Cyclin-Dependent Kinase Inhibitors and Human Cancer

Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 227)

Abstract

As tumor suppressor candidates, cyclin-dependent kinase (CDK) inhibitors have a simple, aesthetic quality. They act directly on the mechanism that drives cells through mitosis and DNA replication. Elimination of CDK inhibitor activity, by mutation for instance, should release CDKs from this form of regulation and remove one of the restraints on cell growth.

Keywords

Toxicity Ethylated Codon Leukemia Adenocarcinoma 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Cairns P, Proctor AJ, Knowles MA (1993) Initiation of bladder cancer may involve deletion of a tumor suppressor gene on chromosome 9. Oncogene 8: 1083–1085PubMedGoogle Scholar
  2. Cairns P, Polascik TJ, Eby Y, Tokino K, Califano J, Merlo A, Mao L, Herath J, Jenkins R, Westra W, Rutter JL, Buckler A, Gabrielson E. Tockman M, Cho KR, Hedrick L, Bova GS, Isaacs W, Koch W, Schwab D, Sidransky D (1995) Frequency of homozygous detection at p16/CDKN2 in primary human tumours. Nature Genet 11: 210–212PubMedCrossRefGoogle Scholar
  3. Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE (1994) Frequent somatic mutations and homozygous deletions of the p16 ( MTSI) gene in pancreatic adenocarcinoma. Nature Genet 8: 27–32PubMedCrossRefGoogle Scholar
  4. Cannon-Albright LA, Goldgar G, Meyer LJ, Lewis CM, Anderson DE, Fountain JW, Hegi ME, Wiseman RW, Petty EM, Bale AE, Olopade 01, Diaz MO, Kwiatkowski DJ, Piepkorn MW, Zone JJ, Skolnick MH (1992) Assignment of a melanoma susceptibility locus, MLM, to chromosome 9p13-p22. Science 258: 1148–152PubMedCrossRefGoogle Scholar
  5. Cannon-Albright LA, Meyer LJ, Goldgar DE, Lewis CM, McWhorter WP, Jost M, Harrison D, Anderson DE, Zone JJ, Skolnick MH (1994) Penetrance and expressivity of the chromosome 9p melanoma susceptibility locus ( MLM ). Cancer Res 54: 6041–6044Google Scholar
  6. Dalbagni G, Presti J, Reuter V, Fair WR, Cardon-Cardo C (1993) Genetic alterations in bladder cancer. Lancet 342: 469–471PubMedCrossRefGoogle Scholar
  7. Gonzalez-Zulueta M, Bender CM, Yang AS, Nguyen T, Beart RW, Van Tornout JM, Jones PA (1995) Methylation of the 5’ CpG island of the p16/CDKN2 tumor suppressor gene in normal and a transformed human tissues correlates with gene silencing. Cancer Res 55: 4531–4535PubMedGoogle Scholar
  8. Gruis NA, Weaver-Feldhaus J, Liu Q, Frye C, Ecles R, Orlow I, Lacombe L, Ponce-Castoneda V, Lianes P, Latres E, Skolnick M, Cardon Cardo C. Kamb A (1995) Genetic evidence in melanoma and bladder cancers that p16 and p53 function in separate pathways of tumor suppression. Am J Pathol 146: 1199–1206PubMedGoogle Scholar
  9. Guan K-L, Jenkins CW, Li Y, Nichols MA, Wu X, O’Keefe CL, Matera AG, Xiong Y (1994) Growth suppression by p18, a p16INK4,narrsi and p14INK4/M rrsi related CDK6 inhibitor, correlates with wild-type pRb function. Genes Dev 8: 2939–2952PubMedCrossRefGoogle Scholar
  10. Hannon GJ, Beach D (1994) p15INK4a is a potential effector of TFG-(3-induced cell cycle arrest. Nature 371: 257–260PubMedCrossRefGoogle Scholar
  11. Healy E, Rehman I, Angus B, Rees JL (1995) Loss of heterozygosity in sporadic primary cutaneous melanoma. Genes Chromosomes Cancer 12: 152–156PubMedCrossRefGoogle Scholar
  12. Herman JG, Merlo A, Mao L, Lapidus RG, Issa JJ-P, Davidson NE, Sidransky D, Bayliin SB (1995) Inactivation of the CDKN2/P 16/MTS 1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res 55: 4525–4530PubMedGoogle Scholar
  13. Herman JG, Jen J, Merlo A, Baylin SB (1996) Hypermethylation-associated inactivation indicates a tumor suppressor role for p161NK4B Cancer Res 56: 722–727PubMedGoogle Scholar
  14. Holland EA, Beaton SC, Becker TM, Grulet OMC, Peters BA, Rizos H, Kefford RF, Mann GJ (1995) Analysis of the p16 gene, CDKN2, in 17 Australian melanoma kindreds. Oncogene 11: 2289–2294PubMedGoogle Scholar
  15. Hussussian CJ, Struewing JP, Goldstein A-MN, Higgins PAT, Ally DS, Sheahan MD, Clark WH Jr, Tucker MA, Dracopoli NC (1994) Germline p16 mutations in familial melanoma. Nature Genet 8: 15–21PubMedCrossRefGoogle Scholar
  16. Kamb A (1995) Cell-cycle regulators and cancer. Trends in Genetics 11: 136–140PubMedCrossRefGoogle Scholar
  17. 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: 436–440PubMedCrossRefGoogle Scholar
  18. Kamb A, Shattuck-Eidens D, 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 (MTSI) as a candidate for the chromosome 9p melanoma susceptibility locus (MLM). Nature Genet 8: 22–26CrossRefGoogle Scholar
  19. Koh J, Enders GH, Cynlacht BD, Harlow E (1995) Tumor-derived p16 alleles encoding proteins defective in cell-cycle inhibition. Nature 375: 506–510PubMedCrossRefGoogle Scholar
  20. Kohn KW, Jackman J, O’Connor PM (1994) Cell cycle and cancer chemotherapy. J Cell Biochem 54: 440–452PubMedCrossRefGoogle Scholar
  21. Kawamata N, Morosetti R, Miller CW, Park D, Spirin KS, Nakamaki T, Takeuchi S, Hatta Y, Simpson J, Wilczynski S, Lee YY, Bartram CR, Koeffler HP (1995) Molecular analysis of the cyclin-dependent kinase inhibitor gene p27/Kip1 in human malignancies. Cancer Res 55: 2266–2269PubMedGoogle Scholar
  22. 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: 6078–6082PubMedGoogle Scholar
  23. Liu Q, Neuhausen S, McClure M, Frye C, Weaver-Feldhaus J, Gruis NA, Eddington K, Allalunis-Turner MJ, Skolnick MH, Fujimura FK, Kamb A (1995) CDKN2(MTSI) tumor suppressor gene mutations in human tumor cell lines. Oncogene 10: 1061–1067PubMedGoogle Scholar
  24. Lukas J, Parry D, Aagaard L, Mann DJ, Bartkova J, Strauss M, Peters G, Bartek J (1995) Retinob- lastoma-protein-dependent cell-cycle inhibition by the tumor suppressor p16. Nature 375: 503–506PubMedCrossRefGoogle Scholar
  25. Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB, Sidransky D (1995) 5’ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/ MTSI in human cancers. Nature Med 1: 686–691PubMedCrossRefGoogle Scholar
  26. Nakamaki T, Kawamata N, Schwaller J, Tobler A, Fey M, Pakkala S, Lee YY, Kim BK, Fukuchi K, Tsuruoka N, Kahan J, Miller CW, Koeffler HP (1995) Structural integrity of the cyclin-dependent kinase inhibitor genes, p15, p16 and p18 in myeloid leukaemias Br J Haematol 91: 139–149PubMedCrossRefGoogle Scholar
  27. Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA (1994) Deletions of the cyclindependent kinase-4 inhibitor gene in multiple human cancers. Nature 368: 753–756PubMedCrossRefGoogle Scholar
  28. Okamoto A, Hussain SP, Hagiwara K, Spillare EA, Rusin MR, Demetrick DJ, Serrano M, Hannon GJ, Shiseki M, Zariwala M, Xiong Y, Beach DH, Yokota J, Harris CC (1995) Mutations in the p16hNK4/ MTSI/CDKN2, p15INK4B/MTS2, and p18 genes in primary and metastatic lung cancer. Cancer Res 55: 1448–1451PubMedGoogle Scholar
  29. Olopade OI, Jenkins R, Linnenbach AJ et al (1990) Molecular analysis of chromosome 9p deletion in human solid tumors. Proc Am Assoc Cancer Res 21: 318Google Scholar
  30. Pardee AB, James LJ (1975) Selective killing of transformed baby hamster kidney ( BHK) cells. Proc Natl Acad Sci USA 72: 4994–4998PubMedCrossRefGoogle Scholar
  31. Parry D, Bates S, Mann DJ, Peters G (1995) Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p161NK4IMTSI tumour suppressor gene product. EMBO J 14: 503–511PubMedGoogle Scholar
  32. Polyak K, Lee M-H, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P, Massague J (1994) Cloning of p27K’PI, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78: 59–66PubMedCrossRefGoogle Scholar
  33. Ranade K, Hussussian CJ, Sikorski RS, Varmus FIE, Goldstein AM, Tucker MA, Serrano M, Hannon GJ, Beach D, Dracopoli NC (1995) Mutations associated with familial melanoma impair p16rN’ 4 function. Nature Genet 10: 114–116PubMedCrossRefGoogle Scholar
  34. Serrano M, Hannon GJ, Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366: 704–707PubMedCrossRefGoogle Scholar
  35. Serrano M, Gomez-Lahoz E, DePinho RA, Beach D, Bar-Sagi D (1995) Inhibition of Ras-induced proliferation and cellular transformation by p161Nxa Science 267: 249–252PubMedCrossRefGoogle Scholar
  36. Smith-Sorenson B, Hovig E (1996) CDKN2A (p16°NK4n) somatic and germline mutations. Hum mutat 7: 294–303CrossRefGoogle Scholar
  37. 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 (MTS2) gene. Oncogene 11: 987–991PubMedGoogle Scholar
  38. Stone S, Jiang P, Dayananth P, Tavtigian SV, Katcher H, Parry D, Peters G, Kamb A (1996) Complex structure and regulation of the p16 (MTSI) locus. Cancer Res 55: 2988–2994Google Scholar
  39. Stone S, Dayananth P, Kamb A (1996) Reversible p16-mediated cell cycle arrest as protection from chemotherapy. Cancer Res 56: 3199–3202PubMedGoogle Scholar
  40. Toyoshima H, Hunter T (1994) p27, anovel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78: 67–74PubMedCrossRefGoogle Scholar
  41. Tsai YC, Nichols PW, Hiti AL, Williams Z, Skinner DG, Jones PA (1990) Allelic losses of chromosomes 9,1 1, and 17 in human bladder cancer. Cancer Res 50: 44–47PubMedGoogle Scholar
  42. Vidal MJ, Loganzo F, Oliveira AR, Hayward NK, Albino AP (1995) Mutations and defective expression of the WAFI p21 tumor suppressor gene in malignant melanomas. Melanoma Res 5: 243–250PubMedCrossRefGoogle Scholar
  43. Watanabe H, Fukuchi K, Takagi Y, Tomoyasu N, Gomi K (1995) Molecular analysis of the Cipl/Waft (p21) gene in diverse types of human tumors. Biochim Biophys Acta 1263: 275–280PubMedGoogle Scholar
  44. Zuo L, Weger J, Yang Q, Goldstein AM, Tucker MA, Walker GJ, Hayward N, Dracopoli NC (1996) Germline mutations in the p16°NK4’ binding domain of CDK4 in familial melanoma. Nature Genet 12: 97–99PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • A. Kamb
    • 1
  1. 1.Myriad Genetics, IncSalt Lake CityUSA

Personalised recommendations