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PMID: 15169868 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Integrative analysis of cell cycle control in budding yeast.

Molecular biology of the cell ·Vol. 15 ·No. 8 ·2004-08-00 ·Pages 3841-62

Chen KC, Calzone L, Csikasz-Nagy A, Cross FR, Novak B, Tyson JJ

Abstract

The adaptive responses of a living cell to internal and external signals are controlled by networks of proteins whose interactions are so complex that the functional integration of the network cannot be comprehended by intuitive reasoning alone. Mathematical modeling, based on biochemical rate equations, provides a rigorous and reliable tool for unraveling the complexities of molecular regulatory networks. The budding yeast cell cycle is a challenging test case for this approach, because the control system is known in exquisite detail and its function is constrained by the phenotypic properties of >100 genetically engineered strains. We show that a mathematical model built on a consensus picture of this control system is largely successful in explaining the phenotypes of mutants described so far. A few inconsistencies between the model and experiments indicate aspects of the mechanism that require revision. In addition, the model allows one to frame and critique hypotheses about how the division cycle is regulated in wild-type and mutant cells, to predict the phenotypes of new mutant combinations, and to estimate the effective values of biochemical rate constants that are difficult to measure directly in vivo.

MeSH Terms
Cell Cycle/physiology Cell Cycle Proteins/genetics,metabolism Computer Simulation Models, Theoretical Saccharomycetales/genetics,physiology
Chemicals
Cell Cycle Proteins
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Chen Katherine C
Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0406, USA. [email protected]
Calzone Laurence
Csikasz-Nagy Attila
Cross Frederick R
Novak Bela
Tyson John J
References (101)
101 references, click to expand
  1. Serial regulation of transcriptional regulators in the yeast cell cycle.
    Cell. 2001 Sep 21;106(6):697-708 PMID: 11572776
  2. Genetic and biochemical evaluation of the importance of Cdc6 in regulating mitotic exit.
    Mol Biol Cell. 2003 Nov;14(11):4592-604 PMID: 12960422
  3. Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization.
    Mol Biol Cell. 1998 Dec;9(12):3273-97 PMID: 9843569
  4. Cdc20 is essential for the cyclosome-mediated proteolysis of both Pds1 and Clb2 during M phase in budding yeast.
    Curr Biol. 1998 Feb 12;8(4):231-4 PMID: 9501986
  5. Late mitotic failure in mice lacking Sak, a polo-like kinase.
    Curr Biol. 2001 Mar 20;11(6):441-6 PMID: 11301255
  6. APC-dependent proteolysis of the mitotic cyclin Clb2 is essential for mitotic exit.
    Nature. 2002 Aug 1;418(6897):556-62 PMID: 12152084
  7. Separase, polo kinase, the kinetochore protein Slk19, and Spo12 function in a network that controls Cdc14 localization during early anaphase.
    Cell. 2002 Jan 25;108(2):207-20 PMID: 11832211
  8. An amplified sensitivity arising from covalent modification in biological systems.
    Proc Natl Acad Sci U S A. 1981 Nov;78(11):6840-4 PMID: 6947258
  9. SIC1 is ubiquitinated in vitro by a pathway that requires CDC4, CDC34, and cyclin/CDK activities.
    Mol Biol Cell. 1997 Aug;8(8):1427-37 PMID: 9285816
  10. Two yeast forkhead genes regulate the cell cycle and pseudohyphal growth.
    Nature. 2000 Jul 6;406(6791):90-4 PMID: 10894548
  11. Qualifying for the license to replicate.
    Cell. 1995 Jun 16;81(6):825-8 PMID: 7781058
  12. Linkage of replication to start by the Cdk inhibitor Sic1.
    Science. 1996 Apr 26;272(5261):560-2 PMID: 8614808
  13. Men and sin: what's the difference?
    Nat Rev Mol Cell Biol. 2001 Nov;2(11):815-26 PMID: 11715048
  14. The B-type cyclin kinase inhibitor p40SIC1 controls the G1 to S transition in S. cerevisiae.
    Cell. 1994 Oct 21;79(2):233-44 PMID: 7954792
  15. DNA replication. Once, and only once.
    Curr Biol. 1995 May 1;5(5):472-5 PMID: 7583091
  16. Mathematical model of the morphogenesis checkpoint in budding yeast.
    J Cell Biol. 2003 Dec 22;163(6):1243-54 PMID: 14691135
  17. The anaphase-promoting complex is required in G1 arrested yeast cells to inhibit B-type cyclin accumulation and to prevent uncontrolled entry into S-phase.
    J Cell Sci. 1997 Jul;110 ( Pt 13):1523-31 PMID: 9224769
  18. Numerical analysis of a comprehensive model of M-phase control in Xenopus oocyte extracts and intact embryos.
    J Cell Sci. 1993 Dec;106 ( Pt 4):1153-68 PMID: 8126097
  19. Mechanisms that help the yeast cell cycle clock tick: G2 cyclins transcriptionally activate G2 cyclins and repress G1 cyclins.
    Cell. 1993 Sep 24;74(6):993-1007 PMID: 8402888
  20. Model scenarios for evolution of the eukaryotic cell cycle.
    Philos Trans R Soc Lond B Biol Sci. 1998 Dec 29;353(1378):2063-76 PMID: 10098216
  21. Sister chromatid separation and chromosome re-duplication are regulated by different mechanisms in response to spindle damage.
    EMBO J. 1999 May 17;18(10):2707-21 PMID: 10329618
  22. Rapid degradation of the G1 cyclin Cln2 induced by CDK-dependent phosphorylation.
    Science. 1996 Mar 15;271(5255):1597-601 PMID: 8599119
  23. G1 cyclin turnover and nutrient uptake are controlled by a common pathway in yeast.
    Genes Dev. 1995 Feb 15;9(4):399-409 PMID: 7883165
  24. Two redundant oscillatory mechanisms in the yeast cell cycle.
    Dev Cell. 2003 May;4(5):741-52 PMID: 12737808
  25. Global analysis of protein localization in budding yeast.
    Nature. 2003 Oct 16;425(6959):686-91 PMID: 14562095
  26. Global analysis of protein expression in yeast.
    Nature. 2003 Oct 16;425(6959):737-41 PMID: 14562106
  27. G1-specific cyclins of S. cerevisiae: cell cycle periodicity, regulation by mating pheromone, and association with the p34CDC28 protein kinase.
    Cell. 1990 Jul 27;62(2):225-37 PMID: 2142620
  28. Testing a mathematical model of the yeast cell cycle.
    Mol Biol Cell. 2002 Jan;13(1):52-70 PMID: 11809822
  29. Modeling regulatory networks at Virginia Tech.
    OMICS. 2003 Fall;7(3):285-99 PMID: 14583117
  30. The cyclin-dependent kinase inhibitor p40SIC1 imposes the requirement for Cln G1 cyclin function at Start.
    Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7772-6 PMID: 8755551
  31. Exit from mitosis is regulated by Drosophila fizzy and the sequential destruction of cyclins A, B and B3.
    EMBO J. 1995 Oct 2;14(19):4827-38 PMID: 7588612
  32. Ubiquitination of the G1 cyclin Cln2p by a Cdc34p-dependent pathway.
    EMBO J. 1995 Jan 16;14(2):303-12 PMID: 7835341
  33. Exit from mitosis in budding yeast: biphasic inactivation of the Cdc28-Clb2 mitotic kinase and the role of Cdc20.
    Mol Cell. 2000 Mar;5(3):501-11 PMID: 10882135
  34. Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2.
    Nat Cell Biol. 2003 Apr;5(4):346-51 PMID: 12629549
  35. Pds1p is required for faithful execution of anaphase in the yeast, Saccharomyces cerevisiae.
    J Cell Biol. 1996 Apr;133(1):85-97 PMID: 8601616
  36. Mutations in CDC14 result in high sensitivity to cyclin gene dosage in Saccharomyces cerevisiae.
    Mol Gen Genet. 2000 Feb;263(1):60-72 PMID: 10732674
  37. Roles and regulation of Cln-Cdc28 kinases at the start of the cell cycle of Saccharomyces cerevisiae.
    EMBO J. 1995 Oct 2;14(19):4803-13 PMID: 7588610
  38. CDC20 and CDH1: a family of substrate-specific activators of APC-dependent proteolysis.
    Science. 1997 Oct 17;278(5337):460-3 PMID: 9334304
  39. The Josef Steiner Lecture: CDKs and cell-cycle control in fission yeast: relevance to other eukaryotes and cancer.
    Int J Cancer. 1997 May 29;71(5):707-8 PMID: 9180132
  40. Timing is everything: regulation of mitotic exit and cytokinesis by the MEN and SIN.
    Trends Cell Biol. 2001 Feb;11(2):89-95 PMID: 11166217
  41. CLN3, not positive feedback, determines the timing of CLN2 transcription in cycling cells.
    Genes Dev. 1995 Nov 15;9(22):2780-94 PMID: 7590253
  42. Mechanisms controlling subcellular localization of the G(1) cyclins Cln2p and Cln3p in budding yeast.
    Mol Cell Biol. 2001 Sep;21(18):6292-311 PMID: 11509671
  43. Cdc18p can block mitosis by two independent mechanisms.
    J Cell Sci. 1998 Oct;111 ( Pt 20):3101-8 PMID: 9739083
  44. The Polo-related kinase Cdc5 activates and is destroyed by the mitotic cyclin destruction machinery in S. cerevisiae.
    Curr Biol. 1998 Apr 23;8(9):497-507 PMID: 9560342
  45. Network dynamics and cell physiology.
    Nat Rev Mol Cell Biol. 2001 Dec;2(12):908-16 PMID: 11733770
  46. Pds1p, an inhibitor of anaphase in budding yeast, plays a critical role in the APC and checkpoint pathway(s).
    J Cell Biol. 1996 Apr;133(1):99-110 PMID: 8601617
  47. Regulation of Cdc28 cyclin-dependent protein kinase activity during the cell cycle of the yeast Saccharomyces cerevisiae.
    Microbiol Mol Biol Rev. 1998 Dec;62(4):1191-243 PMID: 9841670
  48. Regulation of the Bfa1p-Bub2p complex at spindle pole bodies by the cell cycle phosphatase Cdc14p.
    J Cell Biol. 2002 Apr 29;157(3):367-79 PMID: 11970961
  49. S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function.
    Cell. 1991 Aug 9;66(3):507-17 PMID: 1651171
  50. Coordinating DNA replication with cell division: current status of the licensing concept.
    Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):9997-10000 PMID: 8816736
  51. Genetic analysis of the shared role of CLN3 and BCK2 at the G(1)-S transition in Saccharomyces cerevisiae.
    Genetics. 1999 Nov;153(3):1131-43 PMID: 10545447
  52. Exit from mitosis is triggered by Tem1-dependent release of the protein phosphatase Cdc14 from nucleolar RENT complex.
    Cell. 1999 Apr 16;97(2):233-44 PMID: 10219244
  53. Fizzy is required for activation of the APC/cyclosome in Xenopus egg extracts.
    EMBO J. 1998 Jul 1;17(13):3565-75 PMID: 9649427
  54. An inhibitor of yeast cyclin-dependent protein kinase plays an important role in ensuring the genomic integrity of daughter cells.
    Mol Cell Biol. 1994 May;14(5):3320-8 PMID: 8164683
  55. The yeast CDK inhibitor Sic1 prevents genomic instability by promoting replication origin licensing in late G(1).
    Mol Cell. 2002 May;9(5):1067-78 PMID: 12049742
  56. CLB5 and CLB6, a new pair of B cyclins involved in DNA replication in Saccharomyces cerevisiae.
    Genes Dev. 1993 Jul;7(7A):1160-75 PMID: 8319908
  57. Cyclin-B homologs in Saccharomyces cerevisiae function in S phase and in G2.
    Genes Dev. 1992 Nov;6(11):2021-34 PMID: 1427070
  58. Unequal division in Saccharomyces cerevisiae and its implications for the control of cell division.
    J Cell Biol. 1977 Nov;75(2 Pt 1):422-35 PMID: 400873
  59. Cdc6 cooperates with Sic1 and Hct1 to inactivate mitotic cyclin-dependent kinases.
    Nature. 2001 Jul 19;412(6844):355-8 PMID: 11460169
  60. The dynamics of cell cycle regulation.
    Bioessays. 2002 Dec;24(12):1095-109 PMID: 12447975
  61. APC(Cdc20) promotes exit from mitosis by destroying the anaphase inhibitor Pds1 and cyclin Clb5.
    Nature. 1999 Nov 11;402(6758):203-7 PMID: 10647015
  62. p34Cdc28-mediated control of Cln3 cyclin degradation.
    Mol Cell Biol. 1995 Feb;15(2):731-41 PMID: 7823941
  63. Mathematical model of the cell division cycle of fission yeast.
    Chaos. 2001 Mar;11(1):277-286 PMID: 12779461
  64. Yeast G1 cyclins CLN1 and CLN2 and a GAP-like protein have a role in bud formation.
    EMBO J. 1993 Dec 15;12(13):5277-86 PMID: 8262070
  65. Modeling the control of DNA replication in fission yeast.
    Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9147-52 PMID: 9256450
  66. The segment polarity network is a robust developmental module.
    Nature. 2000 Jul 13;406(6792):188-92 PMID: 10910359
  67. Relationship between the function and the location of G1 cyclins in S. cerevisiae.
    J Cell Sci. 2001 Dec;114(Pt 24):4599-611 PMID: 11792824
  68. Cfi1 prevents premature exit from mitosis by anchoring Cdc14 phosphatase in the nucleolus.
    Nature. 1999 Apr 29;398(6730):818-23 PMID: 10235265
  69. SCF and APC: the Yin and Yang of cell cycle regulated proteolysis.
    Curr Opin Cell Biol. 1998 Dec;10(6):759-68 PMID: 9914180
  70. Distinct subcellular localization patterns contribute to functional specificity of the Cln2 and Cln3 cyclins of Saccharomyces cerevisiae.
    Mol Cell Biol. 2000 Jan;20(2):542-55 PMID: 10611233
  71. Net1 stimulates RNA polymerase I transcription and regulates nucleolar structure independently of controlling mitotic exit.
    Mol Cell. 2001 Jul;8(1):45-55 PMID: 11511359
  72. G1 cyclin degradation: the PEST motif of yeast Cln2 is necessary, but not sufficient, for rapid protein turnover.
    Mol Cell Biol. 1994 Dec;14(12):7953-66 PMID: 7969135
  73. Yeast Hct1 is a regulator of Clb2 cyclin proteolysis.
    Cell. 1997 Aug 22;90(4):683-93 PMID: 9288748
  74. Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts.
    Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):975-80 PMID: 12509509
  75. The WHI1+ gene of Saccharomyces cerevisiae tethers cell division to cell size and is a cyclin homolog.
    EMBO J. 1988 Dec 20;7(13):4335-46 PMID: 2907481
  76. Kinetic analysis of a molecular model of the budding yeast cell cycle.
    Mol Biol Cell. 2000 Jan;11(1):369-91 PMID: 10637314
  77. Universal control mechanism regulating onset of M-phase.
    Nature. 1990 Apr 5;344(6266):503-8 PMID: 2138713
  78. Mitotic exit network controls the localization of Cdc14 to the spindle pole body in Saccharomyces cerevisiae.
    Curr Biol. 2002 Jun 4;12(11):944-50 PMID: 12062061
  79. Cycling without the cyclosome: modeling a yeast strain lacking the APC.
    Cell Cycle. 2004 May;3(5):629-33 PMID: 15034296
  80. The Polo-like kinase Cdc5p and the WD-repeat protein Cdc20p/fizzy are regulators and substrates of the anaphase promoting complex in Saccharomyces cerevisiae.
    EMBO J. 1998 Mar 2;17(5):1336-49 PMID: 9482731
  81. Mitotic regulation of the APC activator proteins CDC20 and CDH1.
    Mol Biol Cell. 2000 May;11(5):1555-69 PMID: 10793135
  82. Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Scc1.
    Nature. 1999 Jul 1;400(6739):37-42 PMID: 10403247
  83. Testing cyclin specificity in the exit from mitosis.
    Mol Cell Biol. 2000 Jul;20(13):4483-93 PMID: 10848575
  84. The Swi5 transcription factor of Saccharomyces cerevisiae has a role in exit from mitosis through induction of the cdk-inhibitor Sic1 in telophase.
    Genetics. 1997 Jan;145(1):85-96 PMID: 9017392
  85. At the heart of the budding yeast cell cycle.
    Trends Genet. 1996 Oct;12(10):405-12 PMID: 8909137
  86. Whose end is destruction: cell division and the anaphase-promoting complex.
    Genes Dev. 1999 Aug 15;13(16):2039-58 PMID: 10465783
  87. Systematic identification of pathways that couple cell growth and division in yeast.
    Science. 2002 Jul 19;297(5580):395-400 PMID: 12089449
  88. Zyxin, a regulator of actin filament assembly, targets the mitotic apparatus by interacting with h-warts/LATS1 tumor suppressor.
    J Cell Biol. 2000 May 29;149(5):1073-86 PMID: 10831611
  89. Securin and B-cyclin/CDK are the only essential targets of the APC.
    Nat Cell Biol. 2003 Dec;5(12):1090-4 PMID: 14634663
  90. Fission yeast Slp1: an effector of the Mad2-dependent spindle checkpoint.
    Science. 1998 Feb 13;279(5353):1045-7 PMID: 9461438
  91. Regulation of the APC and the exit from mitosis.
    Nat Cell Biol. 1999 Jun;1(2):E47-53 PMID: 10559897
  92. Cyclins and the wiring of the yeast cell cycle.
    Yeast. 1996 Dec;12(16):1635-46 PMID: 9123966
  93. Cell cycle phases in the unequal mother/daughter cell cycles of Saccharomyces cerevisiae.
    Mol Cell Biol. 1984 Nov;4(11):2529-31 PMID: 6392855
  94. Pds1p of budding yeast has dual roles: inhibition of anaphase initiation and regulation of mitotic exit.
    Genes Dev. 1999 Aug 1;13(15):1950-9 PMID: 10444593
  95. Chemical kinetic theory: understanding cell-cycle regulation.
    Trends Biochem Sci. 1996 Mar;21(3):89-96 PMID: 8882581
  96. Cell cycle regulation in Schizosaccharomyces pombe.
    Curr Opin Microbiol. 2000 Dec;3(6):631-6 PMID: 11121785
  97. Phosphorylation by Cdc28 activates the Cdc20-dependent activity of the anaphase-promoting complex.
    J Cell Biol. 2000 Jun 26;149(7):1377-90 PMID: 10871279
  98. Regulation of the eukaryotic cell cycle: molecular antagonism, hysteresis, and irreversible transitions.
    J Theor Biol. 2001 May 21;210(2):249-63 PMID: 11371178
  99. Genes that can bypass the CLN requirement for Saccharomyces cerevisiae cell cycle START.
    Mol Cell Biol. 1994 Mar;14(3):2041-7 PMID: 8114735
  100. Asymmetrical division of Saccharomyces cerevisiae.
    J Bacteriol. 1980 Jun;142(3):808-18 PMID: 6991494
  101. The role of the polo kinase Cdc5 in controlling Cdc14 localization.
    Mol Biol Cell. 2003 Nov;14(11):4486-98 PMID: 14551257
Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1059-1524
DOI
10.1091/mbc.e03-11-0794
Email
[email protected]
Published
2004-08-00
Epub
2004-00-28
Pages
3841-62
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC491841
Subset
IM
External Links
PubMed source DOI: 10.1091/mbc.e03-11-0794 PMC Full Text View journal details
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