VOOZH about

URL: https://www.nature.com/articles/nrc2602?error=cookies_not_supported&code=bc191298-f8a9-442c-831f-27e8b4235002

⇱ Cell cycle, CDKs and cancer: a changing paradigm | Nature Reviews Cancer

Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Key Points

  • Cell cycle deregulation is a common feature of human cancer. Cancer cells frequently display unscheduled proliferation, genomic instability (increased DNA mutations and chromosomal aberrations) and chromosomal instability (changes in chromosome number).

  • The mammalian cell cycle is controlled by a subfamily of cyclin-dependent kinases (CDKs), the activity of which is modulated by several activators (cyclins) and inhibitors (Ink4, and Cip and Kip inhibitors). The activity of cell cycle CDKs is deregulated in cancer cells owing to genetic or epigenetic changes in either CDKs, their regulators or upstream mitogenic pathways.

  • Recent genetic studies indicate that CDK2, CDK4 and CDK6 are not essential for the mammalian cell cycle. Instead, they are only required for the proliferation of specific cell types. By contrast, CDK1 is essential for cell division in the embryo. Moreover, CDK1 is sufficient among the cell cycle CDKs for driving the cell cycle in all cell types, at least until mid gestation.

  • Constitutive and deregulated CDK activation may contribute not only to unscheduled proliferation but also to genomic and chromosomal instability in cancer cells. The alteration of the DNA damage and mitotic checkpoints frequently results in increased CDK activity that drives tumour cell cycles.

  • Emerging evidence suggests that tumour cells may also have specific requirements for individual CDKs. Therapeutic strategies based on CDK inhibition should take into consideration these specific requirements.

  • For instance, CDK4 is dispensable for mammary gland development, but is required for the development of mammary gland tumours initiated by specific oncogenes such as Erbb2, Hras or Myc depending on cellular context.

Abstract

Tumour-associated cell cycle defects are often mediated by alterations in cyclin-dependent kinase (CDK) activity. Misregulated CDKs induce unscheduled proliferation as well as genomic and chromosomal instability. According to current models, mammalian CDKs are essential for driving each cell cycle phase, so therapeutic strategies that block CDK activity are unlikely to selectively target tumour cells. However, recent genetic evidence has revealed that, whereas CDK1 is required for the cell cycle, interphase CDKs are only essential for proliferation of specialized cells. Emerging evidence suggests that tumour cells may also require specific interphase CDKs for proliferation. Thus, selective CDK inhibition may provide therapeutic benefit against certain human neoplasias.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Comparison of the Saccharomyces cerevisiae cell cycle with the mammalian cell cycle, highlighting the major defects implicated in human cancer.
Figure 2: Genetic interrogation of the roles of cyclin-dependent kinases (CDKs) in the mammalian cell cycle.
Figure 3: An overview of key molecules involved in mitotic progression and chromosomal instability.

Similar content being viewed by others

References

  1. Malumbres, M. & Barbacid, M. To cycle or not to cycle: a critical decision in cancer. Nature Rev. Cancer 1, 222–231 (2001).

    CAS  Google Scholar 

  2. Massague, J. G1 cell-cycle control and cancer. Nature 432, 298–306 (2004).

    CAS  PubMed  Google Scholar 

  3. Kastan, M. B. & Bartek, J. Cell-cycle checkpoints and cancer. Nature 432, 316–323 (2004).

    CAS  PubMed  Google Scholar 

  4. Kops, G. J., Weaver, B. A. & Cleveland, D. W. On the road to cancer: aneuploidy and the mitotic checkpoint. Nature Rev. Cancer 5, 773–785 (2005).

    CAS  Google Scholar 

  5. Malumbres, M. & Barbacid, M. Mammalian cyclin-dependent kinases. Trends Biochem. Sci. 30, 630–641 (2005).

    CAS  PubMed  Google Scholar 

  6. Bartek, J., Lukas, C. & Lukas, J. Checking on DNA damage in S phase. Nature Rev. Mol. Cell Biol. 5, 792–804 (2004).

    CAS  Google Scholar 

  7. Perez de Castro, I., de Carcer, G. & Malumbres, M. A census of mitotic cancer genes: new insights into tumor cell biology and cancer therapy. Carcinogenesis 28, 899–912 (2007).

    CAS  PubMed  Google Scholar 

  8. Musacchio, A. & Salmon, E. D. The spindle-assembly checkpoint in space and time. Nature Rev. Mol. Cell Biol. 8, 379–393 (2007).

    Article  CAS  Google Scholar 

  9. Harbour, J. W., Luo, R. X., Dei Santi, A., Postigo, A. A. & Dean, D. C. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 98, 859–869 (1999).

    CAS  PubMed  Google Scholar 

  10. Lundberg, A. S. & Weinberg, R. A. Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Mol. Cell. Biol. 18, 753–761 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. van den Heuvel, S. & Harlow, E. Distinct roles for cyclin-dependent kinases in cell cycle control. Science 262, 2050–2054 (1993).

    CAS  PubMed  Google Scholar 

  12. Pagano, M. et al. Regulation of the cell cycle by the cdk2 protein kinase in cultured human fibroblasts. J. Cell Biol. 121, 101–111 (1993).

    CAS  PubMed  Google Scholar 

  13. Hochegger, H., Takeda, S. & Hunt, T. Cyclin-dependent kinases and cell-cycle transitions: does one fit all? Nature Rev. Mol. Cell Biol. 9, 910–916 (2008).

    CAS  Google Scholar 

  14. Rane, S. G. et al. Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Nature Genet. 22, 44–52 (1999).

    CAS  PubMed  Google Scholar 

  15. Tsutsui, T. et al. Targeted disruption of CDK4 delays cell cycle entry with enhanced p27Kip1 activity. Mol. Cell. Biol. 19, 7011–7019 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Malumbres, M. et al. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118, 493–504 (2004).

    CAS  PubMed  Google Scholar 

  17. Ortega, S. et al. Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nature Genet. 35, 25–31 (2003).

    CAS  PubMed  Google Scholar 

  18. Berthet, C., Aleem, E., Coppola, V., Tessarollo, L. & Kaldis, P. Cdk2 knockout mice are viable. Curr. Biol. 13, 1775–1785 (2003). References 17 and 18 provide genetic evidence that CDK2 is not essential for DNA synthesis, or for any other essential step within the mitotic cell cycle.

    CAS  PubMed  Google Scholar 

  19. Santamaria, D. et al. Cdk1 is sufficient to drive the mammalian cell cycle. Nature 448, 811–815 (2007). Genetic ablation of all interphase CDKs β€” CDK2, CDK4 and CDK6 β€” does not result in cell cycle defects in most cell types. In addition, this manuscript describes that CDK1 is essential for cell division.

    CAS  PubMed  Google Scholar 

  20. Barriere, C. et al. Mice thrive without Cdk4 and Cdk2. Mol. Oncol. 1, 72–83 (2007). This manuscript demonstrates that the two main interphase CDKs are dispensable for adult homeostasis as well as for proliferation of adult hepatocytes during liver regeneration.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Berthet, C. et al. Combined loss of Cdk2 and Cdk4 results in embryonic lethality and Rb hypophosphorylation. Dev. Cell 10, 563–573 (2006).

    CAS  PubMed  Google Scholar 

  22. Satyanarayana, A. et al. Genetic substitution of Cdk1 by Cdk2 leads to embryonic lethality and loss of meiotic function of Cdk2. Development 135, 3389–3400 (2008).

    CAS  PubMed  Google Scholar 

  23. Ciemerych, M. A. & Sicinski, P. Cell cycle in mouse development. Oncogene 24, 2877–2898 (2005).

    CAS  PubMed  Google Scholar 

  24. Kozar, K. et al. Mouse development and cell proliferation in the absence of D-cyclins. Cell 118, 477–491 (2004). References 14–16 and 24 provide genetic evidence that the D-type cyclins as well as their cognate CDKs, CDK4 and CDK6, are not essential for entry into the cell cycle.

    CAS  PubMed  Google Scholar 

  25. Geng, Y. et al. Cyclin E ablation in the mouse. Cell 114, 431–443 (2003).

    CAS  PubMed  Google Scholar 

  26. Parisi, T. et al. Cyclins E1 and E2 are required for endoreplication in placental trophoblast giant cells. EMBO J. 22, 4794–4803 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Geng, Y. et al. Kinase-independent function of cyclin, E. Mol. Cell 25, 127–139 (2007).

    CAS  PubMed  Google Scholar 

  28. Geng, Y. et al. Rescue of cyclin D1 deficiency by knockin cyclin, E. Cell 97, 767–777 (1999). References 25–28 provide genetic evidence on the essential functions of E-type cyclins, their CDK2-independent roles and their functional overlap with cyclin D1.

    CAS  PubMed  Google Scholar 

  29. Murphy, M. et al. Delayed early embryonic lethality following disruption of the murine cyclin A2 gene. Nature Genet. 15, 83–86 (1997).

    CAS  PubMed  Google Scholar 

  30. Brandeis, M. et al. Cyclin B2-null mice develop normally and are fertile whereas cyclin B1-null mice die in utero. Proc. Natl Acad. Sci. USA 95, 4344–4349 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Kippin, T. E., Martens, D. J. & van der Kooy, D. p21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation capacity. Genes Dev. 19, 756–767 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Choudhury, A. R. et al. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nature Genet. 39, 99–105 (2007).

    CAS  PubMed  Google Scholar 

  33. Fasano, C. A. et al. shRNA knockdown of Bmi-1 reveals a critical role for p21-Rb pathway in NSC self-renewal during development. Cell Stem Cell 1, 87–99 (2007).

    CAS  PubMed  Google Scholar 

  34. Pechnick, R. N., Zonis, S., Wawrowsky, K., Pourmorady, J. & Chesnokova, V. p21Cip1 restricts neuronal proliferation in the subgranular zone of the dentate gyrus of the hippocampus. Proc. Natl Acad. Sci. USA 105, 1358–1363 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Walkley, C. R., Fero, M. L., Chien, W. M., Purton, L. E. & McArthur, G. A. Negative cell-cycle regulators cooperatively control self-renewal and differentiation of haematopoietic stem cells. Nature Cell Biol. 7, 172–178 (2005).

    CAS  PubMed  Google Scholar 

  36. Cheng, T. et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 287, 1804–1808 (2000).

    CAS  PubMed  Google Scholar 

  37. Besson, A. et al. Discovery of an oncogenic activity in p27Kip1 that causes stem cell expansion and a multiple tumor phenotype. Genes Dev. 21, 1731–1746 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Yuan, Y., Shen, H., Franklin, D. S., Scadden, D. T. & Cheng, T. In vivo self-renewing divisions of haematopoietic stem cells are increased in the absence of the early G1-phase inhibitor, p18INK4C. Nature Cell Biol. 6, 436–442 (2004).

    CAS  PubMed  Google Scholar 

  39. Yu, H., Yuan, Y., Shen, H. & Cheng, T. Hematopoietic stem cell exhaustion impacted by p18INK4C and p21Cip1/Waf1 in opposite manners. Blood 107, 1200–1206 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Janzen, V. et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443, 421–426 (2006).

    CAS  PubMed  Google Scholar 

  41. Krishnamurthy, J. et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443, 453–457 (2006).

    CAS  PubMed  Google Scholar 

  42. Pei, X. H., Bai, F., Smith, M. D. & Xiong, Y. p18Ink4c collaborates with Men1 to constrain lung stem cell expansion and suppress non-small-cell lung cancers. Cancer Res. 67, 3162–3170 (2007).

    CAS  PubMed  Google Scholar 

  43. Molofsky, A. V. et al. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443, 448–452 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Rosu-Myles, M., Taylor, B. J. & Wolff, L. Loss of the tumor suppressor p15Ink4b enhances myeloid progenitor formation from common myeloid progenitors. Exp. Hematol. 35, 394–406 (2007).

    CAS  PubMed  Google Scholar 

  45. Carlson, M. E., Hsu, M. & Conboy, I. M. Imbalance between pSmad3 and Notch induces CDK inhibitors in old muscle stem cells. Nature 454, 528–532 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Horsley, V., Aliprantis, A. O., Polak, L., Glimcher, L. H. & Fuchs, E. NFATc1 balances quiescence and proliferation of skin stem cells. Cell 132, 299–310 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Jablonska, B. et al. Cdk2 is critical for proliferation and self-renewal of neural progenitor cells in the adult subventricular zone. J. Cell Biol. 179, 1231–1245 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Ortega, S., Malumbres, M. & Barbacid, M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim. Biophys. Acta 1602, 73–87 (2002).

    CAS  PubMed  Google Scholar 

  49. Sotillo, R. et al. Wide spectrum of tumors in knock-in mice carrying a Cdk4 protein insensitive to INK4 inhibitors. EMBO J. 20, 6637–6647 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Rane, S. G., Cosenza, S. C., Mettus, R. V. & Reddy, E. P. Germ line transmission of the Cdk4R24C mutation facilitates tumorigenesis and escape from cellular senescence. Mol. Cell. Biol. 22, 644–656 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Sotillo, R. et al. Invasive melanoma in Cdk4-targeted mice. Proc. Natl Acad. Sci. USA 98, 13312–13317 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Martin, A. et al. Cdk2 is dispensable for cell cycle inhibition and tumor suppression mediated by p27Kip1 and p21Cip1. Cancer Cell 7, 591–598 (2005).

    CAS  PubMed  Google Scholar 

  53. Aleem, E., Kiyokawa, H. & Kaldis, P. Cdc2–cyclin E complexes regulate the G1/S phase transition. Nature Cell Biol. 7, 831–836 (2005).

    CAS  PubMed  Google Scholar 

  54. Tetsu, O. & McCormick, F. Proliferation of cancer cells despite CDK2 inhibition. Cancer Cell 3, 233–245 (2003). This manuscript illustrates that different human tumour cell lines have selective requirements for CDK activity.

    CAS  PubMed  Google Scholar 

  55. Miliani de Marval, P. L. et al. Lack of cyclin-dependent kinase 4 inhibits c-myc tumorigenic activities in epithelial tissues. Mol. Cell. Biol. 24, 7538–7547 (2004).

    PubMed  PubMed Central  Google Scholar 

  56. Yu, Q. et al. Requirement for CDK4 kinase function in breast cancer. Cancer Cell 9, 23–32 (2006).

    CAS  PubMed  Google Scholar 

  57. Reddy, H. K. et al. Cyclin-dependent kinase 4 expression is essential for neu-induced breast tumorigenesis. Cancer Res. 65, 10174–10178 (2005).

    CAS  PubMed  Google Scholar 

  58. Landis, M. W., Pawlyk, B. S., Li, T., Sicinski, P. & Hinds, P. W. Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell 9, 13–22 (2006). References 56–58 demonstrate the requirement for the mouse CDK4–cyclin D activity in ERBB2-induced breast tumours suggesting possible therapeutic uses of specific CDK4 inhibitors in ERBB2-positive breast cancer.

    CAS  PubMed  Google Scholar 

  59. Yu, Q., Geng, Y. & Sicinski, P. Specific protection against breast cancers by cyclin D1 ablation. Nature 411, 1017–1021 (2001). This pioneer study reports that cyclin D1 (and hence CDK4 or CDK6 activity) is essential for Erbb2 - or Hras -induced tumours but not Myc - or Wnt1 -induced tumours.

    CAS  PubMed  Google Scholar 

  60. Malumbres, M. & Barbacid, M. Is Cyclin D1–CDK4 kinase a bona fide cancer target? Cancer Cell 9, 2–4 (2006).

    CAS  PubMed  Google Scholar 

  61. Aguilera, A. & Gomez-Gonzalez, B. Genome instability: a mechanistic view of its causes and consequences. Nature Rev. Genet. 9, 204–217 (2008).

    CAS  PubMed  Google Scholar 

  62. Cimprich, K. A. & Cortez, D. ATR: an essential regulator of genome integrity. Nature Rev. Mol. Cell Biol. 9, 616–627 (2008).

    CAS  Google Scholar 

  63. Lavin, M. F. Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nature Rev. Mol. Cell Biol. 9, 759–769 (2008).

    CAS  Google Scholar 

  64. Caldecott, K. W. Single-strand break repair and genetic disease. Nature Rev. Genet. 9, 619–631 (2008).

    CAS  PubMed  Google Scholar 

  65. Antoni, L., Sodha, N., Collins, I. & Garrett, M. D. CHK2 kinase: cancer susceptibility and cancer therapy β€” two sides of the same coin? Nature Rev. Cancer 7, 925–936 (2007).

    CAS  Google Scholar 

  66. Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864–870 (2005).

    CAS  PubMed  Google Scholar 

  67. Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).

    CAS  PubMed  Google Scholar 

  68. Gorgoulis, V. G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907–913 (2005).

    CAS  PubMed  Google Scholar 

  69. Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006). This series of articles (references 66–69) demonstrate the tumour suppressor role of the DNA damage response and the effects of its alteration in human tumours.

    CAS  PubMed  Google Scholar 

  70. Halazonetis, T. D., Gorgoulis, V. G. & Bartek, J. An oncogene-induced DNA damage model for cancer development. Science 319, 1352–1355 (2008).

    CAS  PubMed  Google Scholar 

  71. Yata, K. & Esashi, F. Dual role of CDKs in DNA repair: To be, or not to be. DNA Repair (Amst) 8, 6–18 (2009).

    CAS  Google Scholar 

  72. Huertas, P., Cortes-Ledesma, F., Sartori, A. A., Aguilera, A. & Jackson, S. P. CDK targets Sae2 to control DNA-end resection and homologous recombination. Nature 455, 689–692 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Esashi, F. et al. CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature 434, 598–604 (2005). References 72 and 73 report an unexpected function for yeast and mammalian CDKs in DNA repair.

    CAS  PubMed  Google Scholar 

  74. Potapova, T. A. et al. The reversibility of mitotic exit in vertebrate cells. Nature 440, 954–958 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Queralt, E. & Uhlmann, F. Cdk-counteracting phosphatases unlock mitotic exit. Curr. Opin. Cell Biol. 20, 661–668 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Peters, J. M. The anaphase promoting complex/cyclosome: a machine designed to destroy. Nature Rev. Mol. Cell Biol. 7, 644–656 (2006).

    CAS  Google Scholar 

  77. Sullivan, M. & Morgan, D. O. Finishing mitosis, one step at a time. Nature Rev. Mol. Cell Biol. 8, 894–903 (2007).

    CAS  Google Scholar 

  78. Nakayama, K. I. & Nakayama, K. Ubiquitin ligases: cell-cycle control and cancer. Nature Rev. Cancer 6, 369–381 (2006).

    CAS  Google Scholar 

  79. Hayes, M. J. et al. Early mitotic degradation of Nek2A depends on Cdc20-independent interaction with the APC/C. Nature Cell Biol. 8, 607–614 (2006).

    CAS  PubMed  Google Scholar 

  80. Wolthuis, R. et al. Cdc20 and Cks direct the spindle checkpoint-independent destruction of cyclin A. Mol. Cell 30, 290–302 (2008).

    CAS  PubMed  Google Scholar 

  81. Carter, S. L., Eklund, A. C., Kohane, I. S., Harris, L. N. & Szallasi, Z. A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nature Genet. 38, 1043–1048 (2006).

    CAS  PubMed  Google Scholar 

  82. Fukasawa, K. Oncogenes and tumour suppressors take on centrosomes. Nature Rev. Cancer 7, 911–924 (2007).

    CAS  Google Scholar 

  83. Duensing, A. et al. Cyclin-dependent kinase 2 is dispensable for normal centrosome duplication but required for oncogene-induced centrosome overduplication. Oncogene 25, 2943–2949 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Hanashiro, K., Kanai, M., Geng, Y., Sicinski, P. & Fukasawa, K. Roles of cyclins A and E in induction of centrosome amplification in p53-compromised cells. Oncogene 27, 5288–5302 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Hochegger, H. et al. An essential role for Cdk1 in S phase control is revealed via chemical genetics in vertebrate cells. J. Cell Biol. 178, 257–268 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Hanks, S. et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nature Genet. 36, 1159–1161 (2004).

    CAS  PubMed  Google Scholar 

  88. Mantel, C. et al. Checkpoint-apoptosis uncoupling in human and mouse embryonic stem cells: a source of karyotpic instability. Blood 109, 4518–4527 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Jeganathan, K., Malureanu, L., Baker, D. J., Abraham, S. C. & van Deursen, J. M. Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis. J. Cell Biol. 179, 255–267 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Baker, D. J. et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nature Genet. 36, 744–749 (2004).

    CAS  PubMed  Google Scholar 

  91. Perera, D. et al. Bub1 maintains centromeric cohesion by activation of the spindle checkpoint. Dev. Cell 13, 566–579 (2007).

    CAS  PubMed  Google Scholar 

  92. Dai, W. et al. Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency. Cancer Res. 64, 440–445 (2004).

    CAS  PubMed  Google Scholar 

  93. Michel, L. S. et al. MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature 409, 355–359 (2001).

    CAS  PubMed  Google Scholar 

  94. Sotillo, R. et al. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 11, 9–23 (2007). References 93–94 show that both decreased and increased levels of the SAC regulator MAD2L1 cause CIN tumours in mice, suggesting the existence of new group of tumour-related genes with features of both oncogenes and tumour suppressor genes.

    CAS  PubMed  Google Scholar 

  95. Weaver, B. A. & Cleveland, D. W. Aneuploidy: instigator and inhibitor of tumorigenesis. Cancer Res. 67, 10103–10105 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Yuen, K. W. & Desai, A. The wages of CIN. J. Cell Biol. 180, 661–663 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Engelbert, D., Schnerch, D., Baumgarten, A. & Wasch, R. The ubiquitin ligase APCCdh1 is required to maintain genome integrity in primary human cells. Oncogene 27, 907–917 (2008).

    CAS  PubMed  Google Scholar 

  98. Garcia-Higuera, I. et al. Genomic stability and tumour suppression by the APC/C cofactor Cdh1. Nature Cell Biol. 10, 802–811 (2008).

    PubMed  Google Scholar 

  99. Li, M. et al. The adaptor protein of the anaphase promoting complex Cdh1 is essential in maintaining replicative lifespan and in learning and memory. Nature Cell Biol. 10, 1083–1089 (2008). References 98 and 99 provide an in vivo demonstration of the relevance of the APC/C activity in maintaining the control of CDK function and cell cycle regulation for preventing GIN and tumour formation.

    CAS  PubMed  Google Scholar 

  100. Keen, N. & Taylor, S. Aurora-kinase inhibitors as anticancer agents. Nature Rev. Cancer 4, 927–936 (2004).

    CAS  Google Scholar 

  101. Malumbres, M. & Barbacid, M. Cell cycle kinases in cancer. Curr. Opin. Genet. Dev. 17, 60–65 (2007).

    CAS  PubMed  Google Scholar 

  102. Perez de Castro, I., de Carcer, G., Montoya, G. & Malumbres, M. Emerging cancer therapeutic opportunities by inhibiting mitotic kinases. Curr. Opin. Pharmacol. 8, 375–383 (2008).

    CAS  PubMed  Google Scholar 

  103. Petronczki, M., Lenart, P. & Peters, J. M. Polo on the rise β€” from mitotic entry to cytokinesis with Plk1. Dev. Cell 14, 646–659 (2008).

    CAS  PubMed  Google Scholar 

  104. Strebhardt, K. & Ullrich, A. Targeting polo-like kinase 1 for cancer therapy. Nature Rev. Cancer 6, 321–330 (2006).

    CAS  Google Scholar 

  105. Taylor, S. & Peters, J. M. Polo and Aurora kinases: lessons derived from chemical biology. Curr. Opin. Cell Biol. 20, 77–84 (2008).

    CAS  PubMed  Google Scholar 

  106. Malumbres, M., Pevarello, P., Barbacid, M. & Bischoff, J. R. CDK inhibitors in cancer therapy: what is next? Trends Pharmacol. Sci. 29, 16–21 (2008).

    CAS  PubMed  Google Scholar 

  107. Shapiro, G. I. Cyclin-dependent kinase pathways as targets for cancer treatment. J. Clin. Oncol. 24, 1770–1783 (2006).

    CAS  PubMed  Google Scholar 

  108. Larochelle, S. et al. Requirements for Cdk7 in the assembly of Cdk1/cyclin B and activation of Cdk2 revealed by chemical genetics in human cells. Mol. Cell 25, 839–850 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Li, T., Inoue, A., Lahti, J. M. & Kidd, V. J. Failure to proliferate and mitotic arrest of CDK11p110/p58-null mutant mice at the blastocyst stage of embryonic cell development. Mol. Cell. Biol. 24, 3188–3197 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Iorns, E. et al. Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer. Cancer Cell 13, 91–104 (2008).

    CAS  PubMed  Google Scholar 

  111. Chandramouli, A. et al. Haploinsufficiency of the cdc2l gene contributes to skin cancer development in mice. Carcinogenesis 28, 2028–2035 (2007).

    CAS  PubMed  Google Scholar 

  112. Boveri, T. Zur Frage der Entstehung Maligner Tumoren (Gustav Fisher, Jena, Germany, 1914) (in German).

    Google Scholar 

  113. Weaver, B. A., Silk, A. D., Montagna, C., Verdier-Pinard, P. & Cleveland, D. W. Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell 11, 25–36 (2007).

    CAS  PubMed  Google Scholar 

  114. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005). An elegant proof of principle of the therapeutic value of inducing synthetic lethal alterations in tumours.

    CAS  PubMed  Google Scholar 

  115. Huang, D., Friesen, H. & Andrews, B. Pho85, a multifunctional cyclin-dependent protein kinase in budding yeast. Mol. Microbiol. 66, 303–314 (2007).

    CAS  PubMed  Google Scholar 

  116. Nebreda, A. R. CDK activation by non-cyclin proteins. Curr. Opin. Cell Biol. 18, 192–198 (2006).

    CAS  PubMed  Google Scholar 

  117. Bloom, J. & Cross, F. R. Multiple levels of cyclin specificity in cell-cycle control. Nature Rev. Mol. Cell Biol. 8, 149–160 (2007).

    CAS  Google Scholar 

  118. Ren, S. & Rollins, B. J. Cyclin C/cdk3 promotes Rb-dependent G0 exit. Cell 117, 239–251 (2004).

    CAS  PubMed  Google Scholar 

  119. Ye, X., Zhu, C. & Harper, J. W. A premature-termination mutation in the Mus. musculus cyclin-dependent kinase 3 gene. Proc. Natl Acad. Sci. USA 98, 1682–1686 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Zhang, J. et al. Nuclear localization of Cdk5 is a key determinant in the postmitotic state of neurons. Proc. Natl Acad. Sci. USA 105, 8772–8777 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Maestre, C., Delgado-Esteban, M., Gomez-Sanchez, J. C., Bolanos, J. P. & Almeida, A. Cdk5 phosphorylates Cdh1 and modulates cyclin B1 stability in excitotoxicity. EMBO J. 27, 2736–2745 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Fisher, R. P. Secrets of a double agent: CDK7 in cell-cycle control and transcription. J. Cell Sci. 118, 5171–5180 (2005).

    CAS  PubMed  Google Scholar 

  123. Loyer, P., Trembley, J. H., Katona, R., Kidd, V. J. & Lahti, J. M. Role of CDK/cyclin complexes in transcription and RNA splicing. Cell Signal 17, 1033–1051 (2005).

    CAS  PubMed  Google Scholar 

  124. Firestein, R. et al. CDK8 is a colorectal cancer oncogene that regulates Ξ²-catenin activity. Nature 455, 547–551 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Morris, E. J. et al. E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8. Nature 455, 552–556 (2008). References 124 and 125 illustrate the role of CDK8, a CDK not directly implicated in the cell cycle, in human tumour development.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Petretti, C. et al. The PITSLRE/CDK11p58 protein kinase promotes centrosome maturation and bipolar spindle formation. EMBO Rep. 7, 418–424 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Wilker, E. W. et al. 14-3-3Οƒ controls mitotic translation to facilitate cytokinesis. Nature 446, 329–332 (2007).

    CAS  PubMed  Google Scholar 

  128. Yokoyama, H. et al. Cdk11 is a RanGTP-dependent microtubule stabilization factor that regulates spindle assembly rate. J. Cell Biol. 180, 867–875 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Hu, D., Valentine, M., Kidd, V. J. & Lahti, J. M. CDK11p58 is required for the maintenance of sister chromatid cohesion. J. Cell Sci. 120, 2424–2434 (2007).

    CAS  PubMed  Google Scholar 

  130. Hampsey, M. & Kinzy, T. G. Synchronicity: policing multiple aspects of gene expression by Ctk1. Genes Dev. 21, 1288–1291 (2007).

    CAS  PubMed  Google Scholar 

  131. Chen, H. H., Wang, Y. C. & Fann, M. J. Identification and characterization of the CDK12/cyclin L1 complex involved in alternative splicing regulation. Mol. Cell. Biol. 26, 2736–2745 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Chen, H. H., Wong, Y. H., Geneviere, A. M. & Fann, M. J. CDK13/CDC2L5 interacts with L-type cyclins and regulates alternative splicing. Biochem. Biophys. Res. Commun. 354, 735–740 (2007).

    CAS  PubMed  Google Scholar 

  133. Martin, J. et al. Genetic rescue of Cdk4 null mice restores pancreatic Ξ²-cell proliferation but not homeostatic cell number. Oncogene 22, 5261–5269 (2003).

    CAS  PubMed  Google Scholar 

  134. Mettus, R. V. & Rane, S. G. Characterization of the abnormal pancreatic development, reduced growth and infertility in Cdk4 mutant mice. Oncogene 22, 8413–8421 (2003).

    CAS  PubMed  Google Scholar 

  135. Jirawatnotai, S. et al. Cdk4 is indispensable for postnatal proliferation of the anterior pituitary. J. Biol. Chem. 279, 51100–51106 (2004).

    CAS  PubMed  Google Scholar 

  136. Moons, D. S. et al. Pituitary hypoplasia and lactotroph dysfunction in mice deficient for cyclin-dependent kinase-4. Endocrinology 143, 3001–3008 (2002).

    CAS  PubMed  Google Scholar 

  137. Sotillo, R. et al. Cooperation between Cdk4 and p27kip1 in tumor development: a preclinical model to evaluate cell cycle inhibitors with therapeutic activity. Cancer Res. 65, 3846–3852 (2005).

    CAS  PubMed  Google Scholar 

  138. Hartwell, L. H., Culotti, J. & Reid, B. Genetic control of the cell-division cycle in yeast. I. Detection of mutants. Proc. Natl Acad. Sci. USA 66, 352–359 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Nurse, P. Genetic control of cell size at cell division in yeast. Nature 256, 547–551 (1975).

    CAS  PubMed  Google Scholar 

  140. Evans, T., Rosenthal, E. T., Youngblom, J., Distel, D. & Hunt, T. Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell 33, 389–396 (1983).

    CAS  PubMed  Google Scholar 

  141. Lee, M. G. & Nurse, P. Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2. Nature 327, 31–35 (1987).

    CAS  PubMed  Google Scholar 

  142. DeCaprio, J. A. et al. The product of the retinoblastoma susceptibility gene has properties of a cell cycle regulatory element. Cell 58, 1085–1095 (1989).

    CAS  PubMed  Google Scholar 

  143. Buchkovich, K., Duffy, L. A. & Harlow, E. The retinoblastoma protein is phosphorylated during specific phases of the cell cycle. Cell 58, 1097–1105 (1989).

    CAS  PubMed  Google Scholar 

  144. Chen, P. L., Scully, P., Shew, J. Y., Wang, J. Y. & Lee, W. H. Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation. Cell 58, 1193–1198 (1989).

    CAS  PubMed  Google Scholar 

  145. Weinert, T. & Hartwell, L. Control of G2 delay by the rad9 gene of Saccharomyces cerevisiae. J. Cell Sci. Suppl 12, 145–148 (1989).

    CAS  PubMed  Google Scholar 

  146. Xiong, Y., Connolly, T., Futcher, B. & Beach, D. Human D-type cyclin. Cell 65, 691–699 (1991).

    CAS  PubMed  Google Scholar 

  147. Matsushime, H., Roussel, M. F., Ashmun, R. A. & Sherr, C. J. Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell 65, 701–713 (1991).

    CAS  PubMed  Google Scholar 

  148. Lew, D. J., Dulic, V. & Reed, S. I. Isolation of three novel human cyclins by rescue of G1 cyclin (Cln) function in yeast. Cell 66, 1197–1206 (1991).

    CAS  PubMed  Google Scholar 

  149. Matsushime, H. et al. Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins. Cell 71, 323–34 (1992).

    CAS  PubMed  Google Scholar 

  150. Donehower, L. A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221 (1992).

    CAS  PubMed  Google Scholar 

  151. Farmer, G. et al. Wild-type p53 activates transcription in vitro. Nature 358, 83–86 (1992).

    CAS  PubMed  Google Scholar 

  152. Hupp, T. R., Meek, D. W., Midgley, C. A. & Lane, D. P. Regulation of the specific DNA binding function of p53. Cell 71, 875–886 (1992).

    CAS  PubMed  Google Scholar 

  153. Lu, X., Park, S. H., Thompson, T. C. & Lane, D. P. Ras-induced hyperplasia occurs with mutation of p53, but activated ras and myc together can induce carcinoma without p53 mutation. Cell 70, 153–161 (1992).

    CAS  PubMed  Google Scholar 

  154. Lane, D. P. Cancer. p53, guardian of the genome. Nature 358, 15–16 (1992).

    CAS  PubMed  Google Scholar 

  155. Kuerbitz, S. J., Plunkett, B. S., Walsh, W. V. & Kastan, M. B. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc. Natl Acad. Sci. USA 89, 7491–7495 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Kastan, M. B. et al. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71, 587–597 (1992).

    CAS  PubMed  Google Scholar 

  157. Xiong, Y., Zhang, H. & Beach, D. Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation. Genes Dev. 7, 1572–1583 (1993).

    CAS  PubMed  Google Scholar 

  158. Serrano, M., Hannon, G. J. & Beach, D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366, 704–707 (1993).

    CAS  PubMed  Google Scholar 

  159. Xiong, Y. et al. p21 is a universal inhibitor of cyclin kinases. Nature 366, 701–704 (1993).

    CAS  PubMed  Google Scholar 

  160. Polyak, K. et al. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev. 8, 29–22 (1994).

    Google Scholar 

  161. Toyoshima, H. & Hunter, T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78, 67–74 (1994).

    CAS  PubMed  Google Scholar 

  162. Kato, J. Y., Matsuoka, M., Polyak, K., Massague, J. & Sherr, C. J. Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation. Cell 79, 487–96 (1994).

    CAS  PubMed  Google Scholar 

  163. Guan, K. L. et al. Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function. Genes Dev. 8, 2939–2952 (1994).

    CAS  PubMed  Google Scholar 

  164. Polyak, K. et al. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78, 59–66 (1994).

    CAS  PubMed  Google Scholar 

  165. Lee, M. H., Reynisdottir, I. & Massague, J. Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev. 9, 639–49 (1995).

    CAS  PubMed  Google Scholar 

  166. Matsuoka, S. et al. p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dev. 9, 650–662 (1995).

    CAS  PubMed  Google Scholar 

  167. Li, Y. & Benezra, R. Identification of a human mitotic checkpoint gene: hsMAD2. Science 274, 246–248 (1996).

    CAS  PubMed  Google Scholar 

  168. Loda, M. et al. Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nature Med. 3, 231–234 (1997).

    CAS  PubMed  Google Scholar 

  169. Catzavelos, C. et al. Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nature Med. 3, 227–230 (1997).

    CAS  PubMed  Google Scholar 

  170. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997).

    CAS  PubMed  Google Scholar 

  171. Cahill, D. P. et al. Mutations of mitotic checkpoint genes in human cancers. Nature 392, 300–303 (1998).

    CAS  PubMed  Google Scholar 

  172. Hanks, S. et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nature Genet. 36, 1159–1161 (2004).

    CAS  PubMed  Google Scholar 

  173. Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005).

    CAS  PubMed  Google Scholar 

  174. Collado, M. et al. Tumour biology: senescence in premalignant tumours. Nature 436, 642 (2005).

    CAS  PubMed  Google Scholar 

  175. Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005).

    CAS  PubMed  Google Scholar 

  176. Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was funded by grants from the Ministry of Science and Innovation (MICINN) (SAF2006-05186 to M.M. and SAF2006-11773 to M.B.), FundaciΓ³n Mutua MadrileΓ±a Automovilista (to M.M.), Association International for Cancer Research (AICR08-0188 to M.M.) and 7th Framework Programme (CHEMORES LSHG-CT-2007-037,665 to M.B). The Cell Division and Cancer and the Experimental Oncology Groups are also supported by grants from the Comunidad AutΓ³noma de Madrid (S-BIO-0283-2006) and the MICINN (Consolider-Ingenio 2010, CSD2007-00017).

Author information

Authors and Affiliations

  1. Cell Division and Cancer Group, Molecular Oncology Programme, Centro Nacional de Investigaciones OncolΓ³gicas (CNIO), Madrid, 28029, Spain

    Marcos Malumbres

  2. Experimental Oncology Group, Molecular Oncology Programme, Centro Nacional de Investigaciones OncolΓ³gicas (CNIO), Madrid, 28029, Spain

    Mariano Barbacid

Authors
  1. Marcos Malumbres
  2. Mariano Barbacid

Glossary

Unscheduled proliferation

Activation of the cell cycle machinery leading to cell proliferation in the absence or presence, respectively, of appropriate mitogenic or anti-mitogenic signalling.

Genomic instability

(GIN). A tendency of the genome to acquire mutations and chromosomal aberrations owing to dysfunctional replication or repair of the cellular genome.

Chromosomal instability

(CIN). A tendency of the genome to acquire numerical aberrations in the chromosomes when chromosome segregation during mitosis is dysfunctional. CIN is frequently seen as a form of GIN, but we consider them as separate entities for clarity.

Interphase CDKs

CDKs that contribute to several cell cycle processes during interphase. In this review, we use this term to refer to CDK2, CDK4 and CDK6. This working definition does not imply that they contribute equally to the various cell cycle events (for example, G1 progression or DNA replication) that take place during interphase.

Cell cycle checkpoint

Control mechanisms that ensure the fidelity of cell division. These checkpoints verify whether the processes at each phase of the cell cycle have been accurately completed before progression into the next phase.

DNA damage checkpoint

A signal transduction pathway induced by DNA damage that blocks cell cycle progression until DNA is properly repaired.

Spindle-assembly checkpoint

A signalling pathway that monitors the correct attachment of chromosomes to spindles. Activation of this checkpoint causes cell cycle arrest as a result of the inhibition of APC/C.

About this article

Cite this article

Malumbres, M., Barbacid, M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9, 153–166 (2009). https://doi.org/10.1038/nrc2602

Download citation

  • Issue date:

  • DOI: https://doi.org/10.1038/nrc2602

This article is cited by

Search

Advanced search

Quick links

πŸ‘ Nature Briefing

Sign up for the Nature Briefing newsletter β€” what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing