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dc.contributorVirginia Tech
dc.contributor.authorGerard, C.
dc.contributor.authorTyson, John J.
dc.contributor.authorNovak, B.
dc.identifier.citationGerard, Claude; Tyson, John J.; Novak, Bela. "Minimal Models for Cell-Cycle Control Based on Competitive Inhibition and Multisite Phosphorylations of Cdk Substrates," Biophysical Journal 104(6), 1367-1379 (2013); doi: 10.1016/j.bpj.2013.02.012
dc.description.abstractThe eukaryotic cell cycle is characterized by alternating oscillations in the activities of cyclin-dependent kinase (Cdk) and the anaphase-promoting complex (APC). Successful completion of the cell cycle is dependent on the precise, temporally ordered appearance of these activities. A modest level of Cdk activity is sufficient to initiate DNA replication, but mitosis and APC activation require an elevated Cdk activity. In present-day eukaryotes, this temporal order is provided by a complex network of regulatory proteins that control both Cdk and APC activities via sharp thresholds, bistability, and time delays. Using simple computational models, we show here that these dynamical features of cell-cycle organization could emerge in a control system driven by a single Cdk/cyclin complex and APC wired in a negative-feedback loop. We show that ordered phosphorylation of cellular proteins could be explained by multisite phosphorylation/dephosphorylation and competition of substrates for interconverting kinase (Cdk) and phosphatase. In addition, the competition of APC substrates for ubiquitylation can create and maintain sustained oscillations in cyclin levels. We propose a sequence of models that gets closer and closer to a realistic model of cell-cycle control in yeast. Since these models lack the elaborate control mechanisms characteristic of modern eukaryotes, they suggest that bistability and time delay may have characterized eukaryotic cell divisions before the current cell-cycle control network evolved in all its complexity.
dc.description.sponsorshipNational Institutes of Health 5R01-GM078989-07, 1U54-CA149147-03
dc.description.sponsorshipBiotechnology and Biological Sciences Research Council
dc.description.sponsorshipEuropean Community's Seventh Framework Programmes UniCellSys/201142, MitoSys/241548
dc.publisherCELL PRESS
dc.subjectquantitative model
dc.subjectfission yeast
dc.subjectmitotic exit
dc.titleMinimal Models for Cell-Cycle Control Based on Competitive Inhibition and Multisite Phosphorylations of Cdk Substrates
dc.typeArticle - Refereed
dc.title.serialBiophysical Journal

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