PMC

(A) Plot depicting the evolution of the rate of G1-phase progression () as a function of and for a simultaneous step of and signals. (B) Time-dependent changes in normalized concentration of the main G1 regulatory components following cell exposure to a simultaneous step of and signals at time . Before that time, and the cell stands in a G0-like state. Entry into S phase is assessed by the sharp rise of E2F at time . G1-phase duration is defined as the time gap . Four combinations of signal intensities are considered: (a) , ; (b) , ; (c) , ; (d) , . According to the terminology in , the concentrations shown are: (dashed line), (dotted line), (dash-dotted line), (full line).

(A) Schematic representation of how the signal modifies the trajectories of G1-phase progression in the state space in the case of reversible (left panels) and irreversible (right panels) G1-arrest states. Black circles and white circles indicate a stable equilibrium linked to a G1-arrest state and an unstable equilibrium, respectively. Half black and half white circle indicates a saddle-node equilibrium. Left and right panels correspond to two qualitatively distinct scenarios. In case of limit cycle trajectories (connecting S to M), panels (a) and (b) would correspond to a saddle-node bifurcation on invariant cycle and a saddle homoclinic bifurcation, respectively. (B) Typical asymptotic relationship between the rate of G1-phase progression () and strength associated with reversible and irreversible G1-arrest scenarios (see supporting material).

(left panels): standard scenario that gives rise to a reversible G1-arrest state and corresponding to the scheme depicted in and . (right panels): scenarios giving rise to irreversible G1 arrest, combining the schemes depicted in . Numerical simulations were performed on several hundreds of cells subjected to different signals with the same mean and the same coefficient of variation of . In fact, switches every between uniformly distributed random values. (A,B) Plots of and , respectively, as a function of . (C) Time course of in 10 cells subjected to an average stress input indicated by the dashed line in panels A and B. Asterisks indicate the S-phase entry event (G1/S transition).

(A) Cells leaving G0 following growth-factor stimulation () and exposed to stress/differentiation signals () during G1 phase may be driven towards either one of two alternative fates: either G1-phase elongation or G1-arrest, which can be reversible or irreversible. (B) G1-phase progression in the presence of both and signals relies on a tight competition between two major players: -induced cell-cycle activators and -induced cell-cycle inhibitors. Main positive regulators (Grey ellipses) are the G1-specific, D- and E-type cyclins together with their favorite CDK partners and one subfamily of transcriptional factors termed activator E2Fs, which ultimately trigger S-phase entry. Negative regulators (White ellipses) include the unphosphorylated and hypophosphorylated Rb proteins and the members of the Cip/Kip family of CKIs (p21Cip1, p27Kip1, p57Kip2). Note that cyclin D-Cdks and cyclin E-Cdks are differentially regulated by unphosphorylated Rb and Cip/Kip proteins (see asterisks).

Three different situations have been analysed (Top panels): (A) The standard one corresponding to (see ) and two hypothetical ones in which: (B) the Cip/Kip proteins inhibit the activity of cyclin D-Cdk4,6 (, ) and (C) unphosphorylated Rb proteins does not repress cyclin E transcription ( that is compensated by reducing and by ). Bottom panels: plots depicting the changes in the rate of G1-phase progression () as a function of , starting from the G0 state (), when G0 exit is triggered by an step equal to one (like in ). Grey (filled and hatched) regions define intensities for which the G1-arrest state is stable. Hatched regions bounded by and specify intensities for which G0-arrested cells are able to progress toward S-phase entry following growth factor stimulation but for which G1-arrested cells fail to return to the cell cycle following stress signal withdrawal.