Comprehensive Physiology Wiley Online Library

Principles of Cell Cycle Control

Full Article on Wiley Online Library


The sections in this article are:

1 Mitosis
1.1 Cdc2: The Archetypal Cyclin‐Dependent Kinase
1.2 Regulation of Cdc2
1.3 Substrates of Cdc2
1.4 Induction of Chromatin Condensation
1.5 Controls Operating within M Phase
2 Cyclin‐Dependent Kinases Other Than Cdc2
2.1 G1
2.2 Cell Cycle Commitment
2.3 Mammalian Nonmitotic Cyclins
2.4 Cell Cycle Commitment and Cancer
3 Cdk Inhibitors
4 Linking Cell Cycle Commitment to S‐Phase Entry
5 S Phase and G2
6 Concluding Remarks
Figure 1. Figure 1.

Points of commitment in eukaryotic cell cycle. Schematic representation of cell cycle is shown, with major events S (DNA synthesis), M (mitosis), gap phases (G1, G2), and cell division (CD) indicated. In yeast and mammalian cells commitment to enter S phase occurs during period in late G1 , while commitment to enter mitosis is indistinguishable from G2/M transition (for discussion see text).

Figure 2. Figure 2.

Activation of Cdc2 at onset of mitosis. Assembly of Cdc2/cyclin B heterodimers promotes phosphorylation and inactivation of Cdc2 subunit (left). Dephosphorylation of Cdc2 by Cdc25 phosphatase(s) at positions T14 and Y15 leads to generation of active MPF heterodimers (right). Signals relating to DNA damage and completeness of replication impact on balance of Wee1 (a Cdc2 inhibitory kinase) and Cdc25 activities to delay entry into M phase. Additional DNA damage signal may influence aspect of Cdc2 activation other than Y15 phosphorylation (see text).

Figure 3. Figure 3.

Two checkpoints that prevent premature mitosis in fission yeast. In cells that require delay of G1 progression (for example, cells that are too small to satisfy the minimum size requirement for S‐phase entry) Rum1 acts both to delay start and to prevent entry into mitosis. In cells that have passed start, Cdc18 acts to prevent premature mitosis as long as DNA replication is in progress.

Figure 4. Figure 4.

A pathway linking start to the initiation of S phase in fission yeast. Conversion of Cdc2 from “prestart” form to a “poststart” form (asterisk) is inhibited by Rum1. Once activated for its start function, Cdc2 activates transcription factors containing Cdc10 protein and accessory subunits; key target for these transcription factors is cdc18 gene, which encodes protein required for initiation of DNA replication (see text).

Figure 1.

Points of commitment in eukaryotic cell cycle. Schematic representation of cell cycle is shown, with major events S (DNA synthesis), M (mitosis), gap phases (G1, G2), and cell division (CD) indicated. In yeast and mammalian cells commitment to enter S phase occurs during period in late G1 , while commitment to enter mitosis is indistinguishable from G2/M transition (for discussion see text).

Figure 2.

Activation of Cdc2 at onset of mitosis. Assembly of Cdc2/cyclin B heterodimers promotes phosphorylation and inactivation of Cdc2 subunit (left). Dephosphorylation of Cdc2 by Cdc25 phosphatase(s) at positions T14 and Y15 leads to generation of active MPF heterodimers (right). Signals relating to DNA damage and completeness of replication impact on balance of Wee1 (a Cdc2 inhibitory kinase) and Cdc25 activities to delay entry into M phase. Additional DNA damage signal may influence aspect of Cdc2 activation other than Y15 phosphorylation (see text).

Figure 3.

Two checkpoints that prevent premature mitosis in fission yeast. In cells that require delay of G1 progression (for example, cells that are too small to satisfy the minimum size requirement for S‐phase entry) Rum1 acts both to delay start and to prevent entry into mitosis. In cells that have passed start, Cdc18 acts to prevent premature mitosis as long as DNA replication is in progress.

Figure 4.

A pathway linking start to the initiation of S phase in fission yeast. Conversion of Cdc2 from “prestart” form to a “poststart” form (asterisk) is inhibited by Rum1. Once activated for its start function, Cdc2 activates transcription factors containing Cdc10 protein and accessory subunits; key target for these transcription factors is cdc18 gene, which encodes protein required for initiation of DNA replication (see text).

 1. Adachi, Y., M. Luke, and U. K. Laemmli. Chromosome assembly in vitro: topoisomerase II is required for condensation. Cell 64: 137–148, 1991.
 2. Al‐Khodairy, F., and A. M. Carr. DNA repair mutants defining G2 checkpoint pathways in Schizosaccharomyces pombe. EMBO J. 11: 1343–1350, 1992.
 3. Arnold, A., T. Motokura, T. Bloom, H. Kronenberg, J. Ruderman, H. Juppner, and H. G. Kim. The putative oncogene prad1 encodes a novel cyclin. Cold Spring Harb. Symp. Quant. Biol. 56: 93–97, 1991.
 4. Aubin, J. E., M. Osborn, W. W. Franke, and K. Weber. Intermediate filaments of the vimentin type and cytokeratin type are distributed differently during mitosis. Exp. Cell Res. 129: 149–165, 1980.
 5. Axton, J. M., V. Dombradi, P. T. Cohen, and D. M. Glover. One of the protein phosphatase 1 isoenzymes in Drosophila is essential for mitosis. Cell 63: 33–46, 1990.
 6. Bailly, E., M. Doree, P. Nurse, and M. Bornens. p34cdc2 is located in both nucleus and cytoplasm; part is centrosomally associated at G2/M and enters vesicles at anaphase. EMBO J. 8: 3985–3995, 1989.
 7. Barbet, N. C., and A. M. Carr. Fission yeast wee1 protein‐kinase is not required for DNA damage‐dependent mitotic arrest. Nature 364: 824–827, 1993.
 8. Baserga, R. Growth in size and cell DNA replication. Exp. Cell Res. 151: 1–5, 1984.
 9. Bates, S., L. Bonetta, D. MacAllan, D. Parry, A. Holder, C. Dickson, and G. Peters. Cdk6 (plstire) and cdk4 (psk‐J3) are a distinct subset of the cyclin‐dependent kinases that associate with cyclin D1. Oncogene 9: 71–79, 1994.
 10. Beach, D., B. Durkacz, and P. Nurse. Functionally homologous cell cycle control genes in budding and fission yeast. Nature 300: 706–709, 1982.
 11. Beach, D., M. Piper, and P. Nurse. Construction of a Schizosaccharomyces pombe gene bank in a yeast bacterial shuttle vector and its use to isolate genes by complementation. Mol. Gen. Genet. 187: 326–329, 1982.
 12. Belenguer, P., F. M. Caizergues, J. C. Labbé, M. Dorée, and F. Amalric. Mitosis‐specific phosphorylation of nucleolin by p34cdc2 protein kinase. Mol. Cell. Biol. 10: 3607–3618, 1990.
 13. Bellé, R., J. Derancourt, R. Poulhe, J.‐P. Capony, R. Ozon, and O. Mulner‐Lorillon. A purified complex from Xenopus oocytes contains a p47 protein, an in vivo substrate of MPF, and a p30 protein respectively homologous to elongation factors EF‐1γ and EF‐1β. FEBS Lett. 255: 101–104, 1989.
 14. Blow, J. J., and R. A. Laskey. A role for the nuclear envelope in controlling DNA replication within the cell cycle. Nature 332: 546–548, 1988.
 15. Blow, J. J., and A. M. Sleeman. Replication of purified DNA in Xenopus egg extract is dependent on nuclear assembly. J. Cel. Sci. 95: 383–391, 1990.
 16. Bonetta, L. Open questions on p16. Nature 370: 180, 1994.
 17. Booher, R., and D. Beach. Interaction between cdc13+ and cdc2+ in the control of mitosis in fission yeast; dissociation of the G1 and G2 roles of the cdc2+ protein kinase. EMBO J. 6: 3441–3447, 1987.
 18. Booher, R., and D. Beach. Involvement of cdc13+ in mitotic control in Schizosaccharomyces pombe: possible interaction of the gene product with microtubules. EMBO J. 7: 2321–2327, 1988.
 19. Booher, R., and D. Beach. Involvement of a type 1 protein phosphatase encoded by bws1+ in fission yeast mitotic control. Cell 57: 1009–1016, 1989.
 20. Booher, R. N., C. E. Alfa, J. S. Hyams, and D. H. Beach. The fission yeast cdc2/cdc13/suc1 protein kinase: regulation of catalytic activity and nuclear localization. Cell 58: 485–97, 1989.
 21. Bradbury, E. M., R. J. Inglis, and H. R. Matthews. Control of cell division by very lysine rich histone (f1) phosphorylation. Nature 247: 257–261, 1974.
 22. Broek, D., R. Bartlett, K. Crawford, and P. Nurse. Involvement of p34cdc2 in establishing the dependency of S phase on mitosis. Nature 349: 388–394, 1991.
 23. Brooks, R. F. Regulation of the fibroblast cell cycle by serum. Nature 260: 248–250, 1976.
 24. Bueno, A., and P. Russell. Dual functions of Cdc6—a yeast protein required for DNA‐replication also inhibits nuclear division. EMBO J. 11: 2167–2176, 1992.
 25. Chang, F., and I. Herskowitz. Phosphorylation of far1 in response to alpha‐factor—a possible requirement for cell‐cycle arrest. Mol. Biol. Cell 3: 445–450, 1992.
 26. Chong, J. P., H. M. Mahbubani, C. Y. Khoo, and J. J. Blow. Purification of an MCM‐containing complex as a component of the DNA replication licensing system. Nature 375: 418–421, 1995.
 27. Chou, Y.‐H., J. R. Bischoff, D. Beach, and R. D. Goldman. Intermediate filament reorganization during mitosis is mediated by p34cdc2 phosphorylation of vimentin. Cell 62: 1063–1071, 1990.
 28. Cobrinik, D., S. F. Dowdy, P. W. Hinds, S. Mittnacht, and R. A. Weinberg. The retinoblastoma protein and the regulation of cell cycling. Trends Biochem. Sci. 17: 312–315, 1992.
 29. Coleman, T. R., Z. H. Tang, and W. G. Dunphy. Negative regulation of the wee1 protein‐kinase by direct action of the nim1/cdr1 mitotic inducer. Cell 72: 919–929, 1993.
 30. Costello, G., L. Rogers, and D. Beach. Fission yeast enters the stationary phase G0 state from either mitotic G1 or G2. Curr. Genet. 11: 119–125, 1986.
 31. Coue, M., S. E. Kearsey, and M. Mechali. Chromatin binding, nuclear localization and phosphorylation of Xenopus cdc21 are cell‐cycle dependent and associated with the control of initiation of DNA replication. EMBO J. 15: 1085–1097, 1996.
 32. Coutavas, E., M. D. Ren, J. D. Oppenheim, P. Deustachio, and M. G. Rush. Characterization of proteins that interact with the cell‐cycle regulatory protein Ran/TC4. Nature 366: 585–587, 1993.
 33. Coverley, D., and R. A. Laskey. Regulation of eukaryotic DNA replication. Annu. Rev. Biochem. 63: 745–776, 1994.
 34. Cross, F. DAF1, a mutant gene affecting size control, pheromone arrest and cell cycle kinetics of S. cerevisiae. Mol. Cell. Biol. 8: 4675–4684, 1988.
 35. Cross, F. R., M. Hoek, J. D. McKinney, and A. H. Tinkelenberg. Role of Swi4 in cell cycle regulation of Cln2 expression. Mol. Cell. Biol. 14: 4779–4787, 1994.
 36. Cross, S. M., C. A. Sanchez, C. A. Morgan, M. K. Schimke, S. Ramel, R. L. Idzerda, W. H. Raskind, and B. J. Reid. A p53‐dependent mouse spindle checkpoint. Science 267: 1353–1356, 1995.
 37. Cyert, M., and M. Kirschner. Regulation of MPF activity in vitro. Cell 53: 185–195, 1988.
 38. Dasso, M., and J. Newport. Completion of DNA replication is monitored by a feedback system that controls the initiation of mitosis in vitro: studies in Xenopus. Cell 61: 811–823, 1990.
 39. Diller, L., J. Kassel, C. E. Nelson, M. A. Gryka, G. Litwak, M. Gebhardt, B. Bressac, M. Ozturk, S. J. Baker, B. Vogelstein, and S. H. Friend. p53 functions as a cell cycle control protein in osteosarcomas. Mol. Cell. Biol. 10: 5772–5781, 1990.
 40. Dirick, L., T. Moll, H. Auer, and K. Nasmyth. A central role for Swi6 in modulating cell cycle start‐specific transcription in yeast. Nature 357: 508–513, 1992.
 41. Dirick, L., and K. Nasmyth. Positive feedback in the activation of G1 cyclins in yeast. Nature 351: 754–757, 1991.
 42. Donovan, J. D., J. H. Toyn, A. L. Johnson, and L. H. Johnston. P40 (sdb25), a putative cdk inhibitor, has a role in the m/G1 transition in Saccharomyces cerevisiae. Genes Dev. 8: 1640–1653, 1994.
 43. Doonan, J. H., and N. R. Morris. The bimG gene of Aspergillus nidulans, required for completion of anaphase, encodes a homolog of mammalian phosphoprotein phosphatase 1. Cell 57: 987–996, 1989.
 44. Dowdy, S. F., P. W. Hinds, K. Louie, S. I. Reed, A. Arnold, and R. A. Weinberg. Physical interaction of the retinoblastoma protein with human D cyclins. Cell 73: 499–511, 1993.
 45. Downes, C. S., A. M. Mullinger, and R. T. Johnson. Inhibitors of DNA topoisomerase II prevent chromatid separation in mammalian cells but do not prevent exit from mitosis. Proc. Natl. Acad. Sci. U.S.A. 88: 8895–8899, 1991.
 46. Downes, C. S., D. J. Clarke, A. M. Mullinger, J. F. Gimenez‐Abian, A. M. Creighton, and R. T. Johnson. A topoisomerase II‐dependent G2 cycle checkpoint in mammalian cells. Nature 372: 467–470, 1994.
 47. Downward, J. Regulatory mechanisms for ras proteins. Bioessays 14: 177–184, 1992.
 48. Draetta, G., and D. Beach. Activation of cdc2 protein kinase during mitosis in human cells: cell cycle‐dependent phosphorylation and subunit rearrangement. Cell 54: 17–26, 1988.
 49. Draetta, G., D. Beach, and E. Moran. Synthesis of p34, the mammalian homolog of the yeast cdc2+/CDC28 protein kinase, is stimulated during adenovirus‐induced proliferation of primary baby rat kidney cells. Oncogene 2: 553–557, 1988.
 50. Draetta, G., F. Luca, J. Westendorf, L. Brizuela, J. Ruderman, and D. Beach. cdc2 protein kinase is complexed with both cyclin A and B: evidence for proteolytic inactivation of MPF. Cell 56: 829–838, 1989.
 51. Dulic, V., L. F. Drullinger, E. Lees, S. I. Reed, and G. H. Stein. Altered regulation of G1 cyclins in senescent human‐diploid fibroblasts—accumulation of inactive cyclin E‐cdk2 and cyclin D1‐cdk2 complexes. Proc. Natl Acad. Sci. U.S.A. 90: 11034–11038, 1993.
 52. Dulic, V., W. K. Kaufmann, S. J. Wilson, T. D. Tlsty, E. Lees, J. W. Harper, S. J. Elledge, and S. I. Reed. P53‐dependent inhibition of cyclin‐dependent kinase‐activities in human fibroblasts during radiation‐induced G1 arrest. Cell 76: 1013–1023, 1994.
 53. Dulic, V., E. Lees, and S. I. Reed. Association of human cyclin E with a periodic G1‐S phase protein‐kinase. Science 257: 1958–1961, 1992.
 54. Dynlacht, B. D., O. Flores, J. A. Lees, and E. Harlow. Differential regulation of e2f transactivation by cyclin cdk2 complexes. Genes Dev. 8: 1772–1786, 1994.
 55. Earnshaw, W. C. Mitotic chromosome structure. Bioessays 9: 147–150, 1988.
 56. Edgar, B., and P. O'Farrell. Genetic control of cell division patterns in the Drosophilla embryo. Cell 57: 177–187, 1989.
 57. Eldeiry, W. S., T. Tokino, V. E. Velculescu, D. B. Levy, R. Parsons, J. M. Trent, D. Lin, W. E. Mercer, K. W. Kinzler, and B. Vogelstein. Waf1, a potential mediator of p53 tumor suppression. Cell 75: 817–825, 1993.
 58. Elledge, S. J., R. Richman, F. L. Hall, R. T. Williams, N. Lodgson, and J. W. Harper. Cdk2 encodes a 33‐kda cyclin‐a‐associated protein‐kinase and is expressed before cdc2 in the cell‐cycle. Proc. Natl. Acad. Sci. U.S.A. 89: 2907–2911, 1992.
 59. Elledge, S. J., and M. R. Spottswood. A new human p34 protein kinase, CDK2, identified by complementation of a cdc28 mutation in Saccharomyces cerevisiae, is a homolog of Xenopus Eg1. EMBO J. 10: 2653–2659, 1991.
 60. Enoch, T., A. M. Carr, and P. Nurse. Fission yeast genes involved in coupling mitosis to completion of DNA‐replication. Genes Dev. 6: 2035–2046, 1992.
 61. Enoch, T., and C. Norbury. Cellular responses to DNA damage: cell‐cycle checkpoints, apoptosis and the roles of p53 and ATM. Trends Biochem. Sci. 20: 426–430, 1995.
 62. Evans, G. A., and W. L. Farrar. Retinoblastoma protein‐phosphorylation does not require activation of p34cdc2 protein‐kinase. Biochem. J. 287: 965–969, 1992.
 63. Evans, R. M., and L. M. Fink. An alteration in the phosphorylation of vimentin‐type intermediate filaments is associated with mitosis in cultured mammalian cells. Cell 29: 43–52, 1982.
 64. Evans, T., E. Rosenthal, J. Youngbloom, D. Distel, and T. Hunt. Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell 33: 389–396, 1983.
 65. Ewen, M. E., H. K. Sluss, C. J. Sherr, H. Matsushime, J. Y. Kato, and D. M. Livingston. Functional interactions of the retinoblastoma protein with mammalian D‐type cyclins. Cell 73: 487–497, 1993.
 66. Fang, F., and J. W. Newport. Evidence that the G1‐S and G2‐M transitions are controlled by different cdc2 proteins in higher eukaryotes. Cell 66: 731–742, 1991.
 67. Fantes, P., and P. Nurse. Control of the timing of the cell division in fission yeast. Cell size mutants reveal a second control pathway. Exp. Cell. Res. 115: 317–329, 1978.
 68. Feilotter, H., P. Nurse, and P. G. Young. Genetic and molecular analysis of cdr1/nim1 in Schizosaccharomyces pombe. Genetics 127: 309–318, 1991.
 69. Ferrell, J. J., M. Wu, J. C. Gerhart, and G. S. Martin. Cell cycle tyrosine phosphorylation of p34cdc2 and a microtubule‐associated protein kinase homolog in Xenopus oocytes and eggs. Mol. Cell. Biol. 11: 1965–1971, 1991.
 70. Fesquet, D., J. C. Labbe, J. Derancourt, J. P. Capony, S. Galas, F. Girard, T. Lorca, J. Shuttleworth, M. Doree, and J. C. Cavadore. The MO15 gene encodes the catalytic subunit of a protein‐kinase that activates cdc2 and other cyclin‐dependent kinases (cdks) through phosphorylation of Thr161 and its homologs. EMBO J. 12: 3111–3121, 1993.
 71. Fisher, R. P., and D. O. Morgan. A novel cyclin associates with mo15/cdk7 to form the cdk‐activating kinase. Cell 78: 713–724, 1994.
 72. Fleig, U. N., K. L. Gould, and P. Nurse. A dominant negative allele of p34cdc2 shows altered phosphoamino acid content and sequesters p56cdc13 cyclin. Mol. Cell. Biol. 12: 2295–2301, 1992.
 73. Forsburg, S. L., and P. Nurse. Identification of a G1‐type cyclin puc1+ in the fission yeast Schizosaccharomyces pombe. Nature 351: 245–248, 1991.
 74. Forsburg, S. L., and P. Nurse. Analysis of the Schizosaccharomyces pombe cyclin puc1: evidence for a role in cell cycle exit. J. Cell Sci. 107: 601–613, 1994.
 75. Freeman, M., C. Nusslein‐Volhard and D. M. Glover. The dissociation of nuclear and centrosomal division in gnu, a mutation causing giant nuclei in Drosophila. Cell 46: 457–468, 1986.
 76. Furukawa, Y., H. Piwnica‐Worms, T. J. Ernst, Y. Kanakura, and J. D. Griffin. cdc2 gene expression at the G1 to S transition in human T lymphocytes. Science 250: 805–808, 1990.
 77. Galaktionov, K., and D. Beach. Specific activation of cdc25 tyrosine phosphatases by b‐type cyclins—evidence for multiple roles of mitotic cyclins. Cell 67: 1181–1194, 1991.
 78. Gautier, J., J. Minshull, M. Lohka, M. Glotzer, T. Hunt, and J. L. Maller. Cyclin is a component of MPF from Xenopus. Cell 60: 487–494, 1990.
 79. Gautier, J., C. Norbury, M. Lohka, P. Nurse, and J. Maller. Purified maturation‐promoting factor contains the product of a Xenopus homolog of the fission yeast cell cycle control gene cdc2+. Cell 54: 433–439, 1988.
 80. Gelfant, S. Initiation of mitosis in relation to the cell division cycle. Exp. Cell Res. 26: 395–403, 1962.
 81. Gerace, L., and G. Blobel. The nuclear lamina is reversibly depolymerised during mitosis. Cell 19: 277–287, 1980.
 82. Ghiara, J. B., H. E. Richardson, K. Sugimoto, M. Henze, D. J. Lew, C. Wittenberg, and S. I. Reed. A cyclin B homolog in S. cerevisiae: chronic activation of the Cdc28 protein kinase by cyclin prevents exit from mitosis. Cell 65: 163–174, 1991.
 83. Girard, F., U. Strausfeld, A. Fernandez, and N.J.C. Lamb. Cyclin A is required for the onset of DNA replication in mammalian fibroblasts. Cell 67: 1169–1179, 1991.
 84. Glotzer, M., A. W. Murray, and M. W. Kirschner. Cyclin is degraded by the ubiquitin pathway. Nature 349: 132–138, 1991.
 85. Goebl, M., and B. Byers. Cyclin in fission yeast. Cell 54: 739–740, 1988.
 86. Gorbsky, G. J. Cell‐cycle progression and chromosome segregation in mammalian‐cells cultured in the presence of the topoisomerase‐II inhibitors icrf‐187 [(+)‐1,2‐bis (3,5‐dioxopiperazinyl‐1‐yl)propane; adr‐529] and icrf‐159 (razoxane). Cancer Res. 54: 1042–1048, 1994.
 87. Gould, K. L., S. Moreno, D. J. Owen, S. Sazer, and P. Nurse. Phosphorylation at Thr 167 is required for Schizosaccharomyces pombe p34cdc2 function. EMBO J. 10: 3297–3309, 1991.
 88. Gould, K. L., and P. Nurse. Tyrosine phosphorylation of the fission yeast cdc2+ protein kinase regulates entry into mitosis. Nature 342: 39–45, 1989.
 89. Grandin, N., and M. Charbonneau. Intracellular free calcium oscillates during cell division of Xenopus embryos. J. Cell Biol. 112: 711–718, 1991.
 90. Greenwell, P. W., S. L. Kronmal, S. E. Porter, J. Gassenhuber, B. Obermaier, and T. D. Petes. TEL1, a gene involved in controlling telomere length in S. cerevisiae is homologous to the human ataxia telangiectasia gene. Cell 82: 823–829, 1995.
 91. Guadagno, T. M., M. Ohtsubo, J. M. Roberts, and R. K. Assoian. A link between cyclin‐a expression and adhesion‐dependent cell‐cycle progression. Science 262: 1572–1575, 1993.
 92. Hadwiger, J. A., C. Wittenberg, H. E. Richardson, M. De Barros Lopes, and S. I. Reed. A family of cyclin homologs that control the G1 phase in yeast. Proc. Natl. Acad. Sci. U.S.A. 86: 6255–6259, 1989.
 93. Hagan, I., J. Hayles, and P. Nurse. Cloning and sequencing of the cyclin‐related cdc13+ gene and a cytological study of its role in fission yeast mitosis. J. Cell Sci. 91: 587–595, 1988.
 94. Hanks, S. K., A. M. Quinn, and T. Hunter. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241: 42–52, 1988.
 95. Hannon, G. J., and D. Beach. p15INK4B is a potential effector of TGFβ‐induced cell cycle arrest. Nature 371: 257–261, 1994.
 96. Harper, J. W., G. R. Adami, N. Wei, K. Keyomarsi, and S. J. Elledge. The p21 cdk‐interacting protein cip1 is a potent inhibitor of g1 cyclin‐dependent kinases. Cell 75: 805–816, 1993.
 97. Hartwell, L., J. Culotti, and J. Pringle. Genetic control of the cell division cycle in yeast. Science 183: 46, 1974.
 98. Hartwell, L., and T. Weinert. Checkpoints: controls that ensure the order of cell cycle events. Science 246: 629–634, 1989.
 99. Heald, R., and F. McKeon. Mutations of phosphorylation sites in lamin A that prevent nuclear lamina disassembly in mitosis. Cell 61: 579–589, 1990.
 100. Heald, R., M. McLoughlin, and F. McKeon. Human wee1 maintains mitotic timing by protecting the nucleus from cytoplasmically activated cdc2 kinase. Cell 74: 463–474, 1993.
 101. Helin, K., and E. Harlow. The retinoblastoma protein as a transcriptional repressor. Trends Cell Biol. 3: 43–45, 1993.
 102. Hellmich, M. R., H. C. Pant, E. Wada, and J. F. Battey. Neuronal cdc2‐like kinase—a cdc2‐related protein‐kinase with predominantly neuronal expression. Proc. Natl Acad. Sci. U.S.A. 89: 10867–10871, 1992.
 103. Hengst, L., V. Dulic, J. M. Slingerland, E. Lees, and S. I. Reed. A cell‐cycle‐regulated inhibitor of cyclin‐dependent kinases. Proc. Natl Acad. Sci. U.S.A. 91: 5291–5295, 1994.
 104. Hindley, J., and G. A. Phear. Sequence of the cell division gene CDC2 from Schizosaccharomyces pombe; patterns of splicing and homology to protein kinases. Gene 31: 129–134, 1984.
 105. Hinds, P. W., S. Mittnacht, V. Dulic, A. Arnold, S. I. Reed, and R. A. Weinberg. Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell 70: 993–1006, 1992.
 106. Hisatake, K., S. Hasegawa, R. Takada, Y. Nakatani, M. Horikoshi, and R. G. Roeder. The p250 subunit of native tata box‐binding factor‐TFIId is the cell‐cycle regulatory protein CCG1. Nature 362: 179–181, 1993.
 107. Hoffmann, I., P. R. Clarke, M. J. Marcote, E. Karsenti, and G. Draetta. Phosphorylation and activation of human cdc25‐C by cdc2‐cyclin B and its involvement in the self‐amplification of mpf at mitosis. EMBO J. 12: 53–63, 1993.
 108. Holloway, S. L., M. Glotzer, R. W. King, and A. W. Murray. Anaphase is initiated by proteolysis rather than by the inactivation of maturation‐promoting factor. Cell 73: 1393–1402, 1993.
 109. Holm, C., T. Goto, J. Wang, and D. Bostein. DNA topoisomerase II is required at the time of mitosis in yeast. Cell 41: 553–563, 1985.
 110. Hoyt, M. A., L. Trotis, and B. T. Roberts. S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell 66: 507–517, 1991.
 111. Hunter, T., and J. Pines. Cyclins and cancer. Cell 66: 1071–1074, 1991.
 112. Igarashi, M., A. Nagata, S. Jinno, K. Suto, and H. Okayama. Wee1 + ‐like gene in human cells. Nature 353: 80–83, 1991.
 113. Izumi, T., D. H. Walker, and J. L. Maller. Periodic changes in phosphorylation of the Xenopus Cdc25 phosphatase regulates its activity. Mol. Biol. Cell 3: 927–939, 1992.
 114. Jimenez, G., J. Yucel, R. Rowley, and S. Subramani. The rad3+ gene of Schizosaccharomyces pombe is involved in multiple checkpoint functions and in DNA repair. Proc. Natl. Acad. Sci. U.S.A. 89: 4952–4956, 1992.
 115. Johnston, L. H. Cell cycle control of gene expression in yeast. Trends Cell Biol. 2: 353–357, 1992.
 116. Kamb, A., N. A. Gruis, J. Weaverfeldhaus, Q. Y. Liu, K. Harshman, S. V. Tavtigian, E. Stockert, R. S. Day, B. E. Johnson, and M. H. Skolnick. A cell‐cycle regulator potentially involved in genesis of many tumor types. Science 264: 436–440, 1994.
 117. Kapeller, R., and L. C. Cantley. Phosphatidylinositol 3‐kinase. Bioessays 16: 565–576, 1994.
 118. Kastan, M. B., Q. M. Zhan, W. S. Eldeiry, F. Carrier, T. Jacks, W. V. Walsh, B. S. Plunkett, B. Vogelstein, and A. J. Fornace. A mammalian‐cell cycle checkpoint pathway utilizing p53 and gadd45 is defective in ataxia‐telangiectasia. Cell 71: 587–597, 1992.
 119. Kato, J., H. Matsushime, S. W. Hiebert, M. E. Ewen, and C. J. Sherr. Direct binding of cyclin‐d to the retinoblastoma gene‐product (prb) and prb phosphorylation by the cyclin d‐dependent kinase cdk4. Genes Dev. 7: 331–342, 1993.
 120. Kelly, T. J. DNA‐replication in mammalian‐cells—insights from the SV40 model system. Harvey Lect. 85: 1991.
 121. Kelly, T. J., G. S. Martin, S. L. Forsburg, R. J. Stephen, A. Russo, and P. Nurse. The fission yeast cdc18 + gene‐product couples s‐phase to start and mitosis. Cell 74: 371–382, 1993.
 122. Kharbanda, S., A. Saleem, R. Datta, Z. M. Yuan, R. Weichselbaum, and D. Kufe. Ionizing‐radiation induces rapid tyrosine phosphorylation of p34cdc2. Cancer Res. 54: 1412–1414, 1994.
 123. Killander, D., and A. Zetterberg. A quantitative cytochemical investigation of the relationship between cell mass and initiation of DNA synthesis in mouse fibroblasts. Exp. Cell Res. 40: 12–20, 1965.
 124. Kinoshita, N., H. Ohkura, and M. Yanagida. Distinct, essential roles of type 1 and 2A protein phosphatases in the control of the fission yeast cell division cycle. Cell 63: 405–415, 1990.
 125. Kipreos, E. T., and J. Y. J. Wang. Differential phosphorylation of c‐Abl in cell cycle determined by cdc2 kinase and phosphatase activity. Science 248: 217–220, 1990.
 126. Kirschner, M., J. Newport, and J. Gerhart. The timing of early developmental events in Xenopus. Trends Genet. 1: 41–47, 1985.
 127. Kishimoto, T., R. Kuriyama, H. Kondo, and H. Hanatani. Generality of the action of various maturation‐promoting factors. Exp. Cell Res. 137: 121–126, 1982.
 128. Kobayashi, H., E. Stewart, R. Poon, J. P. Adamczewski, J. Gannon, and T. Hunt. Identification of the domains in cyclin‐a required for binding to, and activation of, p34cdc2 and p32cdk2 protein‐kinase subunits. Mol. Biol. Cell 3: 1279–1294, 1992.
 129. Koff, A., F. Cross, A. Fisher, J. Schumacher, K. Le Guellec, M. Philippe, and J. M. Roberts. Human cyclin E, a new cyclin that interacts with two members of the CDC2 gene family. Cell 66: 1217–1228, 1991.
 130. Koff, A., A. Giordano, D. Desai, K. Yamashita, J. W. Harper, S. Elledge, T. Nishimoto, D. O. Morgan, B. R. Franza, and J. M. Roberts. Formation and activation of a cyclin E‐Cdk2 complex during the G1 phase of the human cell‐cycle. Science 257: 1689–1694, 1992.
 131. Kornbluth, S., B. Sebastian, T. Hunter, and J. Newport. Membrane localization of the kinase which phosphorylates p34cdc2 on threonine 14. Mol. Biol. Cell 5: 273–282, 1994.
 132. Krek, W., M. E. Ewen, S. Shirodkar, Z. Arany, W. G. Kaelin, and D. M. Livingston. Negative regulation of the growth‐promoting transcription factor e2f‐1 by a stably bound cyclin a‐dependent protein‐kinase. Cell 78: 161–172, 1994.
 133. Krek, W., and E. A. Nigg. 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, 1991.
 134. Kuerbitz, S. J., B. S. Plunkett, W. V. Walsh, and M. B. Kastan. Wild‐type p53 is a cell‐cycle checkpoint determinant following irradiation. Proc. Natl. Acad. Sci. U.S.A. 89: 7491–7495, 1992.
 135. Kumagai, A., and W. G. Dunphy. The cdc25 protein controls tyrosine dephosphorylation of the cdc2 protein in a cell‐free system. Cell 64: 903–914, 1991.
 136. Kumagai, A. D., W. G. Dunphy. Regulation of the Cdc25 protein during the cell cycle in Xenopus extracts. Cell 70: 139–151, 1992.
 137. Labbe, J. C., J. P. Capony, D. Caput, J. C. Cavadore, M. K. Derancourt, J. M. Lelias, A. Picard, and M. Dorée. MPF from starfish oocytes at first meiotic metaphase is a heterodimer containing one molecule of cdc2 and one molecule of cyclin B. EMBO J. 8: 3053–3058, 1989.
 138. Labbe, J. C., A. Picard, E. Karsenti, and M. Doree. An M‐phase‐specific protein kinase of Xenopus oocytes: partial purification and possible mechanism of its periodic activation. Dev. Biol. 127: 157–169, 1988.
 139. Lane, H. A., A. Fernandez, N. J. C. Lamb, and G. Thomas. P70S6K function is essential for G1 progression. Nature 363: 170–172, 1993.
 140. Langan, T. A., J. Gautier, M. Lohka, R. Hollingsworth, S. Moreno, P. Nurse, J. Maller, and R. A. Sclafani. Mammalian growth‐associated H1 histone kinase: a homolog of cdc2 +/CDC28 protein kinases controlling mitotic entry in yeast and frog cells. Mol. Cell Biol. 9: 3860–3868, 1989.
 141. Lee, M. G., C. J. Norbury, N. K. Spurr, and P. Nurse. Regulated expression and phosphorylation of a possible mammalian cell‐cycle control protein. Nature 333: 676–679, 1988.
 142. Lee, M. G., and P. Nurse. Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2. Nature 327: 31–35, 1987.
 143. Lee, T. H., M. J. Solomon, M. C. Mumby, and M. W. Kirschner. 1NH, a negative regulator of MPF, is a form of protein phosphatase 2A. Cell 64: 415–423, 1991.
 144. Lees, E., B. Faha, V. Dulic, S. I. Reed, and E. Harlow. Cyclin E‐cdk2 and cyclin A‐cdk2 kinases associate with p107 and E2F in a temporally distinct manner. Genes Dev. 6: 1874–1885, 1992.
 145. Lew, J., R. J. Winkfein, H. K. Paudel, and J. H. Wang. Brain proline‐directed protein‐kinase is a neurofilament kinase which displays high sequence homology to p34cdc2. J. Biol. Chem. 267: 25922–25926, 1992.
 146. Li, R., and A. W. Murray. Feedback control of mitosis in budding yeast. Cell 66: 519–531, 1991.
 147. Li, Y., C. W. Jenkins, M. A. Nichols, and Y. Xiong. Cell‐cycle expression and p53 regulation of the cyclin‐dependent kinase inhibitor p21. Oncogene 9: 2261–2268, 1994.
 148. Lin, B.T.Y., S. Gruenwald, A. Morla, W.‐H. Lee, and J.Y.J. Wang. Retinoblastoma cancer suppressor gene product is a substrate of the cell cycle regulator cdc2. EMBO J. 10: 857–864, 1991.
 149. Litchfield, D. W., B. Luscher, F. J. Lozeman, R. N. Eisenman, and E. G. Krebs. Phosphorylation of casein kinase‐II by p34cdc2 in vitro and at mitosis. J. Biol. Chem. 267: 13943–13951, 1992.
 150. Lock, R. B. Inhibition of p34cdc2 kinase activation, p34cdc2 tyrosine dephosphorylation, and mitotic progression in Chinese hamster ovary cells exposed to etoposide. Cancer Res. 52: 1817–1822, 1992.
 151. Lohka, M., and J. Maller. Induction of nuclear membrane breakdown, chromosome condensation and spindle formation in cell free extracts. J. Cell Biol. 101: 518–523, 1985.
 152. Lohka, M. J., M. K. Hayes, and J. L. Maller. Purification of maturation‐promoting factor, an intracellular regulator of early mitotic events. Proc. Natl. Acad. Sci. U.S.A. 85: 3009–3013, 1988.
 153. Lorca, T., F. H. Cruzalegui, D. Fesquet, J. C. Cavadore, J. Mery, A. Means, and M. Doree. Calmodulin‐dependent protein kinase‐II mediates inactivation of MPF and CSF upon fertilization of Xenopus eggs. Nature 366: 270–273, 1993.
 154. Lorincz, A., and S. Reed. Primary structure homology between the product of the yeast cell division control gene CDC28 and vertebrate oncogenes. Nature 307: 183–185, 1984.
 155. Lowndes, N. F., A. L. Johnson, L. Breeden, and L. H. Johnston. Swi6 protein is required for transcription of the periodically expressed DNA‐synthesis genes in budding yeast. Nature 357: 505–508, 1992.
 156. Lowndes, N. F., A. L. Johnson, and L. H. Johnston. Coordination of expression of DNA synthesis genes in budding yeast by a cell‐cycle regulated trans factor. Nature 350: 247–250, 1991.
 157. Lowndes, N. F., C. J. McInerny, A. L. Johnson, P. A. Fantes, and L. H. Johnston. Control of DNA‐synthesis genes in fission yeast by the cell‐cycle gene cdc10+. Nature 355: 449–453, 1992.
 158. Lu, K. P., S. A. Osmani, and A. R. Means. Properties and regulation of the cell cycle‐specific NIMA protein kinase of Aspergillus nidulans. J. Biol. Chem. 268: 8769–8776, 1993.
 159. Lundgren, K., N. Walworth, R. Booher, M. Dembski, M. Kirschner, and D. Beach. mik1 and wee1 cooperate in the inhibitory tyrosine phosphorylation of cdc2. Cell 64: 1111–1122, 1991.
 160. Luscher, B., L. Brizuela, D. Beach, and R. N. Eisenman. A role for p34cdc2 kinase and phosphatases in the regulation of phosphorylation and disassembly of lamin B2 during the cell cycle. EMBO J. 10: 865–875, 1991.
 161. Makela, T. P., J. P. Tassan, E. A. Nigg, S. Frutiger, G. J. Hughes, and R. A. Weinberg. A cyclin associated with the cdk‐activating kinase MO15. Nature 371: 254–257, 1994.
 162. Maller, J. L., and D. S. Smith. Two‐dimensional polyacrylamide gel analysis of changes in protein phosphorylation during maturation of Xenopus oocytes. Dev. Biol. 109: 150–156, 1985.
 163. Marsden, M., and U. K. Laemmli. Metaphase chromosome structure: evidence for a radial loop model. Cell 17: 849–858, 1979.
 164. Massague, J. The transforming growth‐factor‐beta family. Annu. Rev. Cell Biol. 6: 597–641, 1990.
 165. Masui, Y., and C. Markert. Cytoplasmic control of nuclear behaviour during meiotic maturation of frog oocytes. J. Exp. Zool. 177: 129–146, 1971.
 166. Matsuoka, Y., K. Nishizawa, T. Yano, M. Shibata, S. Ando, T. Takahashi, and M. Inagaki. 2 different protein‐kinases act on a different time schedule as glial filament kinases during mitosis. EMBO J. 11: 2895–2902, 1992.
 167. Matsushime, H., M. F. Roussel, R. A. Ashmun, and C. J. Sherr. Colony‐stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell 65: 701–713, 1991.
 168. McGowan, C. H., and P. Russell. Human wee1 kinase inhibits cell‐division by phosphorylating p34cdc2 exclusively on tyr15. EMBO J. 12: 75–85, 1993.
 169. McKinney, J. D., F. Chang, N. Heintz, and F. R. Cross. Negative regulation of far1 at the start of the yeast‐cell cycle. Genes Dev. 7: 833–843, 1993.
 170. Meijer, L., A. Ostvold, S. I. Walaas, T. Lund, and S. G. Laland. High‐mobility‐group proteins P1, I and Y as substrates of the M‐phase‐specific p34cdc2/cyclincdc13 kinase. Eur. J. Biochem. 196: 557–567, 1991.
 171. Melchior, F., B. Paschal, J. Evans, and L. Gerace. Inhibition of nuclear‐protein import by nonhydrolyzable analogs of GTP and identification of the small GTPase ran/tc4 as an essential transport factor. J. Cell Biol. 123: 1649–1659, 1993.
 172. Meyerson, M., G. H. Enders, C. L. Wu, L. K. Su, C. Gorka, C. Nelson, E. Harlow, and L. H. Tsai. A family of human cdc2‐related protein‐kinases. EMBO J. 11: 2909–2917, 1992.
 173. Minella, O., P. Cormier, J. Morales, R. Poulhe, R. Belle, and O. Mulnerlorillon. Cdc2 kinase sets a memory phosphorylation signal on elongation‐factor EF‐1δ during meiotic cell‐division, which perdures in early development. Cell. Mol. Biol. 40: 521–525, 1994.
 174. Minshull, J., J. J. Blow, and T. Hunt. Translation of cyclin mRNA is necessary for extracts of activated Xenopus eggs to enter mitosis. Cell 56: 947–956, 1989.
 175. Minshull, J., R. Golsteyn, C. S. Hill, and T. Hunt. The A‐ and B‐type cyclin associated cdc2 kinases in Xenopus turn on and off at different times in the cell cycle. EMBO J. 9: 2865–2875, 1990.
 176. Minshull, J., J. Pines, R. Golsteyn, N. Standart, S. Mackie, A. Colman, J. Blow, J. V. Ruderman, M. Wu, and T. Hunt. The role of cyclin synthesis, modification and destruction in the control of cell division. J. Cell Sci. Suppl. 12: 77–97, 1989.
 177. Mittnacht, S., J. A. Lees, D. Desai, E. Harlow, D. O. Morgan, and R. A. Weinberg. Distinct subpopulations of the retinoblastoma protein show a distinct pattern of phosphorylation. EMBO J. 13: 118–127, 1994.
 178. Moll, T., G. Tebb, U. Surana, H. Robitsch, and K. Nasmyth. The role of phosphorylation and the Cdc28 protein kinase in cell cycle‐regulated nuclear import of the S. cerevisiae transcription factor Swi5. Cell 66: 743–758, 1991.
 179. Moreno, S., J. Hayles, and P. Nurse. Regulation of p34cdc2 protein kinase during mitosis. Cell 58: 361–372, 1989.
 180. Moreno, S., and P. Nurse. Substrates for p34cdc2: in vivo veritas? Cell 61: 549–551, 1990.
 181. Moreno, S., and P. Nurse. Regulation of progression through the G1 phase of the cell‐cycle by the rum1 + gene. Nature 367: 236–242, 1994.
 182. Morgan, D. O., J. M. Kaplan, J. M. Bishop, and H. E. Varmus. Mitosis‐specific phosphorylation of p60C‐STC by p34cdc2‐associated protein kinase. Cell 57: 775–786, 1989.
 183. Morrow, D. M., D. A. Tagle, Y. Shiloh, F. S. Collins, and P. Hieter. TEL1, an S. cerevisiae homolog of the human gene mutated in ataxia telangiectasia, is functionally related to the yeast checkpoint gene MEC1. Cell 82: 831–840, 1995.
 184. Motokura, T., T. Bloom, H. G. Kim, H. Juppner, J. V. Ruderman, H. M. Kronenberg, and A. Arnold. A novel cyclin encoded by a bcl1‐linked candidate oncogene. Nature 350: 512–515, 1991.
 185. Mulner‐Lorillon, O., P. Cormier, J. C. Labbe, M. Doree, R. Poulhe, H. Osborne, and R. Belle. M‐phase‐specific cdc2 protein kinase phosphorylates the beta subunit of casein kinase II and increases casein kinase II activity. Eur. J. Biochem. 193: 529–534, 1990.
 186. Murray, A. W. Turning on mitosis. Curr. Biol. 3: 291–293, 1993.
 187. Murray, A. W., and M. W. Kirschner. Cyclin synthesis drives the early embryonic cell cycle. Nature 339: 275–280, 1989.
 188. Murray, A. W., M. J. Solomon, and M. W. Kirschner. The role of cyclin synthesis and degradation in the control of maturation promoting factor activity. Nature 339: 280–286, 1989.
 189. Nash, R., G. Tokiwa, S. Anand, K. Erickson, and A. B. Futcher. The WH11 + gene of Saccharomyces cerevisiae tethers cell division to cell size and is a cyclin homolog. EMBO J. 7: 4335–4346, 1988.
 190. Nasmyth, K. Control of the yeast cell cycle by the Cdc28 protein kinase. Curr. Opin. Cell Biol. 5: 166–179, 1993.
 191. Nasmyth, K., and P. Nurse. Cell division cycle mutants altered in DNA replication and mitosis in the fission yeast Schizosaccharomyces pombe. Mol. Gen. Genet. 182: 119–124, 1981.
 192. Newport, J., and M. Kirschner. Regulation of the cell cycle during early Xenopus development. Cell 37: 731–742, 1984.
 193. Newport, J., and T. Spann. Dissassembly of the nucleus in mitotic extracts: membrane vesicularization lamin disassembly and chromosome condensation are independent process. Cell 48: 219–230, 1987.
 194. Ninomiya‐Tsuji, J., S. Nomoto, H. Yasuda, S. I. Reed, and K. Matsumoto. Cloning of a human cDNA encoding a CDC2‐related kinase by complementation of a budding yeast cdc28 mutation. Proc. Natl. Acad. Sci. U.S.A. 88: 9006–9010, 1991.
 195. Nishimoto, T., E. Eilen, and C. Basilico. Premature chromosome condensation in a ts DNA‐mutant of BHK cells. Cell 15: 475–483, 1978.
 196. Nishitani, H., M. Ohtsubo, K. Yamashita, H. Iida, J. Pines, H. Yasudo, Y. Shibata, T. Hunter, and T. Nishimoto. Loss of RCC1, a nuclear DNA‐binding protein, uncouples the completion of DNA replication from the activation of cdc2 protein kinase and mitosis. EMBO J. 10: 1555–1564, 1991.
 197. Nobori, T., K. Miura, D. J. Wu, A. Lois, K. Takabayashi, and D. A. Carson. Deletions of the cyclin‐dependent kinase‐4 inhibitor gene in multiple human cancers. Nature 368: 753–756, 1994.
 198. Norbury, C., J. Blow, and P. Nurse. Regulatory phosphorylation of the p34cdc2 protein kinase in vertebrates. EMBO J. 10: 3321–3329, 1991.
 199. Norbury, C. J., and P. Nurse. Animal cell cycles and their control. Annu. Rev. Biochem. 61: 441–470, 1992.
 200. Nuell, M. J., D. A. Stewart, L. Walker, V. Friedman, C. M. Wood, G. A. Owens, J. R. Smith, E. L. Schneider, R. Dell'Orco, C. K. Lumpkin, D. B. Danner, and J. K. McKlung. Prohibitin, an evolutionarily conserved intracellular protein that blocks DNA synthesis in normal fibroblasts and HeLa cells. Mol. Cell. Biol. 11: 1372–1381, 1991.
 201. Nurse, P. Genetic control of cell size at cell division in yeast. Nature 256: 547–551, 1975.
 202. Nurse, P., and Y. Bissett. Gene required in G1 for commitment to cell cycle and in G2 for control of mitosis in fission yeast. Nature 292: 558–560, 1981.
 203. Nurse, P., and P. Thuriaux. Regulatory genes controlling mitosis in the fission yeast Schizosaccharomyces pombe. Genetics 96: 627–637, 1980.
 204. Nurse, P., P. Thuriaux, and K. Nasmyth. Genetic control of the cell division cycle in the fission yeast Schizosaccharomyces pombe. Mol. Gen. Genet. 146: 167–178, 1976.
 205. O'Connell, M., C. Norbury, and P. Nurse. Premature chromatin condensation upon accumulation of NimA. EMBO J. 13: 4926–4937, 1994.
 206. Ohkura, H., N. Kinoshita, S. Miyatani, T. Toda, and M. Yanagida. The fission yeast dis2+ gene required for chromosome disjoining encodes one of two putative type 1 protein phosphatases. Cell 57: 997–1007, 1989.
 207. Ohkura, H., and M. Yanagida. Spombe gene sds22+ essential for a midmitotic transition encodes a leucine‐rich repeat protein that positively modulates protein phosphatase‐1. Cell 64: 149–157, 1991.
 208. Ohtsubo, M., R. Kai, N. Furuno, T. Sekiguchi, M. Sekiguchi, M. Hayashida, K. Kuma, T. Miyata, S. Fuukushige, T. Murotsu, K. Matsubara, and T. Nishimoto. Isolation and characterisation of the active cDNA of the human cell cycle gene (RCC1) involved in the regulation of onset of chromosome condensation. Genes Dev. 1: 585–593, 1987.
 209. Ohtsubo, M., and J. M. Roberts. Cyclin‐dependent regulation of g in mammalian fibroblasts. Science 259: 1908–1912, 1993.
 210. Okuda, T., J. L. Cleveland, and J. R. Downing. Pctaire‐1 and pctaire‐3, two members of a novel cdc2/cdc28‐related protein‐kinase gene family. Oncogene 7: 2249–2258, 1992.
 211. Osmani, A. H., S. L. McGuire, K. L. Odonnell, R. T. Pu, and S. A. Osmani. Role of the cell‐cycle‐regulated NIMA protein‐kinase during G2 and mitosis—evidence for two pathways of mitotic regulation. Cold Spring Harb. Symp. Quant. Biol. 56: 549–555, 1991.
 212. Osmani, A. H., N. Vanpeij, M. Mischke, M. J. O'Connell, and S. A. Osmani. A single p34cdc2 protein kinase (encoded by nimxcdc2) is required at G1 and G2 in Aspergillus nidulans. J. Cell Sci. 107: 1519–1528, 1994.
 213. Osmani, S., R. Pu, and N. Morris. Mitotic induction and maintenance by over‐expression of a G2‐specific gene that encodes a potential protein kinase. Cell 53: 237–244, 1988.
 214. Pagano, M., R. Pepperkok, F. Verde, W. Ansorge, and G. Draetta. Cyclin A is required at two points in the human cell cycle. EMBO J. 11: 961–971, 1992.
 215. Pagano, M., A. M. Theodoras, S. W. Tam, and G. F. Draetta. Cyclin D1‐mediated inhibition of repair and replicative DNA synthesis in human fibroblasts. Genes Dev. 8: 1627–1639, 1994.
 216. Pardee, A. A restriction point for control of normal animal cell proliferation. Proc. Natl Acad. Sci. U.S.A. 71: 1286–1290, 1974.
 217. Pardee, A., R. Dubrow, J. Hamlin, and R. Kleitzien. Animal cell cycle. Annu. Rev. Biochem. 47: 715–178, 1978.
 218. Paris, J., R. Le Guellec, A. Couturier, K. Le Guellec, F. Omilli, J. Camonis, S. MacNeill, and M. Philippe. Cloning by differential screening of a Xenopus cDNA coding for a protein highly homologous to cdc2. Proc. Natl Acad. Sci. U.S.A. 88: 1039–1043, 1991.
 219. Parker, L., and H. Piwnica‐Worms. Inactivation of the p34cdc2‐cyclin B complex by the human WEE1 tyrosine kinase. Science 257: 1955–1957, 1992.
 220. Parker, L. L., S. A. Walter, P. G. Young, and H. Piwnicaworms. Phosphorylation and inactivation of the mitotic inhibitor wee1 by the nim1/cdr1 kinase. Nature 363: 736–738, 1993.
 221. Pazin, M. J., and L. T. Williams. Triggering signaling cascades by receptor tyrosine kinases. Trends Biochem. Sci. 17: 374–378, 1992.
 222. Pedersen, T., and S. Gelfant. G2‐population cells in mouse kidney and duodenum and their behaviour during the cell division cycle. Exp. Cell Res. 59: 32–36, 1970.
 223. Peter, M., A. Gartner, J. Horecka, G. Ammerer, and I. Herskowitz. Far1 links the signal‐transduction pathway to the cell‐cycle machinery in yeast. Cell 73: 747–760, 1993.
 224. Peter, M., and I. Herskowitz. Direct inhibition of the yeast cyclin‐dependent kinase cdc28‐cln by far1. Science 265: 1228–1231, 1994.
 225. Peter, M., J. Nakagawa, M. Dorée, J. C. Labbé, and E. A. Nigg. Identification of major nucleolar proteins as candidate mitotic substrates of cdc2 kinase. Cell 60: 791–801, 1990.
 226. Peter, M., J. Nakagawa, M. Dorée, and E. A. Nigg. In vitro disassembly of the nuclear lamina and M phase‐specific phosphorylation of lamins by cdc2 kinase. Cell 61: 591–602, 1990.
 227. Philp, A. V., J. M. Axton, R.D.C. Saunders, and D. M. Glover. Mutations in the Drosophila melanogaster gene 3 rows permit aspects of mitosis to continue in the absence of chromatid segregation. J. Cell Sci. 106: 87–98, 1993.
 228. Picard, A., J. P. Capony, D. L. Brautigan, and M. Dorée. Involvement of protein phosphatases 1 and 2A in the control of M phase‐promoting factor activity in starfish. J. Cell Biol. 109: 3347–3354, 1989.
 229. Picard, A., G. Peaucellier, F. LeBouffant, C. LePeuch, and M. Dorée. Role of protein synthesis and proteases in production and inactivation of maturation‐promoting activity during meiotic maturation of starfish oocytes. Dev. Biol. 109: 311–320, 1985.
 230. Pines, J., and T. Hunter. Isolation of a human cyclin cDNA: evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2. Cell 58: 833–846, 1989.
 231. Pines, J., and T. Hunter. Human cyclin A is adenovirus E1A‐associated protein p60 and behaves differently from cyclin B. Nature 346: 760–763, 1990.
 232. Pines, J., and T. Hunter. Human cyclins A and B1 are differentially located in the cell and undergo cell cycle‐dependent nuclear transport. J. Cell Biol. 115: 1–17, 1991.
 233. Polyak, K., J. Y. Kato, M. J. Solomon, C. J. Sherr, J. Massague, J. M. Roberts, and A. Koff. P27 (kip1), a cyclin‐cdk inhibitor, links transforming growth‐factor‐beta and contact inhibition to cell‐cycle arrest. Genes Dev. 8: 9–22, 1994.
 234. Polyak, K., M. H. Lee, H. Erdjumentbromage, A. Koff, J. M. Roberts, P. Tempst, and J. Massague. Cloning of p27 (kip1), a cyclin‐dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78: 59–66, 1994.
 235. Poon, R.Y.C., K. Yamashita, J. P. Adamczewski, T. Hunt, and J. Shuttleworth. The cdc2‐related protein p40 (mo15) is the catalytic subunit of a protein‐kinase that can activate p33cdk2 and p34cdc2. EMBO J. 12: 3123–3132, 1993.
 236. Primig, M., S. Sockanathan, H. Auer, and K. Nasmyth. Anatomy of a transcription factor important for the start of the cell cycle in Saccharomyces cerevisiae. Nature 358: 593–597, 1992.
 237. Quelle, D. E., R. A. Ashmun, S. A. Shurtleff, J. Y. Kato, D. Barsagi, M. F. Roussel, and C. J. Sherr. Overexpression of mouse d‐type cyclins accelerates g phase in rodent fibroblasts. Genes Dev. 7: 1559–1571, 1993.
 238. Raff, J. W., and D. M. Glover. Nuclear and cytoplasmic mitotic cycles continue in Drosophila embryos in which DNA synthesis is inhibited with aphidicolin. J. Cell Biol. 107: 2009–2019, 1988.
 239. Rao, P., and R. Johnson. Mammalian cell fusion studies on the regulation of DNA synthesis and mitosis. Nature 225: 159–164, 1970.
 240. Reed, S. The selection of S. cerevisiae mutants defective in the start event of cell division. Genetics 95: 566–577, 1980.
 241. Reed, S. I., J. A. Hadwiger, and A. T. Lorincz. Protein kinase activity associated with the product of the yeast cell division cycle gene CDC28. Proc. Natl. Acad. Sci. U.S.A. 82: 4055–4059, 1985.
 242. Ren, M. D., G. Drivas, P. D'Eustachio, and M. G. Rush. Ran/tc4—a small nuclear GTP‐binding protein that regulates DNA‐synthesis. J. Cell Biol. 120: 313–323, 1993.
 243. Richardson, H. E., C. Wittenberg, F. Cross, and S. I. Reed. An essential G1 function for cyclin‐like proteins in yeast. Cell 59: 1127–1133, 1989.
 244. Rossow, P. W., V. G. H. Riddle, and A. B. Pardee. Synthesis of labile, serum‐dependent protein in early G1 controls animal cell growth. Proc. Natl. Acad. Sci. U.S.A. 76: 4446–4450, 1979.
 245. Russell, P., and P. Nurse. cdc25 + functions as an inducer in the mitotic control of fission yeast. Cell 45: 145–153, 1986.
 246. Russell, P., and P. Nurse. The mitotic inducer nim11 + functions in a regulatory network of protein kinase homologs controlling the initiation of mitosis. Cell 49: 569–576, 1987.
 247. Russell, P., and P. Nurse. Negative regulation of mitosis by wee1 +, a gene encoding a protein kinase homolog. Cell 49: 559–567, 1987.
 248. Sadhu, K., S. I. Reed, H. Richardson, and P. Russell. Human homolog of fission yeast cdc25 mitotic inducer is predominantly expressed in G2. Proc. Natl Acad. Sci. U.S.A. 87: 5139–5143, 1990.
 249. Sagata, N., N. Watanabe, G. F. Vande Woude, and Y. Ikawa. The c‐mos proto‐oncogene product is a cytostatic factor responsible for meiotic arrest in vertebrate eggs. Nature 342: 512–518, 1989.
 250. Saka, Y., and M. Yanagida. Fission yeast cut5+, Required for S phase onset and M phase restraint, is identical to the radiation‐damage repair gene rad4+. Cell 74: 383–393, 1993.
 251. Satterwhite, L. L., M. J. Lohka, K. L. Wilson, T. Y. Scherson, L. J. Cisek, J. L. Corden, and T. D. Pollard. Phosphorylation of myosin‐II regulatory light chain by cyclin‐p34cdc2—a mechanism for the timing of cytokinesis. J. Cell Biol. 118: 595–605, 1992.
 252. Savitsky, K., A. Bar Shira, S. Gilad, G. Rotman, Y. Ziv, L. Vanagaite, D. A. Tagle, S. Smith, T. Uziel, S. Sfez, et al. A single ataxia telangiectasia gene with a product similar to PI‐3 kinase. Science 268: 1749–1753, 1995.
 253. Sazer, S., and P. Nurse. A fission yeast rcc1‐related protein is required for the mitosis to interphase transition. EMBO J. 13: 606–615, 1994.
 254. Schultz, S. J., and E. A. Nigg. Identification of 21 novel human protein kinases, including 3 members of a family related to the cell cycle regulator nimA of Aspergillus nidulans. Cell Growth Differ. 4: 821–830, 1993.
 255. Schwob, E., and K. Nasmyth. Clb5 and Clb6, a new pair of B‐cyclins involved in DNA replication in Saccharomyces cerevisiae. Genes Dev. 7: 1160–1175, 1993.
 256. Seino, H., H. Nishitani, T. Seki, N. Hisamoto, T. Tazunoki, N. Shiraki, M. Ohtsubo, K. Yamashita, T. Sekiguchi, and T. Nishimoto. Rcc1 is a nuclear‐protein required for coupling activation of cdc2 kinase with DNA‐synthesis and for start of the cell‐cycle. Cold Spring Harb. Symp. Quant. Biol. 56: 367–375, 1991.
 257. Seto, M., K. Yamamoto, S. Iida, Y. Akao, K. R. Utsumi, I. Kubonishi, I. Miyoshi, T. Ohtsuki, Y. Yawata, M. Namba, T. Motokura, A. Arnold, T. Takahashi, and R. Ueda. Gene rearrangement and overexpression of prad1 in lymphoid malignancy with t (q13/q32) translocation. Oncogene 7: 1401–1406, 1992.
 258. Sewing, A., C. Burger, S. Brusselbach, C. Schalk, F. C. Lucibello, and R. Muller. Human cyclin d1 encodes a labile nuclear‐protein whose synthesis is directly induced by growth‐factors and suppressed by cyclic‐amp. J. Cell Sci. 104: 545–554, 1993.
 259. Shamu, C. E., and A. W. Murray. Sister chromatid separation in frog egg extracts requires DNA topoisomerase‐II activity during anaphase. J. Cell Biol. 117: 921–934, 1992.
 260. Sheldrick, K. S., and A. M. Carr. Feedback controls and G2 checkpoints: fission yeast as a model system. Bioessays 15: 775–782, 1993.
 261. Shenoy, S., J. K. Choi, S. Bagrodia, T. D. Copeland, J. L. Maller, and D. Shalloway. Purified maturation promoting factor phosphorylates pp60c‐src at the sites phosphorylated during fibroblast mitosis. Cell 57: 763–774, 1989.
 262. Sherr, C. J. Mammalian G1 cyclins. Cell 73: 1059–1065, 1993.
 263. Shetty, K. T., W. T. Link, and H. C. Pant. Cdc2‐like kinase from rat spinal‐cord specifically phosphorylates kspxk motifs in neurofilament proteins—isolation and characterization. Proc. Natl Acad. Sci. U.S.A. 90: 6844–6848, 1993.
 264. Shiekhattar, R., F. Mermelstein, R. P. Fisher, R. Drapkin, B. Dynlacht, H. C. Wessling, D. O. Morgan, and D. Reinberg. Cdk‐activating kinase complex is a component of human transcription factor TFIIH. Nature. 374: 283–287, 1995.
 265. Shiina, N., T. Moriguchi, K. Ohta, Y. Gotoh, and E. Nishida. Regulation of a major microtubule‐associated protein by mpf and map kinase. EMBO J. 11: 3977–3984, 1992.
 266. Simanis, V., and P. Nurse. The cell cycle control gene cdc2 + of fission yeast encodes a protein kinase potentially regulated by phosphorylation. Cell 45: 261–268, 1986.
 267. Skalli, O., Y. H. Chou, and R. D. Goldman. Cell cycle‐dependent changes in the organization of an intermediate filament‐associated protein—correlation with phosphorylation by p34cdc2. Proc. Natl. Acad. Sci. U.S.A. 89: 11959–11963, 1992.
 268. Smith, J. A., and L. Martin. Do cells cycle? Proc. Natl. Acad. Sci. U.S.A. 70: 1263–1267, 1973.
 269. Smith, L. D., and R. E. Ecker. The interaction of steroids with R. pipiens oocytes in the induction of maturation. Dev. Biol. 25: 233–247, 1971.
 270. Solomon, M., R. Booher, M. Kirschner, and D. Beach. Cyclin in fission yeast. Cell 54: 738–739, 1988.
 271. Solomon, M. J. Cak, a p34cdc2 activating kinase. Mol. Biol. Cell 3: 1992.
 272. Solomon, M. J., M. Glotzer, T. H. Lee, M. Phillippe, and M. Kirschner. Cyclin activation of p34cdc2. Cell 63: 1013–1024, 1990.
 273. Solomon, M. J., J. W. Harper, and J. Shuttleworth. Cak, the p34cdc2 activating kinase, contains a protein identical or closely‐related to p40 (MO15). EMBO J. 12: 3133–3142, 1993.
 274. Stillman, B., S. P. Bell, A. Dutta, and Y. Marahrens. DNA replication and the cell cycle. Ciba Found. Symp. 170: 147–160, 1992.
 275. Stone, E. M., H. Yamano, N. Kinoshita, and M. Yanagida. Mitotic regulation of protein phosphatases by the fission yeast sds22‐protein. Curr. Biol. 3: 13–26, 1993.
 276. Strausfeld, U., J.‐C. Labbé, D. Fesquet, J. C. Cavadore, A. Picard, K. Sadhu, P. Russell, and M. Dorée. Dephosphorylation and activation of a p34cdc2/cyclin B complex in vitro by human CDC25 protein. Nature 351: 242–245, 1991.
 277. Sudbery, P. E., A. R. Goodey, and B.L.A. Carter. Genes which control cell proliferation in the yeast Saccharomyces cerevisiae. Nature 288: 401–404, 1980.
 278. Sunkara, P., D. Wright, and P. Rao. Mitotic factors from mammalian cells induces germinal vesicle breakdown and chromosome condensation in amphibian oocytes. Proc. Natl. Acad. Sci. U.S.A. 76: 2799–2802, 1979.
 279. Surana, U., A. Amon, C. Dowzer, J. McGrew, B. Byers, and K. Nasmyth. Destruction of the cdc28 clb mitotic kinase is not required for the metaphase to anaphase transition in budding yeast. EMBO J. 12: 1969–1978, 1993.
 280. Swenson, K. I., K. M. Farrell, and J. V. Ruderman. The clam embryo protein cyclin A induces entry into M phase and the resumption of mitosis in Xenopus oocytes. Cell 47: 861–870, 1986.
 281. Tachibana, K., N. Yanagishima, and T. Kishimoto. Preliminary characterization of maturation‐promoting factor from yeast Saccharomyces cerevisiae. J. Cell Sci. 88: 273–281, 1987.
 282. Tang, Z. H., T. R. Coleman, and W. G. Dunphy. 2 distinct mechanisms for negative regulation of the wee1 protein‐kinase. EMBO J. 12: 3427–3436, 1993.
 283. Toh‐e, A., K. Tanaka, Y. Uesono, and R. B. Wickner. PHO85, a negative regulator of the PHO system, is a homolog of the protein kinase gene, CDC28, of Saccharomyces cerevisiae. Mol. Gen. Genet. 214: 162–164, 1988.
 284. Toyoshima, H., and T. Hunter. P27, a novel inhibitor of g1 cyclin‐cdk protein‐kinase activity, is related to p21. Cell 78: 67–74, 1994.
 285. Tsai, L. H., E. Lees, B. Faha, E. Harlow, and K. Riabowol. The cdk2 kinase is required for the g1‐to‐s transition in mammalian‐cells. Oncogene 8: 1593–1602, 1993.
 286. Tsujimura, K., J. Tanaka, S. Ando, Y. Matsuoka, M. Kusubata, H. Sugiura, T. Yamauchi, and M. Inagaki. Identification of phosphorylation sites on glial fibrillary acidic protein for cdc2 kinase and ca2+‐calmodulin‐dependent protein‐kinase‐II. J. Biochem. 116: 426–434, 1994.
 287. Tuomikoski, T., M.‐A. Félix, M. Dorée, and J. Gruenberg. Inhibition of endocytic vesicle fusion in vitro by the cell‐cycle control protein kinase cdc2. Nature 342: 942–944, 1989.
 288. Tyers, M., and B. Futcher. Far1 and Fus3 link the mating pheromone signal‐transduction pathway to three G1‐phase Cdc28 kinase complexes. Mol. Cell. Biol. 13: 5659–5669, 1993.
 289. Tyers, M., G. Tokiwa, R. Nash, and B. Futcher. The Cln3‐Cdc28 kinase complex of Saccharomyces cerevisiae is regulated by proteolysis and phosphorylation. EMBO J. 11: 1773–1784, 1992.
 290. Uemura, T., H. Ohkura, Y. Adachi, K. Morino, K. Shiozaki, and M. Yanagida. DNA topoisomerase II is required for condensation and separation of mitotic chromosomes in S. pombe. Cell 50: 917–925, 1987.
 291. Uemura, T., and M. Yanagida. Mitotic spindle pulls but fails to separate chromosomes in type II DNA topoisomerase mutants: uncoordinated mitosis. EMBO J. 5: 1003–1010, 1986.
 292. Vandenheuvel, S., and E. Harlow. Distinct roles for cyclin‐dependent kinases in cell‐cycle control. Science 262: 2050–2054, 1993.
 293. Waga, S., G. J. Hannon, D. Beach, and B. Stillman. The p21 inhibitor of cyclin‐dependent kinases controls DNA‐replication by interaction with pcna. Nature 369: 574–578, 1994.
 294. Walworth, N., S. Davey, and D. Beach. Fission yeast chk1 protein kinase links the rad checkpoint pathway to cd2. Nature 363: 368–371, 1993.
 295. Ward, G. E., and M. W. Kirschner. Identification of cell cycle‐regulated phosphorylation sites on nuclear lamin C. Cell 61: 561–577, 1990.
 296. Weinert, T., and L. Hartwell. The RAD9 gene controls the cell cycle response to DNA damage in Saccharomyces cerevisiae. 241: 317–322, 1988.
 297. Weintraub, S. J., C. A. Prater, and D. C. Dean. Retinoblastoma protein switches the e2f site from positive to negative element. Nature 358: 259–261, 1992.
 298. Whitaker, M., and R. Patel. Calcium and cell cycle control. Development 108: 525–542, 1990.
 299. Williams, M. E., S. H. Swerdlow, C. L. Rosenberg, and A. Arnold. Chromosome‐11 translocation breakpoints at the prad1/cyclin d1 gene locus in centrocytic lymphoma. Leukemia 7: 241–245, 1993.
 300. Wu, L., and P. Russell. Nim1 kinase promotes mitosis by inactivating wee1 tyrosine kinase. Nature 363: 738–741, 1993.
 301. Xiong, Y., G. J. Hannon, H. Zhang, D. Casso, R. Kobayashi, and D. Beach. P21 is a universal inhibitor of cyclin kinases. Nature 366: 701–704, 1993.
 302. Xiong, Y., H. Zhang, and D. Beach. D‐type cyclins associate with multiple protein‐kinases and the DNA‐replication and repair factor pcna. Cell 71: 505–514, 1992.
 303. Xiong, Y., H. Zhang, and D. Beach. Subunit rearrangement of the cyclin‐dependent kinases is associated with cellular‐transformation. Genes Dev. 7: 1572–1583, 1993.
 304. Yamashiro, S., Y. Yamakita, H. Hosoya, and F. Matsumura. Phosphorylation of non‐muscle caldesmon by p34cdc2 kinase during mitosis. Nature 349: 169–172, 1991.
 305. Yamashiro, S., Y. Yamakita, R. Ishikawa, and F. Matsumura. Mitosis‐specific phosphorylation causes 83k non‐muscle caldesmon to dissociate from microfilaments. Nature 344: 675–678, 1990.
 306. Zetterberg, A., and O. Larsson. Kinetic analysis of regulatory events in G1 leading to proliferation or quiescence of Swiss 3T3 cells. Proc. Natl. Acad. Sci. U.S.A. 82: 5365–5369, 1985.
 307. Zirkle, R. E. UV‐microbeam irradiation of newt cell cytoplasm: spindle destruction, false anaphase, and delay of true anaphase. Radiat. Res. 41: 516–537, 1970.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Chris Norbury. Principles of Cell Cycle Control. Compr Physiol 2011, Supplement 31: Handbook of Physiology, Cell Physiology: 819-842. First published in print 1997. doi: 10.1002/cphy.cp140121