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 rapi dly until they undergo growth retardation, proceed through an S phase of lo nger duration, and then undergo apoptosis or cell differentiation preferent ially. These seemingly contradictory model types can be reconciled by restr icting the latter type to the transition from log phase to plateau phase gr owth, 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 dividin g and slowly dividing cells in the same population. Rb appears to play a ma jor role in protecting slowly proliferating cells from apoptosis, permittin g them to differentiate or persist as reserve cells that can be recruited i nto rapid cycle under appropriate circumstances. We examine the mechanistic basis for the recruitment phenomenon in some det ail. The mitogenic signaling pathway is divided into a proximal segment, wh ich consists of growth factor-induced membrane signaling, commonly through ras, raf, and cyclin D/cdk Rb kinase activation, and is subject to checks a nd balances that are designed to Limit the propagation of the mitogenic sig nal. ras and raf compete with wild-type p53 both with respect to mitogenic signal propagation at the Rb node, and, separately, with respect to apoptos is/anti-apoptosis. The distal segment of the mitogenic signaling pathway, w hich consists of Rb phosphorylation, the release of E2F, the induction of c -myc, cyclins E and A, and DNA synthesis, is distinguished by a multiplicit y of nested positive feedback loops; these would be expected to drive a mit ogenic 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 n eoplastic transformation. Chronic mitogenic stimulation of slowly prolifera ting cells would appear to be a common feature of Rb +/+ tumors. Rb -/- tum ors dispense with the early segment of the mitogenic signaling pathway and its and-apoptotic features, and maintain rapid cell cycling to compensate f or high apoptotic rates. (C) 1999 Wiley-Liss, Inc.