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Cyclin-dependent kinases and cell-cycle transitions: does one fit all?

Nature Reviews Molecular Cell Biology volume 9, pages 910–916 (2008)Cite this article

Abstract

Cell-cycle transitions in higher eukaryotes are regulated by different cyclin-dependent kinases (CDKs) and their activating cyclin subunits. Based on pioneering findings that a dominant-negative mutation of CDK1 blocks the cell cycle at G2–M phase, whereas dominant-negative CDK2 inhibits the transition into S phase, a model of cell-cycle control has emerged in which each transition is regulated by a specific subset of CDKs and cyclins. Recent work with gene-targeted mice has led to a revision of this model. We discuss cell-cycle control in light of overlapping and essential functions of the different CDKs and cyclins.

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Figure 1: The classical and minimal models of cell-cycle control.

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References

  1. Morgan, D. O. The Cell Cycle; Principles of Control (New Science Press, London, 2007).

    Google Scholar 

  2. Harper, J. W. & Elledge, S. J. The role of Cdk7 in CAK function, a retro-retrospective. Genes Dev. 12, 285–289 (1998).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Kellogg, D. R. Wee1-dependent mechanisms required for coordination of cell growth and cell division. J. Cell Sci. 116, 4883–4890 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Kobayashi, H., Stewart, E., Poon, R. Y. & Hunt, T. Cyclin A and cyclin B dissociate from p34cdc2 with half-times of 4 and 15 h, respectively, regardless of the phase of the cell cycle. J. Biol. Chem. 269, 29153–29160 (1994).

    CAS  PubMed  Google Scholar 

  6. Nurse, P. A long twentieth century of the cell cycle and beyond. Cell 100, 71–78 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. 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).

    Article  CAS  PubMed  Google Scholar 

  9. Sherr, C. J. Mammalian G1 cyclins. Cell 73, 1059–1065 (1993).

    Article  CAS  PubMed  Google Scholar 

  10. 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).

    Article  CAS  PubMed  Google Scholar 

  11. Berthet, C., Aleem, E., Coppola, V., Tessarollo, L. & Kaldis, P. Cdk2 knockout mice are viable. Curr. Biol. 13, 1775–1785 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Krasinska, L. et al. Cdk1 and Cdk2 activity levels determine the efficiency of replication origin firing in Xenopus. EMBO J. 27, 758–769 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Santamaria, D. et al. Cdk1 is sufficient to drive the mammalian cell cycle. Nature 448, 811–815 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. Barbacid, M. et al. Cell cycle and cancer: genetic analysis of the role of cyclin-dependent kinases. Cold Spring Harb. Symp. Quant. Biol. 70, 233–240 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Berthet, C. & Kaldis, P. Cell-specific responses to loss of cyclin-dependent kinases. Oncogene 26, 4469–4477 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Orlando, D. A. et al. Global control of cell-cycle transcription by coupled CDK and network oscillators. Nature 453, 944–947 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Petri, E. T., Errico, A., Escobedo, L., Hunt, T. & Basavappa, R. The crystal structure of human cyclin B. Cell Cycle 6, 1342–1349 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Loog, M. & Morgan, D. O. Cyclin specificity in the phosphorylation of cyclin-dependent kinase substrates. Nature 434, 104–108 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Fisher, D. L. & Nurse, P. A single fission yeast mitotic cyclin B p34cdc2 kinase promotes both S-phase and mitosis in the absence of G1 cyclins. EMBO J. 15, 850–860 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Stern, B. & Nurse, P. A quantitative model for the cdc2 control of S phase and mitosis in fission yeast. Trends Genet. 12, 345–350 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Arias, E. E. & Walter, J. C. Strength in numbers: preventing rereplication via multiple mechanisms in eukaryotic cells. Genes Dev. 21, 497–518 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Zegerman, P. & Diffley, J. F. Phosphorylation of Sld2 and Sld3 by cyclin-dependent kinases promotes DNA replication in budding yeast. Nature 445, 281–285 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Tanaka, S. et al. CDK-dependent phosphorylation of Sld2 and Sld3 initiates DNA replication in budding yeast. Nature 445, 328–332 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Blethrow, J. D., Glavy, J. S., Morgan, D. O. & Shokat, K. M. Covalent capture of kinase-specific phosphopeptides reveals Cdk1–cyclin B substrates. Proc. Natl Acad. Sci. USA 105, 1442–1447 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pines, J. & Hunter, T. The differential localization of human cyclins A and B is due to a cytoplasmic retention signal in cyclin B. EMBO J. 13, 3772–3781 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kozar, K. et al. Mouse development and cell proliferation in the absence of D-cyclins. Cell 118, 477–491 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  33. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu, D. et al. Cyclin A1 is required for meiosis in the male mouse. Nature Genet. 20, 377–380 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. Jacobs, H. W., Knoblich, J. A. & Lehner, C. F. Drosophila cyclin B3 is required for female fertility and is dispensable for mitosis like cyclin B. Genes Dev. 12, 3741–3751 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jin, P., Hardy, S. & Morgan, D. O. Nuclear localization of cyclin B1 controls mitotic entry after DNA damage. J. Cell Biol. 141, 875–885 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hagting, A., Karlsson, C., Clute, P., Jackman, M. & Pines, J. MPF localization is controlled by nuclear export. EMBO J. 17, 4127–4138 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  39. Nurse, P. Regulation of the eukaryotic cell cycle. Eur. J. Cancer 33, 1002–1004 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Zhou, B. B. & Elledge, S. J. The DNA damage response: putting checkpoints in perspective. Nature 408, 433–439 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Pomerening, J. R., Ubersax, J. A. & Ferrell, J. E. Jr. Rapid cycling and precocious termination of G1 phase in cells expressing CDK1AF. Mol. Biol. Cell 19, 3426–3441 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ubersax, J. A. et al. Targets of the cyclin-dependent kinase Cdk1. Nature 425, 859–64 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Peter, M., Heitlinger, E., Haner, M., Aebi, U. & Nigg, E. A. Disassembly of in vitro formed lamin head-to-tail polymers by CDC2 kinase. EMBO J. 10, 1535–1544 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Heald, R. & McKeon, F. Mutations of phosphorylation sites in lamin A that prevent nuclear lamina disassembly in mitosis. Cell 61, 579–589 (1990).

    Article  CAS  PubMed  Google Scholar 

  45. Galy, V. et al. A role for gp210 in mitotic nuclear-envelope breakdown. J. Cell Sci. 121, 317–328 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Onischenko, E. A., Gubanova, N. V., Kiseleva, E. V. & Hallberg, E. Cdk1 and okadaic acid-sensitive phosphatases control assembly of nuclear pore complexes in Drosophila embryos. Mol. Biol. Cell 16, 5152–5162 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Stegmeier, F. & Amon, A. Closing mitosis: the functions of the Cdc14 phosphatase and its regulation. Annu. Rev. Genet. 38, 203–232 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Berdougo, E., Nachury, M. V., Jackson, P. K. & Jallepalli, P. V. The nucleolar phosphatase Cdc14B is dispensable for chromosome segregation and mitotic exit in human cells. Cell Cycle 7, 1184–1190 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Sola, M. M., Langan, T. & Cohen, P. p34cdc2 phosphorylation sites in histone H1 are dephosphorylated by protein phosphatase 2A1. Biochim. Biophys. Acta 1094, 211–216 (1991).

    Article  CAS  PubMed  Google Scholar 

  50. Chen, F. et al. Multiple protein phosphatases are required for mitosis in Drosophila. Curr. Biol. 17, 293–303 (2007).

    Article  PubMed  Google Scholar 

  51. Caspari, T., Murray, J. M. & Carr, A. M. Cdc2–cyclin B kinase activity links Crb2 and Rqh1-topoisomerase III. Genes Dev. 16, 1195–1208 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ferreira, M. G. & Cooper, J. P. The fission yeast Taz1 protein protects chromosomes from Ku-dependent end-to-end fusions. Mol. Cell 7, 55–63 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Ira, G. et al. DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. Nature 431, 1011–1017 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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 20 Aug 2008 (doi:10.1038/nature07215).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hinchcliffe, E. H. & Sluder, G. “It takes two to tango”: understanding how centrosome duplication is regulated throughout the cell cycle. Genes Dev. 15, 1167–1181 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Tsou, M. F. & Stearns, T. Controlling centrosome number: licenses and blocks. Curr. Opin. Cell Biol. 18, 74–78 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Hinchcliffe, E. H., Li, C., Thompson, E. A., Maller, J. L. & Sluder, G. Requirement of Cdk2–cyclin E activity for repeated centrosome reproduction in Xenopus egg extracts. Science 283, 851–854 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Lacey, K. R., Jackson, P. K. & Stearns, T. Cyclin-dependent kinase control of centrosome duplication. Proc. Natl Acad. Sci. USA 96, 2817–2822 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Matsumoto, Y., Hayashi, K. & Nishida, E. Cyclin-dependent kinase 2 (Cdk2) is required for centrosome duplication in mammalian cells. Curr. Biol. 9, 429–432 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Okuda, M. et al. Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 103, 127–140 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Blangy, A. et al. Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 83, 1159–1169 (1995).

    Article  CAS  PubMed  Google Scholar 

  62. Jackman, M., Lindon, C., Nigg, E. A. & Pines, J. Active cyclin B1–Cdk1 first appears on centrosomes in prophase. Nature Cell Biol. 5, 143–148 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Xiong, W. & Ferrell, J. E. Jr. A positive-feedback-based bistable 'memory module' that governs a cell fate decision. Nature 426, 460–465 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Toyoshima-Morimoto, F., Taniguchi, E., Shinya, N., Iwamatsu, A. & Nishida, E. Polo-like kinase 1 phosphorylates cyclin B1 and targets it to the nucleus during prophase. Nature 410, 215–220 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Hirota, T. et al. Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells. Cell 114, 585–598 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Malik, R., Nigg, E. A. & Korner, R. Comparative conservation analysis of the human mitotic phosphoproteome. Bioinformatics 24, 1426–1432 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank T. Carr, N. Hegarat, T. Hunter, J. Pines and R. Poon for critical comments on the manuscript. H.H. is a Wellcome Trust Career Development Fellow at the Genome Damage and Stability Centre at the University of Sussex, S.T. holds the chair for Radiation Genetics at Kyoto University Medical School and T.H. is a principal investigator at CRUK Clare Hall laboratories.

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Authors and Affiliations

  1. Helfrid Hochegger is at the Genome Damage and Stability Centre, University of Sussex, Falmer Brighton, BN1 9RQ, UK.,

    Helfrid Hochegger

  2. Shunichi Takeda is at the Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.,

    Shunichi Takeda

  3. Tim Hunt is at Clare Hall Laboratories Cancer Research UK, Blanche Lane, South Mimms, EN6 3LD, UK.,

    Tim Hunt

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Hochegger, H., Takeda, S. & Hunt, T. Cyclin-dependent kinases and cell-cycle transitions: does one fit all?. Nat Rev Mol Cell Biol 9, 910–916 (2008). https://doi.org/10.1038/nrm2510

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