Cell cycle models for molecular biology and molecular oncology: exploring new dimensions.

Some cell cycle models assume that cells are normally in a quiescent state until they are stimulated to enter the cell cycle and proceed through an S phase of fixed duration. Other models assume that cells normally cycle rapidly until they undergo growth retardation, proceed through an S phase of longer duration, and then undergo apoptosis or cell differentiation preferentially. These seemingly contradictory model types can be reconciled by restricting the latter type to the transition from log phase to plateau phase growth, and the former type to the recruitment of slowly proliferating cells into rapid cycle. Both proliferative states can be unified in a single cell cycle model that recognizes differences in the behavior of rapidly dividing and slowly dividing cells in the same population. Rb appears to play a major role in protecting slowly proliferating cells from apoptosis, permitting them to differentiate or persist as reserve cells that can be recruited into rapid cycle under appropriate circumstances. We examine the mechanistic basis for the recruitment phenomenon in some detail. The mitogenic signaling pathway is divided into a proximal segment, which consists of growth factor-induced membrane signaling, commonly through ras, raf, and cyclin D/cdk Rb kinase activation, and is subject to checks and balances that are designed to limit the propagation of the mitogenic signal. ras and raf compete with wild-type p53 both with respect to mitogenic signal propagation at the Rb node, and, separately, with respect to apoptosis/anti-apoptosis. The distal segment of the mitogenic signaling pathway, which consists of Rb phosphorylation, the release of E2F, the induction of c-myc, cyclins E and A, and DNA synthesis, is distinguished by a multiplicity of nested positive feedback loops; these would be expected to drive a mitogenic signal that entered the distal segment through at least one round of DNA synthesis. Using this model, we can identify two separate mechanistic strategies for neoplastic transformation. Chronic mitogenic stimulation of slowly proliferating cells would appear to be a common feature of Rb +/+ tumors. Rb -/- tumors dispense with the early segment of the mitogenic signaling pathway and its anti-apoptotic features, and maintain rapid cell cycling to compensate for high apoptotic rates.