title: Cell cycle control by a minimal Cdk network.
abstract: In present-day eukaryotes, the cell division cycle is controlled by a complex network of interacting proteins, including members of the cyclin and cyclin-dependent protein kinase (Cdk) families, and the Anaphase Promoting Complex (APC). Successful progression through the cell cycle depends on precise, temporally ordered regulation of the functions of these proteins. In light of this complexity, it is surprising that in fission yeast, a minimal Cdk network consisting of a single cyclin-Cdk fusion protein can control DNA synthesis and mitosis in a manner that is indistinguishable from wild type. To improve our understanding of the cell cycle regulatory network, we built and analysed a mathematical model of the molecular interactions controlling the G1/S and G2/M transitions in these minimal cells. The model accounts for all observed properties of yeast strains operating with the fusion protein. Importantly, coupling the model's predictions with experimental analysis of alternative minimal cells, we uncover an explanation for the unexpected fact that elimination of inhibitory phosphorylation of Cdk is benign in these strains while it strongly affects normal cells. Furthermore, in the strain without inhibitory phosphorylation of the fusion protein, the distribution of cell size at division is unusually broad, an observation that is accounted for by stochastic simulations of the model. Our approach provides novel insights into the organization and quantitative regulation of wild type cell cycle progression. In particular, it leads us to propose a new mechanistic model for the phenomenon of mitotic catastrophe, relying on a combination of unregulated, multi-cyclin-dependent Cdk activities.
authors: Oxford Centre for Integrative Systems Biology, Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
authors: Claude
authors: C
authors: Gérard
authors: Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia, United States of America.
authors: John J
authors: JJ
authors: Tyson
authors: Institut de Génétique et Développement de Rennes, CNRS UMR 6290, Rennes, France.
authors: Damien
authors: D
authors: Coudreuse
authors: Oxford Centre for Integrative Systems Biology, Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
authors: Béla
authors: B
authors: Novák
mesh_terms: D059447:Cell Cycle Checkpoints / Q000502:physiology*; D019295:Computational Biology; D018844:Cyclin-Dependent Kinases / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D010766:Phosphorylation / Q000502:physiology; D012568:Schizosaccharomyces / Q000378:metabolism / Q000502:physiology
chemical_list: D018844:Cyclin-Dependent Kinases