI-SENSE: YES (vi) ORIGINAL SOURCE: (A) ORGANISM: Homo sapiens (viii) POSITION IN GENOME: (A) CHROMOSOME/SEGMENT: pi9 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15: GCGTCCCTGC GATGGAGATC AGATT 25

Claims: What Is Claimed Is: 1. An isolated nucleic acid molecule containing nucleotide sequences from an InK4d-p 19 ge wherein said nucleic acid molecule comprises from about 30 to about 20,000 base pairs and optiona carries a detectable label. 2. The isolated nucleic acid molecule of claim 1 , wherein said isolated nucleic acid molec is selected from the group consisting of SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO: 3. An isolated nucleic acid molecule containing nucleotide sequences from the sense stra of an InK4d-pl9 gene, wherein said nucleic acid molecule comprises from about 10 to about 30 nucleotid and optionally carries a detectable label. 4. An isolated nucleic acid molecule containing nucleotide sequences from the antisense stra of an InK4d-pl9 gene, wherein said nucleic acid molecule comprises from about 10 to about 30 nucleotid and optionally carries a detectable label. 5. A method of stimulating chromosomal DNA replication and stimulating cell grow wherein said method comprises the step of contacting a eukaryotic cell with the isolated nucleic a molecule of claim 4. 6. A method of detecting a nucleic acid encoding an InK4d-pl9 protein, wherein said meth comprises the step of contacting a sample containing nucleic acids with the isolated nucleic acid molec of claim 1. 7. A method of inhibiting chromosomal DNA replication and arresting cell growth, wher said method comprises the step of introducing into a eukaryotic cell an expression vector containing t isolated nucleic acid of claim 1. δ . A method of producing a protein containing InK4d-p 19 polypeptide sequences, wherein s method comprises the step of introducing into a cell an expression vector containing the isolated nucleic a of claim 1. 9. A method of determining the oncogenic or carcinogenic potential of a compositi comprising the steps of: (a) obtaining a sample containing nucleic acids from an animal that has not be contacted with said composition; (b) obtaining a sample containing nucleic acids from an animal that has been contact with said composition; (c) contacting the sample of step (a) and the sample of step (b) with the isolated nucl acid molecule of claim 1; (d) determining the concentration of a nucleic acid encoding an InK4d-pl9 protein the sample of step (a) and the sample of step (b), wherein a decreased amount of said nucleic acid encoding an InK4d-pl9 protein in the sample of step (b) compared to the amount in the sample of step (a) correlates with an increased oncogenic or carcinogenic potential of said composition. 10. An isolated nucleic acid molecule containing nucleotide sequences from an InK4c-pl 8 gene, wherein said nucleic acid molecule comprises from about 30 to about 20,000 base pairs, optionally carries a detectable label, and wherein said InK4c-pl8 gene is derived from a non-human mammal. 11. The isolated nucleic acid molecule of claim 10, wherein said isolated nucleic acid molecule is selected from the group consisting of SEQ ID NO:3 and SEQ ID NO:4. 12. An isolated nucleic acid molecule containing nucleotide sequences from the sense strand of an InK4c-plδ gene derived from a non-human mammal, wherein said nucleic acid molecule comprises from about 10 to about 30 nucleotides and optionally carries a detectable label. 13. An isolated nucleic acid molecule containing nucleotide sequences from the antisense strand of an InK4c-plδ gene derived from a non-human mammal, wherein said nucleic acid molecule comprises from about 10 to about 30 nucleotides and optionally carries a detectable label. 14. A method of stimulating chromosomal DNA replication and stimulating cell growth, wherein said method comprises the step of contacting a eukaryotic cell with the isolated nucleic acid molecule of claim 13. 15. A method of producing a protein containing InK4c-p 18 polypeptide sequences, wherein said method comprises the step of introducing into a cell an expression vector containing the isolated nucleic acid of claim 10. 16. A method of determining the oncogenic or carcinogenic potential of a composition, comprising the steps of: (a) obtaining a sample containing nucleic acids from an animal that has not been contacted with said composition; (b) obtaining a sample containing nucleic acids from an animal that has been contacted with said composition; (c) contacting the sample of step (a) and the sample of step (b) with the isolated nucleic acid molecule of claim 10; (d) determining the concentration of a nucleic acid encoding an InK4c-pl 8 protein in the sample of step (a) and the sample of step (b), wherein a decreased amount of said nucleic acid encoding an InK4c-pl8 protein in the sample of step (b) compared to the amount in the sample of step (a) correlates with an increased oncogenic or carcinogenic potential of said composition. 17. A substantially pure protein having from 5 to 166 contiguous amino acid residues of a polypeptide sequence selected from the group consisting of SEQ ID NO:2 and SEQ ID NO:9, wherein said substantially pure protein binds specifically to a cyclin-dependent kinase-cyclin D complex, and wherein said cyclin-dependent kinase is selected from the group consisting of CDK4 and CDK6. 18. A substantially pure protein, wherein said protein has a polypeptide sequence selected from the group consisting of SEQ ID NO:2 and SEQ ID NO:9. 19. A method of inhibiting chromosomal DNA replication and arresting cell growth, wherei said method comprises the step of contacting a cell with the substantially protein of claim 17. 20. An antibody composition that specifically binds the substantially pure protein of claim 17. 21. A method of detecting an InK4d-pl9 protein, wherein said method comprises the step o contacting a sample containing proteins with the antibody composition of claim 20. 22. A method of determining the oncogenic or carcinogenic potential of a composition comprising the steps of: (a) obtaining a sample containing proteins from an animal that has not been contacte with said composition; (b) obtaining a sample containing proteins from an animal that has been contacted wit said composition; (c) contacting the sample of step (a) and the sample of step (b) with the antibod composition of claim 20; (d) determ ining the concentration of an InK4d-p 19 protein in the sample of step (a) an the sample of step (b), wherein a decreased amount of said InK4d-pl9 protein in the sample of step (b) compared to the amoun in the sample of step (a) correlates with an increased oncogenic or carcinogenic potential of sai composition. 23. A substantially pure protein, wherein said protein has from 5 to 168 contiguous amino aci residues of the polypeptide sequence of SEQ ID NO: 1 , wherein said protein is isolated from a non-huma mammal, wherein said substantially pure protein binds specifically to a cyclin-dependent kinase-cyclin complex, and wherein said cyclin-dependent kinase is selected from the group consisting of CDK4 an CDK6. 24. A substantially pure protein, wherein said protein has the polypeptide sequence of SEQ I NO:l. 25. An antibody composition that specifically binds the substantially pure protein of claim 23 26. A method of detecting an InK4c-pl8 protein, wherein said method comprises the step o contacting a sample containing proteins with the antibody composition of claim 25. 27. A method of determining the oncogenic or carcinogenic potential of a composition comprising the steps of: (a) obtaining a sample containing proteins from an animal that has not been contacted with said composition; (b) obtaining a sample containing proteins from an animal that has been contacted with said composition; (c) contacting the sample of step (a) and the sample of step (b) with the antibody composition of claim 25; (d) determ ining the concentration of an InK4c-p 18 protein in the sample of step (a) and the sample of step (b), wherein a decreased amount of said InK4c-pl8 protein in the sample of step (b) compared to the amount in the sample of step (a) correlates with an increased oncogenic or carcinogenic potential of said composition. 2δ. A transgenic non-human animal having a having a phenotype selected from the group consisting of reduced or altered InK4c-p 1 δ activity, a phenotype of reduced or altered InK4d-p 19 activity, and a phenotype of reduced or altered activity of both InK4c-plδ and InK4d-pl9. 29. A method of determining the therapeutic value of a potential anti-cancer composition, wherein said method comprises the step of contacting said composition to the transgenic non-human animal of claim 31. 30. A method of determining the risk of a potential oncogenic or carcinogenic composition, wherein said method comprises the step of contacting said composition to the transgenic non-human animal of claim 31. AMENDED CLAIMS [received by the International Bureau on 15 Duly 1996 (15.07.96); original claims 1-5 and 7-9 amended; remaining claims unchanged (4 pages)] 1. An isolated nucleic acid molecule containing nucleotide sequences from an InK4d-pl 9 gene, wherein said nucleic acid molecule comprises from about 10-1000 nucleotides encoding a pl9 polypeptide having more than 40% identity to an amino acid sequence of SEQ ID NO:2 as a mouse InK4d-pl9 gene or SEQ ID N0.9 as a human lnK4d-pl9 gene, and optionally carries a detectable label. 2. The isolated nucleic acid molecule of claim 1, wherein said nucleotides encoding a pl9 polynucleotide have at least 90% identity to DNA sequences selected from the group consisting of SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:δ. 3. An isolated oligonucleotide probe containing nucleotide sequences from a sense strand of an InK4d-pl9 gene according to claim 1, wherein said nucleic acid molecule comprises from about 10 to about 30 nucleotides and optionally carries a detectable label. 4. An isolated oligonucleotide probe containing nucleotide sequences from an antisense strand of an InK4d-pl9 gene according to claim 1, wherein said nucleic acid molecule comprises from about 10 to about 30 nucleotides and optionally carries a detectable label. 5. A method of stimulating chromosomal DNA replication and stimulating cell growth, wherein said method comprises the step of contacting a eukaryotic cell with the isolated oligonucleotide probe of claim 4. 6. A method of detecting a nucleic acid encoding an lnK4d-pl9 protein, wherein said method comprises the step of contacting a sample containing nucleic acids with the isolated nucleic acid molecule of claim 1. 7. A method of inhibiting chromosomal DNA replication and arresting cell growth, wherein said method comprises the step of introducing into a eukaryotic cell an expression vector containing the isolated nucleic acid molecule of claim 1. 8. A method of producing a protein containing InK4d-pl 9 polypeptide sequences, wherein said method comprises the step of introducing into a cell an expression vector containing the isolated nucleic acid molecule of claim 1. 9. A method of determining the oncogenic or carcinogenic potential of a composition, comprising the steps of: (a) obtaining a sample containing nucleic acids from an animal that has not been contacted with said composition; (b) obtaining a sample containing nucleic acids from an animal that has been contacted with said composition: (c) contacting the sample of step (a) and the sample of step (b) with the isolated nucleic acid molecule of claim 1 ; (d) determining the concentration of a nucleic acid encoding an InK4d-p 19 polypeptide in the sample of step (a) and the sample of step (b), wherein a decreased amount of said nucleic acid encoding an InK4d-pl9 polypeptide in the sample of step (b) compared to the amount in the sample of step (a) correlates with an increased oncogenic or carcinogenic potential of said composition. 10. An isolated nucleic acid molecule containing nucleotide sequences from an lnK4c-p 18 gene, wherein said nucleic acid molecule comprises from about 30 to about 20,000 base pairs, optionally carries a detectable label, and wherein said InK4c-pl 8 gene is derived from a non-human mammal. 1 1. The isolated nucleic acid molecule of claim 10, wherein said isolated nucleic acid molecule is selected from the group consisting of SEQ ID NO:3 and SEQ ID NO:4. 12. An isolated nucleic acid molecule containing nucleotide sequences from the sense strand of an InK4c-pl8 gene derived from a non-human mammal, wherein said nucleic acid molecule comprises from about 10 to about 30 nucleotides and optionally carries a detectable label. 13. An isolated nucleic acid molecule containing nucleotide sequences from the antisense strand of an InK4c-pl8 gene derived from a non-human mammal, wherein said nucleic acid molecule comprises from about 10 to about 30 nucleotides and optionally carries a detectable label. 14. A method of stimulating chromosomal DNA replication and stimulating cell growth, wherein said method comprises the step of contacting a eukaryotic cell with the isolated nucleic acid molecule of claim 13. 15. A method of producing a protein containing InK4c-p 18 polypeptide sequences, wherein said method comprises the step of introducing into a cell an expression vector containing the isolated nucleic acid of claim 10. 16. A method of determining the oncogenic or carcinogenic potential of a composition, comprising the steps of: (a) obtaining a sample containing nucleic acids from an animal that has not been contacted with said composition; (b) obtaining a sample containing nucleic acids from an animal that has been contacted with said composition; (c) contacting the sample of step (a) and the sample of step (b) with the isolated nucleic acid molecule of claim 10: (d) determining the concentration of a nucleic acid encoding an InK4c-pl 8 protein in the sample of step (a) and the sample of step (b), wherein a decreased amount of said nucleic acid encoding an lnK4c-pl 8 protein in the sample of step (b) compared to the amount in the sample of step (a) correlates with an increased oncogenic or carcinogenic potential of said composition. 17. A substantially pure protein having from 5 to 166 contiguous amino acid residues of a polypeptide sequence selected from the group consisting of SEQ ID N0:2 and SEQ ID NO:9, wherein said substantially pure protein binds specifically to a cyclin-dependent kinase-cyclin D complex, and wherein said cyclin-dependent kinase is selected from the group consisting of CDK4 and CDK6. 18. A substantially pure protein, wherein said protein has a polypeptide sequence selected from the group consisting of SEQ ID NO:2 and SEQ ID NO:9. 19. A method of inhibiting chromosomal DNA replication and arresting cell growth, wherein said method comprises the step of contacting a cell with the substantially protein of claim 17. 20. An antibody composition that specifically binds the substantially pure protein of claim 17. 21. A method of detecting an lnK4d-pl9 protein, wherein said method comprises the step of contacting a sample containing proteins with the antibody composition of claim 20. 22. A method of determining the oncogenic or carcinogenic potential of a composition, comprising the steps of: (a) obtaining a sample containing proteins from an animal that has not been contacted with said composition; (b) obtaining a sample containing proteins from an animal that has been contacted with said composition; (c) contacting the sample of step (a) and the sample of step (b) with the antibody composition of claim 20; (d) determining the concentration of an InK4d-pl9 protein in the sample of step (a) and the sample of step (b), wherein a decreased amount of said lnK4d-pl9 protein in the sample of step (b) compared to the amount in the sample of step (a) correlates with an increased oncogenic or carcinogenic potential of said composition. 23. A substantially pure protein, wherein said protein has from 5 to 168 contiguous amino acid residues of the polypeptide sequence of SEQ ID NO: 1, wherein said protein is isolated from a non-human mammal, wherein said substantially pure protein binds specifically to a cyclin-dependent kinase-cyclin D complex, and wherein said cyclin-dependent kinase is selected from the group consisting of CDK4 and CDK6. 24. A substantially pure protein, wherein said protein has the polypeptide sequence of SEQ ID NO: l . 25. An antibody composition that specifically binds the substantially pure protein of claim 23. 26. A method of detecting an InK4c-pl protein, wherein said method comprises the step of contacting a sample containing proteins with the antibody composition of claim 25. 27. A method of determining the oncogenic or carcinogenic potential of a composition, comprising the steps of: (a) obtaining a sample containing proteins from an animal that has not been contacted with said composition; (b) obtaining a sample containing proteins from an animal that has been contacted with said composition; (c) contacting the sample of step (a) and the sample of step (b) with the antibody composition of claim 25; (d) determining the concentration of an InK4c-plδ protein in the sample of step (a) and the sample of step (b), wherein a decreased amount of said InK4c-pl protein in the sample of step (b) compared to the amount in the sample of step (a) correlates with an increased oncogenic or carcinogenic potential of said composition. 28. A transgenic non-human animal having a having a phenotype selected from the group consisting of reduced or altered InK4c-pl8 activity, a phenotype of reduced or altered InK4d-pl9 activity, and a phenotype of reduced or altered activity of both InK4c-pl8 and InK4d-pl9. 29. A method of determining the therapeutic value of a potential anti-cancer composition, wherein said method comprises the step of contacting said composition to the transgenic non-human animal of claim 28. 30. A method of determining the risk of a potential oncogenic or carcinogenic composition, wherein said method comprises the step of contacting said composition to the transgenic non-human animal of claim 28. AMENDED SHEET (ARTICLE %9)

Inventors: DOWNING JAMES R, HIRAI HIROSHI, OKUDA TSUKASA, SHERR CHARLES J, DOWNING, JAMES, R., HIRAI, HIROSHI, ODUKA, TSUKASA, SHERR, CHARLES, J.
Applicants: ST JUDE CHILDRENS RES HOSPITAL, ST. JUDE CHILDREN'S RESEARCH HOSPITAL
Application year: 1996
Main classification: C07H21
IPC codes: A61K31, A61K48, A61P35, C07K14, C07K16, C12N15, C12Q1, G01N33