Skip to main content
PMC home page
Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 1998 Dec 29;353(1378):2063–2076. doi: 10.1098/rstb.1998.0352

Model scenarios for evolution of the eukaryotic cell cycle.

B Novak 1, A Csikasz-Nagy 1, B Gyorffy 1, K Nasmyth 1, J J Tyson 1
PMCID: PMC1692434  PMID: 10098216

Abstract

Progress through the division cycle of present day eukaryotic cells is controlled by a complex network consisting of (i) cyclin-dependent kinases (CDKs) and their associated cyclins, (ii) kinases and phosphatases that regulate CDK activity, and (iii) stoichiometric inhibitors that sequester cyclin-CDK dimers. Presumably regulation of cell division in the earliest ancestors of eukaryotes was a considerably simpler affair. Nasmyth (1995) recently proposed a mechanism for control of a putative, primordial, eukaryotic cell cycle, based on antagonistic interactions between a cyclin-CDK and the anaphase promoting complex (APC) that labels the cyclin subunit for proteolysis. We recast this idea in mathematical form and show that the model exhibits hysteretic behaviour between alternative steady states: a Gl-like state (APC on, CDK activity low, DNA unreplicated and replication complexes assembled) and an S/M-like state (APC off, CDK activity high, DNA replicated and replication complexes disassembled). In our model, the transition from G1 to S/M ('Start') is driven by cell growth, and the reverse transition ('Finish') is driven by completion of DNA synthesis and proper alignment of chromosomes on the metaphase plate. This simple and effective mechanism for coupling growth and division and for accurately copying and partitioning a genome consisting of numerous chromosomes, each with multiple origins of replication, could represent the core of the eukaryotic cell cycle. Furthermore, we show how other controls could be added to this core and speculate on the reasons why stoichiometric inhibitors and CDK inhibitory phosphorylation might have been appended to the primitive alternation between cyclin accumulation and degradation.

Full Text

The Full Text of this article is available as a PDF (329.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Amon A. Regulation of B-type cyclin proteolysis by Cdc28-associated kinases in budding yeast. EMBO J. 1997 May 15;16(10):2693–2702. doi: 10.1093/emboj/16.10.2693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Borgne A., Meijer L. Sequential dephosphorylation of p34(cdc2) on Thr-14 and Tyr-15 at the prophase/metaphase transition. J Biol Chem. 1996 Nov 1;271(44):27847–27854. doi: 10.1074/jbc.271.44.27847. [DOI] [PubMed] [Google Scholar]
  3. Correa-Bordes J., Nurse P. p25rum1 orders S phase and mitosis by acting as an inhibitor of the p34cdc2 mitotic kinase. Cell. 1995 Dec 15;83(6):1001–1009. doi: 10.1016/0092-8674(95)90215-5. [DOI] [PubMed] [Google Scholar]
  4. Deshaies R. J. Phosphorylation and proteolysis: partners in the regulation of cell division in budding yeast. Curr Opin Genet Dev. 1997 Feb;7(1):7–16. doi: 10.1016/s0959-437x(97)80103-7. [DOI] [PubMed] [Google Scholar]
  5. Donachie W. D. The cell cycle of Escherichia coli. Annu Rev Microbiol. 1993;47:199–230. doi: 10.1146/annurev.mi.47.100193.001215. [DOI] [PubMed] [Google Scholar]
  6. 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. 1996 Feb 15;15(4):850–860. [PMC free article] [PubMed] [Google Scholar]
  7. Futcher B. Cyclins and the wiring of the yeast cell cycle. Yeast. 1996 Dec;12(16):1635–1646. doi: 10.1002/(SICI)1097-0061(199612)12:16%3C1635::AID-YEA83%3E3.0.CO;2-O. [DOI] [PubMed] [Google Scholar]
  8. Félix M. A., Labbé J. C., Dorée M., Hunt T., Karsenti E. Triggering of cyclin degradation in interphase extracts of amphibian eggs by cdc2 kinase. Nature. 1990 Jul 26;346(6282):379–382. doi: 10.1038/346379a0. [DOI] [PubMed] [Google Scholar]
  9. Goldbeter A., Koshland D. E., Jr An amplified sensitivity arising from covalent modification in biological systems. Proc Natl Acad Sci U S A. 1981 Nov;78(11):6840–6844. doi: 10.1073/pnas.78.11.6840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gould K. L., Nurse P. Tyrosine phosphorylation of the fission yeast cdc2+ protein kinase regulates entry into mitosis. Nature. 1989 Nov 2;342(6245):39–45. doi: 10.1038/342039a0. [DOI] [PubMed] [Google Scholar]
  11. Jallepalli P. V., Kelly T. J. Rum1 and Cdc18 link inhibition of cyclin-dependent kinase to the initiation of DNA replication in Schizosaccharomyces pombe. Genes Dev. 1996 Mar 1;10(5):541–552. doi: 10.1101/gad.10.5.541. [DOI] [PubMed] [Google Scholar]
  12. King R. W., Deshaies R. J., Peters J. M., Kirschner M. W. How proteolysis drives the cell cycle. Science. 1996 Dec 6;274(5293):1652–1659. doi: 10.1126/science.274.5293.1652. [DOI] [PubMed] [Google Scholar]
  13. Lundgren K., Walworth N., Booher R., Dembski M., Kirschner M., Beach D. mik1 and wee1 cooperate in the inhibitory tyrosine phosphorylation of cdc2. Cell. 1991 Mar 22;64(6):1111–1122. doi: 10.1016/0092-8674(91)90266-2. [DOI] [PubMed] [Google Scholar]
  14. Martin-Castellanos C., Labib K., Moreno S. B-type cyclins regulate G1 progression in fission yeast in opposition to the p25rum1 cdk inhibitor. EMBO J. 1996 Feb 15;15(4):839–849. [PMC free article] [PubMed] [Google Scholar]
  15. Minshull J., Sun H., Tonks N. K., Murray A. W. A MAP kinase-dependent spindle assembly checkpoint in Xenopus egg extracts. Cell. 1994 Nov 4;79(3):475–486. doi: 10.1016/0092-8674(94)90256-9. [DOI] [PubMed] [Google Scholar]
  16. Moreno S., Nurse P. Regulation of progression through the G1 phase of the cell cycle by the rum1+ gene. Nature. 1994 Jan 20;367(6460):236–242. doi: 10.1038/367236a0. [DOI] [PubMed] [Google Scholar]
  17. Nasmyth K. At the heart of the budding yeast cell cycle. Trends Genet. 1996 Oct;12(10):405–412. doi: 10.1016/0168-9525(96)10041-x. [DOI] [PubMed] [Google Scholar]
  18. Nasmyth K. Evolution of the cell cycle. Philos Trans R Soc Lond B Biol Sci. 1995 Sep 29;349(1329):271–281. doi: 10.1098/rstb.1995.0113. [DOI] [PubMed] [Google Scholar]
  19. Nasmyth K., Hunt T. Cell cycle. Dams and sluices. Nature. 1993 Dec 16;366(6456):634–635. doi: 10.1038/366634a0. [DOI] [PubMed] [Google Scholar]
  20. Nurse P. Ordering S phase and M phase in the cell cycle. Cell. 1994 Nov 18;79(4):547–550. doi: 10.1016/0092-8674(94)90539-8. [DOI] [PubMed] [Google Scholar]
  21. Russell P., Nurse P. Negative regulation of mitosis by wee1+, a gene encoding a protein kinase homolog. Cell. 1987 May 22;49(4):559–567. doi: 10.1016/0092-8674(87)90458-2. [DOI] [PubMed] [Google Scholar]
  22. Schwob E., Böhm T., Mendenhall M. D., Nasmyth K. The B-type cyclin kinase inhibitor p40SIC1 controls the G1 to S transition in S. cerevisiae. Cell. 1994 Oct 21;79(2):233–244. doi: 10.1016/0092-8674(94)90193-7. [DOI] [PubMed] [Google Scholar]
  23. Wheeler R. T., Shapiro L. Bacterial chromosome segregation: is there a mitotic apparatus? Cell. 1997 Mar 7;88(5):577–579. doi: 10.1016/s0092-8674(00)81898-x. [DOI] [PubMed] [Google Scholar]

Articles from Philosophical Transactions of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society

RESOURCES