Abstract
Cyclin-dependent kinase inhibitors are a growing family of molecules that regulate important transitions in the cell cycle. At least one of these molecules, p16, has been implicated in human tumorigenesis while its close homolog, p15, is induced by cell contact and transforming growth factor-β (TGF-β). To investigate the evolutionary and functional features of p15 and p16, we have isolated mouse (Mus musculus) homologs of each gene. Comparative analysis of these sequences provides evidence that the genes have similar functions in mouse and human. In addition, the comparison suggests that a gene conversion event is part of the evolution of the human p15 and p16 genes.
Similar content being viewed by others
References
Baltimore D (1981) Gene conversion: some implications for immunoglobulin genes. Cell 24:592–594
Chan FK, Zhang J, Cheng L, Shapiro DN, Winto A (1995) Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16INK4. Mol Cell Biol 15:2682–2688
El-Deiry WF, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75:817–825
Gu W, Turck CW, Morgan DO (1993) Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit. Nature 366:707–710
Guan K-L, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y (1995) Growth suppression by p18, a p16INK4/MTS1 and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function. Genes Dev 8:2939–2952
Hannon GJ, Beach D (1994) p15INK4B is a potential effector of TFGβ-induced cell cycle arrest. Nature 371:257–260
Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge KK (1993) The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclindependent kinases. Cell 75:805–816
Hirai H, Roussel MF, Kato JY, Ashman RA, Sherr CJ (1995) Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. Mol Cell Biol 15:2672–2681
Hogstrand K, Bohme J (1994) A determination of the frequency of gene conversion in unmanipulated mouse sperm. Proc Natl Acad Sci USA 91:9921–9925
Hussussian CJ, Struewing JP, Goldstein AM, Higgins PAT, Ally DS, Sheahan MD, Clark WHJ, Tucker MA, Dracopoli NC (1994) Germline p16 mutations in familial melanoma. Nature Genet 8:15–21
Kamb A, Weir, M, Rudy B, Varmus H, Kenyon C (1989) Identification of genes from pattern formation, tyrosine kinase, and potassium channel families by DNA amplification. Proc Natl Acad Sci USA 86:4372–4376
Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS III, Johnson BE, Skolnick MH (1994a) A cell cycle regulator potentially involved in genesis of many tumor types. Science 264:436–440
Kamb A, Shattuck-Eidens S, Eeles R, Liu Q, Gruis NA, Ding W, Hussey C, Tran T, Miki Y, Weaver-Feldhaus J McClure M, Aitken JF, Anderson DE, Bergman W, Frants R, Goldgar DE, Green A, MacLennan R, Martin NG, Meyer LJ, Youl P, Zone JJ, Skolnick MH, Cannon-Albright LA (1994b) Analysis of CDKN2 (MTS1) as a candidate for the chromosome 9p melanoma susceptibility locus (MLM). Nature Genet 8:22–26
Kamb A (1995) Cell-cycle regulators and cancer. Trends Genet 11: 136–140
Kozak CA, Pyser M, Krall M, Mariano TM, Kumar CS, Pestka S, Mock BA (1990) Molecular genetic markers spanning mouse chromosome 10. Genomics 8:519–524
Lee M-H, Reynisdottir I, Massague J (1995) Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev 9:639–649
Li Y, Nichols MA, Shay JW, Xiong Y (1994) Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb. Cancer Res 54: 6078–6082
Mao L, Merlo A, Bedi G, Shapiro GI, Edwards CD, Rollins BJ, Sidransky DA (1995) novel p16INK4a transcript. Cancer Res 55:2995–2997
Matsuoka S, Edwards MC, Bai C, Parker S, Shang P, Baldini A, Warper JW, Elledge SJ (1995) p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dev 9:650–662
Mellor AL, Weiss EH, Ramachandran K, Flavell RA (1983) A potential donor gene for the brut gene conversion event in the C57BL mouse. Nature 306:792–795
Parry D, Bates S, Mann DJ, Peters G (1995) Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product. EMBO J 14:503–511
Peter M, Herskowitz I (1994) Joining the complex: cyclin-dependent kinase inhibitory proteins and the cell cycle. Cell 79:181–184
Polyak K, Kato J-Y, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A (1994a) p27Kip1, a cyclin-CDK inhibitor, links transforming growth factor β and contact inhibition to cell cycle arrest. Genes Dev 8:9–22
Polyak K, Lee M-H, Bromage HE, Koff A, Roberts JM, Tempst P, Massague J (1994b) Cloning of p27ip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78:59–66
Quelle DE, Ashman RA, Hannon GJ, Rehberger PA, Trono D, Richter KH, Walker C, Beach D, Sherr CJ, Serrano M (1995) Cloning and characterization of murine p16INK4a and p151NK4b genes. Oncogene 11:635–645
Radding C (1978) Genetic recombination: Strand transfer and mismatch repair. Annu Rev Biochem 47:847–880
Sambrook J, Fritsch EF, Maniatis T, (1989) Molecular cloning: a laboratory manual, 2nd ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY
Sato TN, Qin Y, Kozak CA, Adus KL (1993) tie-1 and tie-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular systems. Proc Natl Acad Sci USA 90:9355–9358
Serrano M, Gomez-Lahoz E, DePinho RA, Beach D, Bar-Sagi D (1995) Inhibition of ras-induced proliferation and cellular transformation by p16INK4. Science 267:249–252
Serrano M, Hannon GJ, Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366:704–707
Slightom JL, Blechl AE, Smithies O (1980) Human fetal Gγ- and Aγ-globin genes: complete nucleotide sequences suggest that DNA can be exchanged between these duplicated genes. Cell 21:627–638
Smith TF, Waterman MS (1981) Identification of common molecular subsequences. J Mol Biol 147:195–197
Stone S, Dayananth P, Jiang P, Weaver-Feldhaus JM, Tavtigian SV, Cannon-Albright L, Kamb A (1995a) Genomic structure, expression and mutational analysis of the P15 (MTS 2) gene. Oncogene 11:87–991
Stone S, Jiang P, Dayananth P, Tavtigian SV, Katcher H, Parry D, Peters G, Kamb A (1995b) Complex structure and regulation of the P16 (MTS1) locus. Cancer Res 55:2988–2994
Toyoshima H, Hunter T (1994) p27, a novel inhibitor of G 1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78:67–74
Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D (1993) p21 is a universal inhibitor of cyclin kinases. Nature 366: 701–704
Author information
Authors and Affiliations
Additional information
Correspondence to: A. Kamb
Rights and permissions
About this article
Cite this article
Jiang, P., Stone, S., Wagner, R. et al. Comparative analysis of Homo sapiens and Mus musculus cyclin-dependent kinase (CDK) inhibitor genes P16 (MTS1) and P15 (MTS2). J Mol Evol 41, 795–802 (1995). https://doi.org/10.1007/BF00173159
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00173159