Overview of the Cell Cycle

Michele S. Park1, Andrew Koff1

1 Memorial Sloan‐Kettering Cancer Center, New York, New York
Publication Name:  Current Protocols in Cell Biology
Unit Number:  Unit 8.1
DOI:  10.1002/0471143030.cb0801s00
Online Posting Date:  May, 2001
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Progression through the cell cycle is regulated by inductive signals from outside the cell and intracellular signal pathways, while the cycle itself is regulated by cyclin‐dependent kinases (CDKs). An understanding of the functions of these molecules is necessary to understand the processes of mitosis, differentiation, senescence, apoptosis, and tumorigenesis. This overview reviews the current state of knowledge for the biology of the cell‐cycle, the CDKs, the role of proteolysis, targets of the cell cycle machinery, and a paradigm of cell cycle analysis.

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Table of Contents

  • The Biology of the Cell Cycle
  • The Cell Cycle Engine
  • Targets of the Cell Cycle Machinery
  • A Paradigm of Cell Cycle Analysis
  • Literature Cited
  • Figures
  • Tables
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Literature Cited

Literature Cited
   Amon, A., Tyers, M., Futcher, B., and Nasmyth, K., 1993. Mechanisms that help the yeast cell cycle clock tick: G2 cyclins transcriptionally activate G2 cyclins and repress G1 cyclins. Cell 74:993‐1007.
   Amon, A., Irniger, S., and Nasmyth, K. 1994. Closing the cell cycle circle in yeast: G2 cyclin proteins initiated at mitosis persist until the activation of G1 cyclins in the next cycle. Cell 77:1037‐1050.
   Bai, C., Sen, P., Hofmann, K., Ma, L., Goebl, M., Harper, J.W., and Elledge, S.J. 1996. SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F‐box. Cell 86:263‐274.
   Bartek, J., Bartkova, J., and Lukas, J. 1996. The retinoblastoma protein pathway and the restriction point. Curr. Opin. Cell Biol. 8:805‐814.
   Brandeis, M. and Hunt, T. 1996. The proteolysis of mitotic cyclins in mammalian cells persists from the end of mitosis until the onset of S phase. EMBO J. 15:5280‐5289.
   Clurman, B.E., Sheaff, R.J., Thress, K., Groudine, M., and Roberts, J.M. 1996. Turnover of cyclin E by the ubiquitin‐proteasome pathway is regulated by CDK2 binding and cyclin phosphorylation. Genes & Dev. 10:1979‐1990.
   Cobrinik, D., Lee, M.‐H., Hannon, G., Mulligan, G., Bronson, R.T., Dyson, N., Harlow, E., Beach, D., Weinberg, R.A., and Jacks, T. 1996. Shared role of the pRb‐related p130 and p107 in limb development. Genes & Dev. 10:1633‐1644.
   Diehl, J.A., Zindy, F., and Sherr, C.J. 1997. Inhibition of cyclin D1 phosphorylation on threonine‐286 prevents its rapid degradation via the ubiquitin‐proteasome pathway. Genes & Dev. 11:957‐972.
   Dulic, V., Lees, E., and Reed, S. 1992. Association of human cyclin E with a periodic G1‐S phase protein kinase. Science 257:1958‐1961.
   El‐Deiry, W.S., Tokin, T., Velculescu, V.E., Levy, D.B., Parsons, R., Trent, J.M., Lin, D., Mercer, W.E., Kinzler, K.W., and Vogelstein, B. 1993. WAF1, a potent mediator of p53 tumor suppression. Cell 75:817‐825.
   Feldman, R.M., Correll, C.C., Kaplan, K.B., and Deshaies, R.J. 1997. A complex of Cdc4p, Skp1p, and Cdc53p/Cullin catalyzes ubiquitination of the phosphorylated CDK inhibitor Sic1p. Cell 91:221‐230.
   Fisher, R.P. and Morgan, D.O. 1994. A novel cyclin associates with MO15/CDK7 to form the CDK‐activating kinase. Cell 78:713‐724.
   Glotzer, M., Murray, A.W., and Kirschner, M.W. 1991. Cyclin is degraded by the ubiquitin pathway. Nature 349:132‐138.
   Gu, Y., Turck, C.W., and Morgan, D.O. 1993. Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit. Nature 366:707‐710.
   Hannon, G.J. and Beach, D. 1994. p15INK4B is a potential effector of TGF‐β‐induced cell cycle arrest. Nature 371:257‐261.
   Harper, J., Adami, G., Wei, N., Keyomarsi, K., and Elledge, S. 1993. The p21 CDK‐interacting protein Cip1 is a potent inhibitor of G1 cyclin‐dependent kinases. Cell 75:805‐816.
   Henchoz, S., Chi, Y., Catarin, B., Herskowitz, I., Deshaies, R., and Peter, M. 1997. Phosphorylation‐and ubiquitin‐dependent degradation of the cyclin‐dependent kinase inhibitor Far1p in budding yeast. Genes & Dev. 11:3046‐3060.
   Jacks, T., Fazeli, A., Schmitt, E.M., Bronson, R.T., Goodell, M.A., and Weinbert, R.A. 1992. Effects of an Rb mutation in the mouse. Nature 359:295‐300.
   Knoblich, J., Sauer, K., Jones, L., Richardson, H., Saint, R., and Lehner, C. 1994. Cyclin E controls S phase progression and its down‐regulation during Drosophila embryogenesis is required for the arrest of cell proliferation. Cell 77:107‐120.
   Koff, A., Giordano, A., Desai, D., Yamashita, K., Harper, W., Elledge, S., Nishimoto, T., Morgan, D., Franza, R., and Roberts, J. 1992. Formation and activation of a cyclin E/CDK2 complex during the G1 phase of the human cell cycle. Science 257:1689‐1694.
   Koff, A., Ohtsuki, M., Polyak, K., Roberts, J.M., and Massague, J. 1993. Negative regulation of G1 in mammalian cells; inhibition of cyclin E–dependent kinase by TGF‐β. Science 260:536‐538.
   Krek, W. and Nigg, E.A. 1991. Differential phosphorylation of vertebrate p34Cdc2 kinase at the G1/S and G2/M transitions of the cell cycle: Identification of major phosphorylation sites. EMBO J. 10:305‐316.
   Kuerbitz, S.J., Plunkett, B.S., Walsh, W.W., and Kastan, M.B. 1992. Wild type p53 is a cell cycle checkpoint determinant following irradiation. Proc. Natl. Acad. Sci. U.S.A. 89:7491‐7495.
   Lee, E., Chang, C.‐Y., Hu, N., Wang, Y.‐C., Lai, C.‐C., Herrup, K., Lee, W.‐H., and Bradley, A. 1992. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359:288‐294.
   Lee, M.‐H., Reynisdottir, I., and Massague, J. 1995. Cloning of p57Kip2, a cyclin‐dependent kinase inhibitor with unique domain structure and tissue distribution. Genes & Dev. 9:639‐649.
   Lee, M.‐H., Williams, B.O., Mulligan, G., Mukai, S., Bronson, R.T., Dyson, N., Harlow, E., and Jacks, T. 1996. Targeted disruption of p107: Functional overlap between p107 and Rb. Genes & Dev. 10:1621‐1632.
   Lew, D.J., Dulic, V., and Reed, S.I. 1991. Isolation of three novel human cyclins by rescue of G1 cyclin (CLN) function in yeast. Cell 66:1197‐1206.
   Lowe, S.W., Schmitt, E.M., Smith, S.W., Osborne, B.A., and Jacks, T. 1993. p53 is required for radiation‐induced apoptosis in mouse thymocytes. Nature 362:847‐849.
   Matsuoka, S., Edwards, M.C., Bai, C., Parker, S., Zhang, P., Baldini, A., Harper, J.W., and Elledge, S.J. 1995. p57Kip2, a structurally distinct member of the p21CIP1 CDK‐inhibitor family, is a candidate tumor suppressor gene. Genes & Dev. 9:650‐662.
   Matsushime, H., Ewen, M.E., Strom, D.K., Kato, J., Hanks, S.K., Roussel, M.F., and Sherr, C.J. 1992. Identification and properties of an atypical catalytic subunit (p34PSK‐13)/CDK4) for mammaliam D‐type cyclins. Cell 71:323‐334.
   Matsushime, H., Quelle, D.E., Shurtleff, S.A., Shibuya, M., Sherr, C.J., and Kato, J.‐Y. 1994. D‐type cyclin‐dependent kinase activity in mammalian cells. Mol. Cell. Biol. 14:2066‐2076.
   Meyerson, M. and Harlow, E. 1994. Identification of a G1‐kinase activity for CDK6, a novel cyclin D partner. Mol. Cell. Biol. 14:2077‐2086.
   Morgan, D. 1995. Principles of CDK regulation. Nature 374:131‐133.
   Murray, A. 1994. Cell cycle checkpoints. Curr. Opin. Cell Biol. 6:872‐876.
   Nevins, J.R. 1992. E2F: A link between the Rb tumor suppressor protein and viral oncoproteins. Science 258:424‐429.
   Pagano, M., Tam, S.W., Theodoras, A.M., Beer‐Romero, P., Del Sal, G., Chau, V., Yew, P.R., Draetta, G.F., and Rolfe, M. 1995. Role of the ubiquitin‐proteasome pathway in regulating amounts of the cyclin‐dependent kinase inhibitor p27. Science 269:682‐685.
   Pardee, A.B. 1989. G1 events and regulation of cell proliferation. Science 246:603‐608.
   Parker, L.L. and Piwnica‐Worms, H. 1992. Inactivation of the p34cdc− cyclin B complex by the human Wee 1 tyrosine kinase. Science 257:1955‐1977.
   Parker, L.L., Atherton‐Fessler, S., Lee, M.S., Ogg, S., Falk, J.L., Swenson, K.I., and Piwnica‐Worms, H. 1991. Cyclin promotes tyrosine phosphorylation of p34cdc2 in a wee1+‐dependent manner. EMBO J. 10:1255‐1263.
   Piatti, S., Bohm, T., Cocker, J.H., Diffley, J.F.X., and Nasmyth, K. 1996. Activation of S phase–promoting CDKs in late G1 defines a “point of no return” after which Cdc6 synthesis cannot promote DNA replication in yeast. Genes & Dev. 10:1516‐1531.
   Pines, J. and Hunter, T. 1989. Isolation of human cyclin cDNA: Evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2. Cell 58:833‐846.
   Pines, J. and Hunter, T. 1990. Human cyclin A is adenovirus E1A–associated protein p60 and behaves differently from cyclin B. Nature 346:760‐763.
   Polyak, K., Kato, J.Y., Soloman, M.J., Sherr, C.J., Massague, J., Roberts, J.M., and 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., Erdjument‐Bromage, H., Koff, A., Roberts, J.M., Tempst, P., and Massague, J. 1994b. Cloning of p27Kip1, a cyclin‐dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78:59‐66.
   Serrano, M., Hannon, G.J., and Beach, D. 1993. A new regulatory motif in cell‐cycle control causing specific inhibition of cyclin D/CDK4. Nature 366:704‐707.
   Sheaff, R.J., Groudine, M., Gordon, M., Roberts, J.M., and Clurman, B.E. 1997. Cyclin E–CDK2 is a regulator of p27KIP1. Genes & Dev. 11:1464‐1478.
   Sherr, C.J. 1994. G1 phase progression: Cycling on cue. Cell 79:551‐555.
   Sherr, C.J. and Roberts, J.M. 1995. Inhibitors of mammalian G1 cyclin‐dependent kinases. Genes & Dev. 9:1149‐1163.
   Stillman, B. 1996. Cell cycle control of DNA replication. Science 274:1659‐1663.
   Toyoshima, H. and Hunter, T. 1994. p27, a novel inhibitor of G1 cyclin–CDK protein kinase activity, is related to p21. Cell 78:67‐74.
   Vlach, J., Hennecke, S., and Amati, B. 1997. Phosphorylation‐dependent degradation of the cyclin‐dependent kinase inhibitor p27Kip1. EMBO J. 16:5334‐5344.
   Xiong, Y., Connolly, T., Futcher, B., and Beach, D. 1991. Human D‐type cyclin. Cell 65:691‐695.
   Xiong, Y., Hannon, G.J., Zhang, H., Casso, D., Kobayashi, R., and Beach, D. 1993. p21 is a universal inhibitor of cyclin kinases. Nature 366:701‐704.
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