SUPPRESSION OF C-MYC-INDUCED APOPTOSIS BY RAS SIGNALING THROUGH PI(3)K AND PKB

The viability of vertebrate cells depends on survival factors which ac tivate signal transduction pathways that suppress apoptosis. Defects i n anti-apoptotic signalling pathways are implicated in many pathologie s including cancer, in which apoptosis induced by deregulated oncogene s must be forestalled for a tumour to become established. Phosphatidyl inositol-3-kinase (PI(3)K) is involved in the intracellular signal tra nsduction of many receptors and has been implicated in the transductio n of survival signals in neuronal cells(1). We therefore examined the role of PI(3)K, its upstream effector Ras(2), and its putative downstr eam protein kinase effecters PKB/Akt(3,4) and p70(S6K) (ref. 5) in the modulation of apoptosis induced in fibroblasts by the oncoprotein c-M yc. Here we show that Ras activation of PI(3)K suppresses c-Myc-induce d apoptosis through the activation of PKB/Akt but not p70(S6K). Howeve r, we also found that Ras is an effective promoter of apoptosis, throu gh the Raf pathway. Thus Ras activates contradictory intracellular pat hways that modulate cell viability. Induction of apoptosis by Ras may be an important factor in limiting the expansion of somatic cells that sustain oncogenic ras mutations.