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Minimal Models for Cell-Cycle Control Based on Competitive Inhibition and Multisite Phosphorylations of Cdk Substrates

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dc.contributorVirginia Techen
dc.contributor.authorGerard, Claudeen
dc.contributor.authorTyson, John J.en
dc.contributor.authorNovak, Belaen
dc.contributor.departmentBiological Sciencesen
dc.date.accessed2014-02-05en
dc.date.accessioned2014-02-26T19:10:04Zen
dc.date.available2014-02-26T19:10:04Zen
dc.date.issued2013-03en
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.en
dc.description.sponsorshipNational Institutes of Health 5R01-GM078989-07, 1U54-CA149147-03en
dc.description.sponsorshipBiotechnology and Biological Sciences Research Councilen
dc.description.sponsorshipEuropean Community's Seventh Framework Programmes UniCellSys/201142, MitoSys/241548en
dc.format.mimetypeapplication/pdfen
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.2013.02.012en
dc.identifier.doihttps://doi.org/10.1016/j.bpj.2013.02.012en
dc.identifier.issn0006-3495en
dc.identifier.urihttp://hdl.handle.net/10919/25770en
dc.identifier.urlhttp://www.sciencedirect.com/science/article/pii/S0006349513002026en
dc.language.isoenen
dc.publisherCELL PRESSen
dc.rightsIn Copyrighten
dc.rights.holderBiophysical Societyen
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectquantitative modelen
dc.subjectfission yeasten
dc.subjectmitotic exiten
dc.subjects-phaseen
dc.subjectkinaseen
dc.subjectnetworken
dc.subjectcooperativityen
dc.subjectbistabilityen
dc.subjectdynamicsen
dc.subjectsecurinen
dc.titleMinimal Models for Cell-Cycle Control Based on Competitive Inhibition and Multisite Phosphorylations of Cdk Substratesen
dc.title.serialBiophysical Journalen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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