TRANSLATIONAL CONTROL OF PROGRAMMED CELL-DEATH - EUKARYOTIC TRANSLATION INITIATION-FACTOR 4E BLOCKS APOPTOSIS IN GROWTH-FACTOR-RESTRICTED FIBROBLASTS WITH PHYSIOLOGICALLY EXPRESSED OR DEREGULATED MYC

There is increasing evidence that cell cycle transit is potentially le thal, with survival depending on the activation of metabolic pathways which block apoptosis. However, the identities of those pathways coupl ing cell cycle transit to survival remain undefined, Here we show that the eukaryotic translation initiation factor 4E (eIF4E) can mediate b oth proliferative and survival signaling, Overexpression of eIF4E comp letely substituted for serum or individual growth factors in preservin g the viability of established NIH 3T3 fibroblasts. An eIF4E mutant (S er-53 changed to Ala) defective in mediating its growth-factor-regulat ed functions was also defective in its survival signaling, Survival si gnaling by enforced expression of eIF4E did not result from autocrine release of survival factors, nor did it lead to increased expression o f the apoptosis antagonists Bcl-2 and Bcl-X(L). In addition, the execu tion apparatus of the apoptotic response in eIF4E-overexpressing cells was found to be intact, Increased expression of eIF4E was sufficient to inhibit apoptosis in serum-restricted primary fibroblasts with enfo rced expression of Myc. In contrast, activation of Ha-Ras, which is re quired for eIF4E proliferative signaling, did not suppress Myc-induced apoptosis. These data suggest that the eIF4E-activated pathways leadi ng to survival and cell cycle progression are distinct. This dual sign aling of proliferation and survival might be the basis for the potency of eIF4E as an inducer of neoplastic transformation.