The opposing roles of the Akt and c-Myc signalling pathways in survival from CD95-mediated apoptosis

Expression of the proto-oncogene c-myc stimulates cell proliferation in the presence of the appropriate survival factors and triggers apoptosis in the ir absence; this dual capacity ensures that cell growth is restricted to th e correct paracrine environment and is thereby strictly controlled. Recentl y our laboratory demonstrated that c-Myc-induced apoptosis requires the CD9 5 death receptor pathway and that insulin-like growth factor (IGF-1) signal ling suppresses this killing. To investigate further the links between c-My c and IGF-1 pathways in CD95-induced apoptosis, we examined the effects of c-Myc and a downstream IGF-I survival kinase, Akt, on killing mediated by C D95 and its recruited effector proteins (FADD and caspase-8). Here, we show that c-Myc activation does not exacerbate killing induced by FADD or pro-c aspase-8, which narrows the point at which c-Myc exerts its action downstre am of the interaction of CD95 with its ligand and upstream of FADD. We show further that activated Akt suppresses CD95-induced apoptosis and that Akt exerts its activity at a point downstream of FADD but upstream of caspase-8 . These results restrict the possible mechanisms by which CD95-induced apop tosis is modulated by death signals and survival factors.