Underlying principles of cell fate determination during G1 phase of the mammalian cell cycle.

Upon their exit from mitosis, mammalian cells enter a G(1) phase during which they acutely sense all sorts of environmental stimuli. On the basis of these signals that they first need to decipher and integrate, they decide whether to undergo division, differentiation, senescence or apoptosis. We questioned whether, despite the complexity of the G(1) regulatory network, simple organizing principles might be identified that could explain how specific input signals are converted into appropriate cell fates. For this purpose, we formulated a mathematical model of the G(1) regulatory network using a simplified description of activities linked to signal transduction, cell growth, cell division and cell death. Bifurcation analysis of the model revealed the existence of multistability between several attractor states corresponding to G(0)-arrest, G(1)-arrest, S-phase entry and apoptosis cell fates. We further unravelled interlinked feedback and feedforward loops within the G(1) regulatory network that drive the signal-dependent transition between G(0) arrest and the other cell fates. Initially, exit from G(0) and progression in early G(1) entail growth factor-dependent activation of an upstream positive feedback loop that activates the cell-growth machinery. Once ribosome synthesis is restored in G(1), a competition develops between a downstream positive feedback loop, which, upon activation, triggers S phase entry, and stress-activated pathways that promote G(1) arrest. If S phase entry prevails over G(1) arrest, cells are sensitized to apoptosis due to stress-induced activation of pro-apoptotic pathways or repression of pro-survival pathways. Thus, the choice between the four possible cell fates in the G(1) phase relies on the flexibly interlinked growth-activatory and division-activatory modules, certain components of which have antagonistic effects on pathways involved in driving apoptosis and G(1) arrest. The final outcome ultimately depends on the context-dependent coordination between the cell-growth and cell-division processes.