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Effect of positive feedback loops on the robustness of oscillations in the network of cyclin-dependent kinases driving the mammalian cell cycle : Effect of positive feedback on the robustness of Cdk oscillations

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Gérard, Claude [Université libre de Bruxelles (Unit of Theoretical Biology)] Gonze, Didier [Université libre de Bruxelles (Unit of Theoretical Biology)] Goldbeter, Albert [Université libre de Bruxelles (Unit of Theoretical Biology)]

The transitions between the G(1), S, G(2) and M phases of the mammalian cell cycle are driven by a network of cyclin-dependent kinases (Cdks), whose sequential activation is regulated by intertwined negative and positive feedback loops. We previously proposed a detailed computational model for the Cdk network, and showed that this network is capable of temporal self-organization in the form of sustained oscillations, which govern ordered progression through the successive phases of the cell cycle [Gérard and Goldbeter (2009) Proc Natl Acad Sci USA 106, 21643-21648]. We subsequently proposed a skeleton model for the cell cycle that retains the core regulatory mechanisms of the detailed model [Gérard and Goldbeter (2011) Interface Focus 1, 24-35]. Here we extend this skeleton model by incorporating Cdk regulation through phosphorylation/dephosphorylation and by including the positive feedback loops that underlie the dynamics of the G(1)/S and G(2)/M transitions via phosphatase Cdc25 and via phosphatase Cdc25 and kinase Wee1, respectively. We determine the effects of these positive feedback loops and ultrasensitivity in phosphorylation/dephosphorylation on the dynamics of the Cdk network. The multiplicity of positive feedback loops as well as the existence of ultrasensitivity promote the occurrence of bistability and increase the amplitude of the oscillations in the various cyclin/Cdk complexes. By resorting to stochastic simulations, we further show that the presence of multiple, redundant positive feedback loops in the G(2)/M transition of the cell cycle markedly enhances the robustness of the Cdk oscillations with respect to molecular noise.

Document type Article de périodique (Journal article)
Publication date 2012
Language Anglais
Journal information "FEBS Journal" - Vol. 279, p. 3411-3431 (2012)
Peer reviewed yes
Publisher Wiley-Blackwell
issn 1742-464X
Publication status Publié
Affiliation Université libre de Bruxelles - (Unit of Theoretical Biology)
Keywords Cell Biology ; Biochemistry ; Molecular Biology
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Bibliographic reference Gérard, Claude ; Gonze, Didier ; Goldbeter, Albert. Effect of positive feedback loops on the robustness of oscillations in the network of cyclin-dependent kinases driving the mammalian cell cycle : Effect of positive feedback on the robustness of Cdk oscillations. In: FEBS Journal, Vol. 279, p. 3411-3431 (2012)
Permanent URL http://hdl.handle.net/2078/192957