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Analysis of a Generic Model of Eukaryotic Cell-Cycle Regulation

Attila Csikász-Nagy ^* , Dorjsuren Battogtokh ^*, Katherine C. Chen ^*, Béla Novák  and John J. Tyson ^*

^* Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0406; and Molecular Network Dynamics Research Group of the Hungarian Academy of Sciences and Department of Agricultural and Chemical Technology, Budapest University of Technology and Economics, H-1521 Budapest, Hungary

Correspondence: Address reprint requests to John J. Tyson, Tel.: 540-231-4662; Fax: 540-231-9307; E-mail: tyson{at}vt.edu; or Attila Csikász-Nagy, E-mail: csikasz{at}mail.bme.hu.

We propose a protein interaction network for the regulation of DNA synthesis and mitosis that emphasizes the universality of the regulatory system among eukaryotic cells. The idiosyncrasies of cell cycle regulation in particular organisms can be attributed, we claim, to specific settings of rate constants in the dynamic network of chemical reactions. The values of these rate constants are determined ultimately by the genetic makeup of an organism. To support these claims, we convert the reaction mechanism into a set of governing kinetic equations and provide parameter values (specific to budding yeast, fission yeast, frog eggs, and mammalian cells) that account for many curious features of cell cycle regulation in these organisms. Using one-parameter bifurcation diagrams, we show how overall cell growth drives progression through the cell cycle, how cell-size homeostasis can be achieved by two different strategies, and how mutations remodel bifurcation diagrams and create unusual cell-division phenotypes. The relation between gene dosage and phenotype can be summarized compactly in two-parameter bifurcation diagrams. Our approach provides a theoretical framework in which to understand both the universality and particularity of cell cycle regulation, and to construct, in modular fashion, increasingly complex models of the networks controlling cell growth and division.