Circadian Gating of the Mammalian Cell Cycle Restriction Point: A Mathematical Analysis

A critical decision in the mammalian cell cycle is whether to pass through the restriction point (R-point) or enter the cell cycle. In this letter, we modeled the decision-making system of the mammalian cell cycle entry and the simulated circadian regulation of the R-point driven by external epithelial growth factor (EGF) patterns. Our conceptual model replicated key signaling behaviors observed experimentally, suggesting that the proposed network captured the essential system features. The model revealed the dramatic importance of the EGF dynamics on promoting cell proliferation, showed that the EGF signal duration was more important than the signal strength for driving cells past the R-point, and suggested that the loss of circadian control of the cell cycle entry could be associated with cancer development.