Stochastic E2F Activation and Reconciliation of Phenomenological Cell-Cycle Models

A new, stochastic model of entry into the mammalian cell cycle provides a mechanistic understanding of the temporal variability observed across populations of cells and reconciles previously proposed phenomenological cell-cycle models.The transition of the mammalian cell from quiescence to proliferation 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 various forms of the transition probability (TP) model and the growth control (GC) model, which lack mechanistic details. The GC model was further proposed as an alternative explanation for the concept of the 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 essence reflect different aspects of stochastic 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, which in turn may account for the temporal variability in cell cycle entry. Moreover, we show that temporal dynamics of E2F activation can be recast into the frameworks of both the TP model and the GC model via parameter mapping. This mapping suggests that the two lines of phenomenological models can be reconciled through the stochastic dynamics of the Rb-E2F switch. It also suggests a potential utility of the TP or GC models in defining concise, quantitative phenotypes of cell physiology. This may have implications in classifying cell types or states.Author Summary: Mammalian cells enter the division cycle in response to appropriate growth signals. For each cell, the decision to do so is critically dependent on the interplay between environmental cues and the internal state of the cell and is influenced by random fluctuations in cellular processes. Indeed, experimental evidence indicates that cell cycle entry is highly variable from cell to cell, even within a clonal population. To account for such variability, a number of phenomenological models have been previously proposed. These models primarily fall into two types depending on their fundamental assumptions on the origin of the variability. “Transition probability” models presume that variability in cell cycle entry originates from the fact that entry in each individual cell is random but also governed by a fixed probability. In contrast, “growth-controlled” models assume that the growth rates across a population are variable and result in cells that are out of phase developmentally. While both kinds of models provide a good fit to experimental data, their lack of mechanistic details limits their predictive power and has led to unresolved debate between their practitioners. In this study, we developed a mechanistically based stochastic model of the temporal dynamics of activation of the E2F transcription factor, which is used here as a marker of the transition of cells from quiescence to active cell cycling. Using this model, we show that “transition probability” and “growth-controlled” models can be reconciled by incorporation of a small number of basic cellular parameters related to protein synthesis and turnover, protein modification, stochasticity, and the like. Essentially our work shows that each kind of phenomenological model holds true for describing a particular aspect of the cell cycle transition. We suggest that incorporation of basic cellular parameters in this manner into phenomenological models may constitute a broadly applicable approach to defining concise, quantitative phenotypes of cell physiology.