Computational Analysis of the Control of Cell Cycle Entry

The reactivation of quiescent cells (e.g. stem cells) into proliferation is a crucial process for tissue repair and regeneration. The start of cell proliferation from quiescence is dependent on a "bistable" Rb-E2F gene pathway. The bistable nature allows the Rb-E2F pathway, in response to serum growth signals, to exist in two distinct states: an E2F-OFF/quiescence state and an E2F-ON/ proliferation state. In 2008, Yao at al. derived a mathematical model that predicts the effects of serum stimulation on the Rb-E2F pathway. The research described in this paper involved altering the values of model parameters (corresponding to individual gene regulation events) systematically to understand how cellular factors affect the serum threshold to activate the Rb-E2F bistable switch. Many of the model parameters that displayed the highest sensitivity on the OFF-to-ON serum threshold of the Rb-E2F model were involved with cyclin D activity. In addition, the model was used to predict the time required for cell to reach the R-point under a variety of stimulant conditions and gene mutations