stochastic e2f activation and reconciliation of phenomenological cell-cycle models现象学细胞循环模型的随机e2f激活与和解.pdfVIP

Stochastic E2F Activation and Reconciliation of Phenomenological Cell-Cycle Models 1 2,3 4 2,3 1,2,5 Tae J. Lee , Guang Yao , Dorothy C. Bennett , Joseph R. Nevins , Lingchong You * 1 Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States of America, 2 Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America, 3 Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America, 4 Molecular and Metabolic Signalling Centre, St George’s, University of London, London, United Kingdom, 5 Center for Systems Biology, Duke University, Durham, North Carolina, United States of America Abstract 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