Origin of bistability underlying mammalian cell cycle entry

Precise control of cell proliferation is fundamental to tissue homeostasis and differentiation. Mammalian cells commit to proliferation and become independent of growth signals at the restriction point (R-point). It has long been recognized that the R-point is tightly regulated by the Rb-E2F signaling pathway. We recently further demonstrated that the tight R-point regulation is mediated by a bistable switch mechanism. However, it remains elusive as to what regulatory features in the Rb-E2F pathway create this bistable switch. Here we analyzed a library of gene circuits comprising all possible link combinations in a simplified Rb-E2F network. We identified a minimal gene circuit that was able to generate a robust Rb-E2F bistable switch. This minimal circuit contains a coupled feed-forward regulation and a mutually-inhibitory feedback loop, which forms an AND-gate control of the E2F activation. This gene circuit was robust against both perturbations of kinetic constants and alterations of circuit topology. Our findings suggested basic design principles for the robust control of the bistable cell cycle entry at the R-point.

Research reported here was partially supported by grants from the U.S. National Science Foundation (DMS-0342172) and National Institutes of Health (U54-CA-112952, P50-GM081883). Any opinions, findings and conclusions or recommendations expressed in this work are those of the authors and do not necessarily reflect the views of the NIH.