Modeling cell signaling networks that control cell proliferation and cell fate decisions
Institute for Genome Sciences and Policy, Duke University
(January 20, 2009 2:30 PM - 3:30 PM)
In response to environmental signals, mammalian cells face constant cell fate choices, including quiescence, proliferation, differentiation, or cell death. In the process of cell proliferation, there is a critical time point when a mammalian cell makes an all-or-none growth decision -- known as the restriction point (R point). After passing the R-point, cell growth becomes autonomous and independent of continuous growth signals. Although the R-point has been linked to various activities involved in the regulation of the G1-S transition of the cell cycle, the underlying decision-making mechanism remains unclear. Using single-cell quantifications coupled with mathematical modeling, we have shown that the Rb-E2F signaling network functions as a bistable switch to convert graded growth inputs into all-or-none E2F responses. Once turned ON by sufficient growth stimulation, E2F can memorize and maintain this ON state even in the absence of continuous growth signals. We have further shown that, at each critical concentration and duration of growth stimulation, bistable E2F activation correlates directly with the ability of a cell to traverse the R-point and begin DNA replication. Lastly, we have shown that the Rb-E2F bistable switch also functions as a "digital counter". This counter mechanism enables precise quantitation of transient growth stimulation, and allocates corresponding numbers of cells to enter proliferation. The counting process can be described by a simple mathematical function, which is determined by the inherent stochasticity and bistability of the Rb-E2F pathway, and can be modified by altering the network dynamics with Cdk inhibitors. We are now extending this study to develop an integrated, quantitative understanding of the "design principles" of gene regulatory networks underlying diverse cell-fate decisions, particularly as they serve to connect the decisions of proliferation and cell death.