Translational control of the antiapoptotic function of Ras.
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 apoptosis, whereas synthesis of proteins mediating apoptosis can occur independently of the cap.
Polunovsky
V A
VA
Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
Gingras
A C
AC
Sonenberg
N
N
Peterson
M
M
Tan
A
A
Rubins
J B
JB
Manivel
J C
JC
Bitterman
P B
PB
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D003001:Cloning, Molecular; D003513:Cycloheximide / Q000494:pharmacology; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D011905:Genes, ras; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008819:Mice, Nude; D010448:Peptide Initiation Factors / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D014162:Transfection; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C499527:Eif4ebp1 protein, mouse; C499526:Eif4ebp1 protein, rat; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; D047908:Intracellular Signaling Peptides and Proteins; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; D003513:Cycloheximide; D018631:ras Proteins; D020123:Sirolimus