Translational control of the antiapoptotic function of Ras

Vitaly A Polunovsky, A. C. Gingras, N. Sonenberg, M. Peterson, A. Tan, Jeff B Rubins, J. C. Manivel, Peter B Bitterman

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

Activated Ras has been shown to provide powerful antiapoptotic signals to cells through well defined transcriptional and post- translational pathways, whereas translational control as a mechanism of Ras survival signaling remains unexplored. Here we show a direct relationship between assembly of the cap-dependent translation initiation apparatus and suppression of apoptosis by oncogenic Ras in vitro and in vivo. Decreasing protein synthesis with rapamycin, which is known to inhibit cap-dependent translation, increases the susceptibility of Ras-transformed fibroblasts to cytostatic drug-induced apoptosis. In contrast, suppressing global protein synthesis with equipotent concentrations of cycloheximide actually prevents apoptosis. Enforced expression of the cap-dependent translational repressor, the eukaryotic translation initiation factor (eIF) 4E-binding protein (4E-BPI), sensitizes fibroblasts to apoptosis in a manner strictly dependent on its ability to sequester eIF4E from a translationally active complex with eIF4GI and the co-expression of oncogenic Ras. Ectopic expression of 4E-BP1 also promotes apoptosis of Ras-transformed cells injected into immunodeficient mice and markedly diminishes their tumorigenicity. These results establish that eIF4E-dependent protein synthesis is essential for survival of fibroblasts bearing oncogenic Ras and support the concept that activation of cap-dependent translation by extracellular ligands or intrinsic survival signaling molecules suppresses apoptosls, whereas synthesis of proteins mediating apoptosis can occur independently of the cap.

Original languageEnglish (US)
Pages (from-to)24776-24780
Number of pages5
JournalJournal of Biological Chemistry
Volume275
Issue number32
DOIs
StatePublished - Aug 11 2000

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