Translational control of the antiapoptotic function of Ras

Activated Ras has been shown to provide powerful antiapoptotic signals to c ells through well defined transcriptional and post- translational pathways, whereas translational control as a mechanism of Ras survival signaling rem ains unexplored, Here we show a direct relationship between assembly of the cap-dependent translation initiation apparatus and suppression of apoptosi s by oncogenic Ras in vitro and in vice. Decreasing protein synthesis with rapamycin, which is known to inhibit cap-dependent translation, increases t he susceptibility of Ras-transformed fibroblasts to cytostatic drug-induced apoptosis, In contrast, suppressing global protein synthesis with equipote nt concentrations of cycloheximide actually prevents apoptosis. Enforced ex pression of the cap-dependent translational repressor, the eukaryotic trans lation initiation factor (eIF) 4E-binding protein (4E-BPI), sensitizes fibr oblasts to apoptosis in a manner strictly dependent on its ability to seque ster eIF4E from a translationally active complex with eIF4GI and the co-exp ression of oncogenic Ras, Ectopic expression of 4E-BP1 also promotes apopto sis of Ras-transformed cells injected into immunodeficient mice and markedl y diminishes their tumorigenicity, These results establish that eIF4E-depen dent protein synthesis is essential for survival of fibroblasts bearing onc ogenic Ras and support the concept that activation of cap-dependent transla tion by extracellular ligands or intrinsic survival signaling molecules sup presses apoptosis, whereas synthesis of proteins mediating apoptosis can oc cur independently of the cap.