title: Quantitative characterization of a mitotic cyclin threshold regulating exit from mitosis.
abstract: Regulation of cyclin abundance is central to eukaryotic cell cycle control. Strong overexpression of mitotic cyclins is known to lock the system in mitosis, but the quantitative behavior of the control system as this threshold is approached has only been characterized in the in vitro Xenopus extract system. Here, we quantitate the threshold for mitotic block in budding yeast caused by constitutive overexpression of the mitotic cyclin Clb2. Near this threshold, the system displays marked loss of robustness, in that loss or even heterozygosity for some regulators becomes deleterious or lethal, even though complete loss of these regulators is tolerated at normal cyclin expression levels. Recently, we presented a quantitative kinetic model of the budding yeast cell cycle. Here, we use this model to generate biochemical predictions for Clb2 levels, asynchronous as well as through the cell cycle, as the Clb2 overexpression threshold is approached. The model predictions compare well with biochemical data, even though no data of this type were available during model generation. The loss of robustness of the Clb2 overexpressing system is also predicted by the model. These results provide strong confirmation of the model's predictive ability.
authors.affiliation: The Rockefeller University, New York, NY 10021, USA. fcross@rockefeller.edu
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Cross
authors.forename: Lea
authors.initials: L
authors.lastname: Schroeder
authors.forename: Martin
authors.initials: M
authors.lastname: Kruse
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Chen
mesh_terms: D002453:Cell Cycle / Q000502:physiology; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005800:Genes, Fungal; D007700:Kinetics; D008938:Mitosis / Q000502:physiology*; D008954:Models, Biological; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C093749:CLB2 protein, S cerevisiae; D019926:Cyclin B; D029701:Saccharomyces cerevisiae Proteins
references.citation: Proc Natl Acad Sci U S A. 1980 Jan;77(1):462-6
references.pmid: 6928638
references.citation: Mol Biol Cell. 2004 Aug;15(8):3841-62
references.pmid: 15169868
references.citation: Nature. 1989 May 25;339(6222):275-80
references.pmid: 2566917
references.citation: Nature. 1989 May 25;339(6222):280-6
references.pmid: 2566918
references.citation: Mol Biol Cell. 1992 Jul;3(7):805-18
references.pmid: 1387566
references.citation: EMBO J. 1993 May;12(5):1969-78
references.pmid: 8491189
references.citation: J Cell Sci. 1993 Dec;106 ( Pt 4):1153-68
references.pmid: 8126097
references.citation: Trends Genet. 1996 Sep;12(9):345-50
references.pmid: 8855663
references.citation: Trends Genet. 1996 Oct;12(10):405-12
references.pmid: 8909137
references.citation: Science. 1996 Dec 6;274(5293):1659-64
references.pmid: 8939847
references.citation: Prog Cell Cycle Res. 1995;1:1-8
references.pmid: 9552349
references.citation: Mol Biol Cell. 1998 Dec;9(12):3273-97
references.pmid: 9843569
references.citation: Genes Dev. 1999 Aug 15;13(16):2039-58
references.pmid: 10465783
references.citation: Mol Biol Cell. 2000 Jan;11(1):369-91
references.pmid: 10637314
references.citation: J Cell Biol. 2000 Jun 26;149(7):1377-90
references.pmid: 10871279
references.citation: Curr Biol. 2001 Nov 13;11(22):1781-7
references.pmid: 11719221
references.citation: Mol Biol Cell. 2002 Jan;13(1):52-70
references.pmid: 11809822
references.citation: Cell. 2002 Jan 25;108(2):207-20
references.pmid: 11832211
references.citation: Dev Biol. 2002 Mar 1;243(1):34-43
references.pmid: 11846475
references.citation: J Cell Sci. 2002 Mar 1;115(Pt 5):869-72
references.pmid: 11870205
references.citation: Curr Opin Cell Biol. 2002 Apr;14(2):140-8
references.pmid: 11891111
references.citation: Nature. 2002 Aug 1;418(6897):556-62
references.pmid: 12152084
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):975-80
references.pmid: 12509509
references.citation: Nat Cell Biol. 2003 Apr;5(4):346-51
references.pmid: 12629549
references.citation: Dev Cell. 2003 May;4(5):741-52
references.pmid: 12737808
references.citation: Mol Biol Cell. 2003 Nov;14(11):4592-604
references.pmid: 12960422
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4781-6
references.pmid: 15037758
references.citation: Cell Cycle. 2004 May;3(5):629-33
references.pmid: 15034296
references.citation: Cell. 1983 Jun;33(2):389-96
references.pmid: 6134587