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Cdk Inhibitors

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Cell Cycle Inhibitors in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

The cell cycle is the series of events which regulate the life of the cell. Two main events characterize the cell cycle: S phase, in which the cell duplicates its genome, and M phase, in which the cell splits into two daughter cells. It is necessary that these two crucial events are regulated and coordinated to occur in an ordered fashion at precisely the right time (for a review see refs. 1,2). This regulation and coordination results from a combination of several signals from different regulatory pathways that are activated in response to the presence of specific stimuli (for a review see ref. 1).

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References

  1. Sherr CJ. G1 phase progression: cycling on cue. Cell 1994; 79: 551–555.

    Article  PubMed  CAS  Google Scholar 

  2. Nurse P. Ordering S phase and M phase in the cell cycle. Cell 1994; 79: 547–550.

    Article  PubMed  CAS  Google Scholar 

  3. Sherr CJ. Cancer cell cycles. Science 1996; 274: 1672–1677 (1996).

    Article  Google Scholar 

  4. Morgan DO. Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu Rev Cell Dev Biol 1997; 13: 261–291.

    Article  PubMed  CAS  Google Scholar 

  5. Connel-Crowley L, Solomon MJ, Wei N, Harper JW. Phosphorylation independent activation of human cyclin-dependent kinase 2 by cyclin A in vitro. Mol Cell Biol Cell 1993; 4: 79–92.

    Google Scholar 

  6. Deshaies RJ. The self-destructive personality of a cell cycle in transition. Curr Opin Cell Biol 1995; 7: 781–789.

    Article  PubMed  CAS  Google Scholar 

  7. Hochstrasser M. Ubiquitin, proteasomes, and the regulation of intracellular protein degradation. Curr Opin Cell Biol 1995; 7: 215–223.

    Article  PubMed  CAS  Google Scholar 

  8. Kobajashi H, Stewart E, Poon R, et al. Identification of the domains in cyclin A required for binding to, and inactivation of p34cdc2, and p32cdk2 protein kinase subunits. Mol Biol Cell 1992; 3: 1279–1294.

    Google Scholar 

  9. Lee MH, Reynisdottir I, Massaguè J. Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dey 1995; 9: 639–649.

    Article  CAS  Google Scholar 

  10. Fesquet D, Labbè JC, Derancourt J, Capony JP, Galas S, Girard F, et al. The MO15 gene.encodes the catalytic subunit of a protein kinase that activates cdc2 and other cyclin-dependent kinases (CDKs) through phosphorylation ogf Thr 161 and its homologues. EMBO J 1993; 12: 3111–3121.

    PubMed  CAS  Google Scholar 

  11. Solomon MJ. Activation of the various cyclin/cdc2 protein kinases. Curr Opin Cell Biol 1993; 5: 180–186.

    Article  PubMed  CAS  Google Scholar 

  12. Fisher RP, Jin P, Chamberlin HM, Morgan DO. Alternative mechanisms of CAK assembly require an assembly factor or an activating kinase. Cell 1995; 83: 47–57.

    Article  PubMed  CAS  Google Scholar 

  13. Devault A, Martinez AM, Fesquet D., Labbè JC, Morin N, Tassan JP, et al. MAT 1 (“menage à trois”), a new RING-finger protein stabilizing cyclin H-CDK7 complexes in starfish and Xenopus oocytes. EMBO J 1995; 14: 5027–5036.

    PubMed  CAS  Google Scholar 

  14. Yee A, Nichols MA, Wu L, Hall FL, Kobajashi R, Xiong Y. Molecular cloning of CDK7associated human MATI, a cyclin-dependent kinase-activating kinase (CAK) assembly factor. Cancer Res 1995; 55: 6058–6062.

    PubMed  CAS  Google Scholar 

  15. Nurse P. Universal control mechanism regulating onset of M-phase. Nature 1990; 344: 503–508.

    Article  PubMed  CAS  Google Scholar 

  16. Nigg E. Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle. Bioessays 1995; 17: 471–480.

    Article  PubMed  CAS  Google Scholar 

  17. Dunphy WG. The decision to enter mitosis. Trends Cell Biol 1994; 4: 433–442.

    Google Scholar 

  18. Pines J. Cyclin from sea urchins to Helas: making the human cell cycle. Colworth Medal Lecture. Biochem Soc Trans 1996; 24; 15–33.

    PubMed  CAS  Google Scholar 

  19. Peter M., Herskowitz I. Joining the complex: cyclin-dependent kinase inhibitory proteins and the cell cycle. Cell 1994; 79: 181–184.

    Article  PubMed  CAS  Google Scholar 

  20. Lees E. Cyclin dependent kinase regulation. Curr Opin Cell Biol 1995a; 7: 773–780.

    Article  PubMed  CAS  Google Scholar 

  21. Lees EM, Harlow E. Sequences within the conserved cyclin box of human cyclin A are sufficient for binding to and inactivation of Cdc2 kinase. Cell 1995b; 81: 149–152.

    Article  Google Scholar 

  22. Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dey 1995; 9: 1149–1163.

    Article  CAS  Google Scholar 

  23. Elledge SJ, Winston J, Harper JW. A question of balance: the role of cyclin-kinase inhibitors in development and tumorigenesis. Trends Cell Biol 1996; 6: 388–392.

    Article  PubMed  CAS  Google Scholar 

  24. Alcorta DA, Xiong Y, Phelps D, Hannon G, Beach D, Barret JC. Involvement of the cyclindependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc Nail Acad Sci USA 1996; 93: 13743–13747.

    Article  Google Scholar 

  25. Polyak K, Kato J, Solomon MJ, Sherr CJ, Massaguè J, Roberts JM, Koff A. p27kipl, a cyclincdk inhibitor, links transforming growth factor-(3 and contact inhibition to cell cycle arrest. Genes Dey 1994a; 8: 9–22.

    Article  CAS  Google Scholar 

  26. Reynisdottir I, Polyak K, Iavarone A, Massaguè J. Kip/Cip and Ink4 inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. Genes Dey 1995; 9: 1831–1845.

    Article  CAS  Google Scholar 

  27. el-Deiry WS, Tokino T, Velulsescu VE, Levy DB, Parson R, Trent JM, et al. WAF1, apotential mediator of p53 tumor suppression. Cell 1993; 75: 817–825.

    Article  PubMed  CAS  Google Scholar 

  28. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell cycle control causing specific inhibition of cyclin D/CDK4. Nature 1993; 366: 704–707.

    Article  PubMed  CAS  Google Scholar 

  29. Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tatvigian SV, et al. A cell cycle regulator potentially involved in genesis of many tumor-types. Science 1994; 264: 436–440.

    Article  PubMed  CAS  Google Scholar 

  30. Nobori T, Miura K, Wu DJ, Lois A, Takabajashi K, Carson DA. Deletions of the cyclindependent kinase 4 inhibitor gene in multiple human cancers. Nature 1994; 368: 753–756.

    Article  PubMed  CAS  Google Scholar 

  31. Porter PL, Malone KE, Heagerty PJ, Alexander GM, Gatti LA, Firpo EJ, et al. Expression of cell-cycle regulators p27 Kip 1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nature Med 1997; 3: 222–225.

    Article  PubMed  CAS  Google Scholar 

  32. Arellano M, Moreno S. Regulation of CDK/cyclin complexes during the cell cycle. Int J Biochem Cell Biol 1997; 4: 559–573.

    Article  Google Scholar 

  33. Hannon GJ, Beach D. p15 INK4b is a potential effector of cell cycle arrest mediated by TGF-(3. Nature 1994; 371: 257–261.

    Article  PubMed  CAS  Google Scholar 

  34. Guan K, Jenkins CW, Li Y, Nichols MA, Wu X, O’Keeffe CL, et al. Growth suppression by p18, a p16 INK4aMTS2-related CDK6 inhibitor, correlates with wild-type RB function. Genes Dey 1994; 8: 2939–2952.

    Article  CAS  Google Scholar 

  35. Hirai H, Roussel MF, Kato J, Ashmun RA, Sherr CJ. Novel INK4 proteins, p19 and p18, are specific inhibitors of cyclin D-dependent kinases CDK4 and CDK6. Mol Cell Biol 1995; 15: 2672–2681.

    PubMed  CAS  Google Scholar 

  36. Chan FKM, Zhan J, Chen L, Shapiro DN, Winoto A. Identification of human/mouse p19, a novel cdk4/cdk6 inhibitor with homology to p16 INK4. Mol Cell Biol 1995; 15: 2682–2688.

    PubMed  CAS  Google Scholar 

  37. Gu Y, Turek CW, Morgan DO. Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit. Nature 1993; 366: 707–710.

    Article  PubMed  CAS  Google Scholar 

  38. Harper JW, Adami GR, Wei N, Keyomarse K, Elledge SJ. The p21 Cdk-interacting protein Cipl is a potent inhibitor of G1 cyclin-dependent kinases. Cell 1993; 75: 805–816.

    Article  PubMed  CAS  Google Scholar 

  39. Xiong Y, Hannon GJ, Zhang H, Casso D, Kobajashi R, Beach D. p21 is a universal inhibitor of cyclin-dependent kinases. Nature 1993a; 366: 701–704.

    Article  PubMed  CAS  Google Scholar 

  40. Dulic V, Kauffmann WK, Wilson SJ, Tlsty TD, Lees E, Harper JW, et al. p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblast during radiation-induced G1 arrest. Cell 1994; 76: 1013–1023.

    Article  PubMed  CAS  Google Scholar 

  41. Noda A, Ning Y, Venable SF, Pereira-Smith OM, Smith JR. Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Expl Cell Res 1994; 211: 90–98.

    Article  CAS  Google Scholar 

  42. Polyak K, Lee MH, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P, Massaguè J. Cloning of p27Kipl, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 1994b; 78: 59–66.

    Article  PubMed  CAS  Google Scholar 

  43. Toyoshima H., Hunter T. p27, a novel inhibitor of G1 cyclin/cdk protein kinase activity, is related to p21. Cell 1994; 78: 67–74.

    Article  PubMed  CAS  Google Scholar 

  44. Matsuoka D, Edwards MC, Bai C, Parker S, Zhang P, Baldini A, et al. p57kip2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dey 1995; 9: 650–662.

    Article  CAS  Google Scholar 

  45. Chen J, Jackson PK, Kirschner MW, Dutta A. Separate domains of p21 involved in the inhibition of cdk kinase and PCNA. Nature 1995; 374: 386–388.

    Article  PubMed  CAS  Google Scholar 

  46. Nakanish M, Robertorge RS, Adam GR, et al. Identification of the active region of the DNA synthesis inhibitory gene p215di1CIP1WAF1. Embo J 1995; 14: 555–563.

    Google Scholar 

  47. Warbrick E, Lane DP, Glover DM, Cox LS. A small peptide inhibitor of DNA replication defines the site of interaction between the cyclin-dependent kinase inhibitor p21WAF1 and proliferating cell nuclear antigen. Curr Biol 1995; 5: 275–282.

    Article  PubMed  CAS  Google Scholar 

  48. Lin JC, Reichner C, Wu X, Levine AJ. Analysis of wild-type and mutant p21WAF-I gene activities. Mol Biol Cell 1996; 16: 1786–1793.

    CAS  Google Scholar 

  49. Russo AA, Jeffrey PD, Patten AK, Massaguè J, Pavletich NP. Crystal structure of the p27kip 1 cyclin-dependent kinase inhibitor bound to the cyclin A-cdk2 complex. Nature 1996; 366: 704–707.

    Google Scholar 

  50. Serrano M. The tumor suppressor protein pl6INK4a. Exp Cell Res 1997; 237: 7–13.

    Article  PubMed  CAS  Google Scholar 

  51. Otterson GA, Kratze RA, Coxon A, Kim YW, Kaye H. Absence of p16INK4 protein is restricted to the subset of lung cancer lines that retains wild-type RB. Oncogene 1994; 9: 3375–3378.

    PubMed  CAS  Google Scholar 

  52. Sheaff RJ, Roberts JM. Lessons in p16 from phylum Falconium Curr Biol 1995; 5: 28–30.

    Article  PubMed  CAS  Google Scholar 

  53. Serrano M, Lee HW, Chin L, Cordon-Cardo C, Beach D, Depinto RA. Role of the INK4a locus in tumor suppression and cell mortality. Cell 1996; 85: 27–37.

    Article  PubMed  CAS  Google Scholar 

  54. Xiong Y, Zhang H, Beach D. Subunits rearrangements of the cyclin-dependent kinases is associated with cellular transformation. Genes Dey 1993b; 7: 1572–1583.

    Article  CAS  Google Scholar 

  55. Zhang H, Hannon GJ, Beach D. p21-containing cyclin kinases exist in both active and inactive states. Genes Dey 1994; 8: 1750–1758.

    Article  CAS  Google Scholar 

  56. Xiong Y, Zhang H, Beach D. D-type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell 1992; 71: 505–514.

    Article  PubMed  CAS  Google Scholar 

  57. Harper JW, Elledge SJ, Keyomarse K, Dynlacht B, Tsai L-H, Zhang P, et al. Inhibition of cyclin-dependent kinases by p21. Mol Cell Biol 1995; 6: 387–400.

    CAS  Google Scholar 

  58. Luo Y, Hurwitz J, Massaguè J. Cell cycle inhibition mediated by functionally independent CDK and PCNA inhibitory domains in p21CIP1. Nature 1995; 375: 159–161.

    Article  PubMed  CAS  Google Scholar 

  59. Hengst L, Reed SI. Translational control of p27Kipl accumulation during the cell cycle. Science 1996; 271: 1861–1864.

    Article  PubMed  CAS  Google Scholar 

  60. Russo AA, Tong L, Lee JO, Jeffrey PD, Pavletich NP. Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumor suppressor p16INK4a. Nature 1998; 395: 237–243.

    Article  PubMed  CAS  Google Scholar 

  61. Pavletich NP. Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, their cyclin activators, and Cip and INK4 inhibitors. J Mol Biol 1999; 287: 821–828.

    Article  PubMed  CAS  Google Scholar 

  62. Tsihlias J, Kapusta L, Slingerland J. The prognostic significance of altered cyclin-dependent kinase inhibitors in human cancer. Annu Rev Med 1999; 50: 401–423.

    Article  PubMed  CAS  Google Scholar 

  63. Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, et al. Decreased levels of the cell-cycle inhibitor p27kipl protein: prognostic implication in primary breast cancer. Nature Med 1997; 3: 227–230.

    Article  PubMed  CAS  Google Scholar 

  64. Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, et al. Increases proteasomedependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med 1997; 3: 231–234.

    Article  PubMed  CAS  Google Scholar 

  65. Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ. The murine gene p27kipl is haploinsufficient for tumour suppression. Nature 1998; 396: 177–180.

    Article  PubMed  CAS  Google Scholar 

  66. Garrett MD, Fattaey A. CDK inhibition and cancer therapy. CurrOpin Gen Dey 1999; 9: 104–111.

    Article  CAS  Google Scholar 

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Authors
  1. Giulia De Falco PhD
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  2. Catherine Soprano
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  3. Antonio Giordano MD, PhD
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Editor information

Editors and Affiliations

  1. Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, Temple University, Philadelphia, PA, USA

    Antonio Giordano MD, PhD

  2. Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, USA

    Kenneth J. Soprano PhD

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© 2003 Springer Science+Business Media New York

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De Falco, G., Soprano, C., Giordano, A. (2003). Cdk Inhibitors. In: Giordano, A., Soprano, K.J. (eds) Cell Cycle Inhibitors in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-401-6_1

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  • DOI: https://doi.org/10.1007/978-1-59259-401-6_1

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-257-5

  • Online ISBN: 978-1-59259-401-6

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