Revisiting a skeleton model for the mammalian cell cycle: From bistability to Cdk oscillations and cellular heterogeneity.

A network of cyclin-dependent kinases (Cdks) regulated by multiple negative and positive feedback loops controls progression in the mammalian cell cycle. We previously proposed a detailed computational model for this network, which consists of four coupled Cdk modules. Both this detailed model and a reduced, skeleton version show that the Cdk network is capable of temporal self-organization in the form of sustained Cdk oscillations, which correspond to the orderly progression along the different cell cycle phases G1, S (DNA replication), G2 and M (mitosis). We use the skeleton model to revisit the role of positive feedback (PF) loops on the dynamics of the mammalian cell cycle by showing that the multiplicity of PF loops extends the range of bistability in the isolated Cdk modules controlling the G1/S and G2/M transitions. Resorting to stochastic simulations we show that, through their effect on the range of bistability, multiple PF loops enhance the robustness of Cdk oscillations with respect to molecular noise. The model predicts that a rise in the total level of Cdk1 also enlarges the domain of bistability in the isolated Cdk modules as well as the range of oscillations in the full Cdk network. Surprisingly, stochastic simulations indicate that Cdk1 overexpression reduces the robustness of Cdk oscillations towards molecular noise; this result is due to the increased distance between the two branches of the bistable switch at higher levels of Cdk1. At intermediate levels of growth factor stochastic simulations show that cells may randomly switch between cell cycle arrest and cell proliferation, as a consequence of fluctuations. In the presence of Cdk1 overexpression, these transitions occur even at low levels of growth factor. Extending stochastic simulations from single cells to cell populations suggests that stochastic switches between cell cycle arrest and proliferation may provide a source of heterogeneity in a cell population, as observed in cancer cells characterized by Cdk1 overexpression.