Translational control of the antiapoptotic function of Ras

J Biol Chem. 2000 Aug 11;275(32):24776-80. doi: 10.1074/jbc.M001938200.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Apoptosis / physiology*
  • Carrier Proteins*
  • Cell Cycle Proteins
  • Cell Line, Transformed
  • Cell Transformation, Neoplastic*
  • Cloning, Molecular
  • Cycloheximide / pharmacology
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factors
  • Fibroblasts / metabolism
  • Gene Expression Regulation* / drug effects
  • Genes, ras*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Nude
  • Peptide Initiation Factors / metabolism*
  • Phosphoproteins / metabolism*
  • Protein Biosynthesis* / drug effects
  • Rats
  • Signal Transduction
  • Sirolimus / pharmacology
  • Transfection
  • ras Proteins / genetics*
  • ras Proteins / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Eif4ebp1 protein, mouse
  • Eif4ebp1 protein, rat
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factors
  • Intracellular Signaling Peptides and Proteins
  • Peptide Initiation Factors
  • Phosphoproteins
  • Cycloheximide
  • ras Proteins
  • Sirolimus