Modulation of Transition Probability and Temporal Dynamics by the Bistable Rb-E2F Switch

The cell's transition from the quiescent to the proliferative state is a highly variable process. Over the last four decades, two lines of apparently contradictory, phenomenological models have been proposed to account for such temporal variability. These include the transition probability (TP) model, the growth control (GC) model, and their variants. The growth control model was further proposed as an alternative explanation of the concept of restriction point, which we recently demonstrated as being controlled by a bistable Rb-E2F switch. Here, through a combination of modeling and experiments, we show that these different lines of models in essential reflect different aspects of the temporal dynamics in cell cycle entry.

In particular, we show that the variable activation of E2F can be described by stochastic activation of the bistable Rb-E2F switch. Importantly, this activation dynamics can be accurately recast into the framework of the TP model and that of the GC model. While the phenomenological models lack direct mechanistic insights into the underlying dynamics, we show that there is a quantitative mapping between these models and the mechanistic model. As such they can potentially serve as concise, quantitative phenotypes of the cell physiology.