Original Research ARTICLE

Front. Physiol., 02 November 2012 | doi: 10.3389/fphys.2012.00413

From quiescence to proliferation: Cdk oscillations drive the mammalian cell cycle

  • Faculté des Sciences, Université Libre de Bruxelles (ULB), Campus Plaine, Brussels, Belgium

We recently proposed a detailed model describing the dynamics of the network of cyclin-dependent kinases (Cdks) driving the mammalian cell cycle (Gérard and Goldbeter, 2009). The model contains four modules, each centered around one cyclin/Cdk complex. Cyclin D/Cdk4–6 and cyclin E/Cdk2 promote progression in G1 and elicit the G1/S transition, respectively; cyclin A/Cdk2 ensures progression in S and the transition S/G2, while the activity of cyclin B/Cdk1 brings about the G2/M transition. This model shows that in the presence of sufficient amounts of growth factor the Cdk network is capable of temporal self-organization in the form of sustained oscillations, which correspond to the ordered, sequential activation of the various cyclin/Cdk complexes that control the successive phases of the cell cycle. The results suggest that the switch from cellular quiescence to cell proliferation corresponds to the transition from a stable steady state to sustained oscillations in the Cdk network. The transition depends on a finely tuned balance between factors that promote or hinder progression in the cell cycle. We show that the transition from quiescence to proliferation can occur in multiple ways that alter this balance. By resorting to bifurcation diagrams, we analyze the mechanism of oscillations in the Cdk network. Finally, we show that the complexity of the detailed model can be greatly reduced, without losing its key dynamical properties, by considering a skeleton model for the Cdk network. Using such a skeleton model for the mammalian cell cycle we show that positive feedback (PF) loops enhance the amplitude and the robustness of Cdk oscillations with respect to molecular noise. We compare the relative merits of the detailed and skeleton versions of the model for the Cdk network driving the mammalian cell cycle.

Keywords: cell cycle, computational model, Cdk oscillations, limit cycle, quiescence, proliferation, cellular rhythms

Citation: Gérard C and Goldbeter A (2012) From quiescence to proliferation: Cdk oscillations drive the mammalian cell cycle. Front. Physio. 3:413. doi: 10.3389/fphys.2012.00413

Received: 03 August 2012; Accepted: 04 October 2012;
Published online: 02 November 2012.

Edited by:

Matteo Barberis, Humboldt University Berlin, Germany; Max Planck Institute for Molecular Genetics, Berlin, Germany

Reviewed by:

Pavel Kraikivski, Virginia Polytechnic Institute and State University, USA
Attila Csikasz-Nagy, The Microsoft Research - University of Trento COSBI, Italy

Copyright © 2012 Gérard and Goldbeter. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

*Correspondence: Albert Goldbeter, Faculté des Sciences, Université Libre de Bruxelles (ULB), Campus Plaine, CP 231, B-1050 Brussels, Belgium. e-mail: agoldbet@ulb.ac.be

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