A model of cell cycle behavior dominated by kinetics of a pathway stimulated by growth factors

A modified version of a previously developed mathematical model [Obeyesekere et al., Cell Prolif. (1997)] of the G1-phase of the cell cycle is presented. This model describes the regulation of the G1-phase that includes the interactions of the nuclear proteins, RB, cyclin E, cyclin D, cdk2, cdk4 and E2F. The effects of the growth factors on cyclin D synthesis under saturated or unsaturated growth factor conditions are investigated based on this model. The solutions to this model (a system of nonlinear ordinary differential equations) are discussed with respect to existing experiments. Predictions based on mathematical analysis of this model are presented. In particular, results are presented on the existence of two stable solutions, i.e., bistability within the G1-phase. It is shown that this bistability exists under unsaturated growth factor concentration levels. This phenomenon is very noticeable if the efficiency of the signal transduction, initiated by the growth factors leading to cyclin D synthesis, is low. The biological significance of this result as well as possible experimental designs to test these predictions are presented.