INTEGRATED CONTROL OF CELL-PROLIFERATION AND CELL-DEATH BY THE C-MYC ONCOGENE

Regulation of multicellular architecture involves a dynamic equilibriu m between cell proliferation, differentiation with consequent growth a rrest, and cell death. Apoptosis is one particular form of active cell death that is extremely rapid and characterized by auto-destruction o f chromatin, cellular blebbing and condensation, and vesicularization of internal components. The c-myc proto-oncogene encodes an essential component of the cell's proliferative machinery and its deregulated ex pression is implicated in most neoplasms. Intriguingly, c-myc can also act as a potent inducer of apoptosis. Myc-induced apoptosis occurs on ly in cells deprived of growth factors or forcibly arrested with cytos tatic drugs. Myc-induced apoptosis is dependent upon the level at whic h it is expressed and deletion mapping shows that regions of c-Myc req uired for apoptosis overlap with regions necessary for co-transformati on, autoregulation, inhibition of differentiation, transcriptional act ivation and sequence-specific DNA binding. Moreover, induction of apop tosis by c-Myc requires association with c-Myc's heterologous partner, Max. All of this strongly implies that c-Myc drives apoptosis through a transcriptional mechanism: presumably by modulation of target genes . Two simple models can be invoked to explain the induction of apoptos is by c-Myc. One holds that death arises from a conflict in growth sig nals which is generated by the inappropriate or unscheduled expression of c-Myc under conditions that would normally promote growth arrest. In this 'Conflict' model, induction of apoptosis is not a normal funct ion of c-Myc but a pathological manifestation of its deregulation. It thus has significance only for models of carcinogenic progression in w hich myc genes are invariably disrupted. The other model holds that in duction of apoptosis is a normal obligate function of c-Myc which is m odulated by specific survival factors. Thus, every cell that enters th e cycle invokes an obligate abort suicide pathway which must be contin uously suppressed by signals from the immediate cellular environment f or the proliferating cell to survive. Evidence will be presented suppo rting this second 'Dual Signal' model for cell growth and survival, an d its widespread implications will be discussed.