Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation

EMBO J. 1996 Feb 1;15(3):658-64.

Abstract

The immunosuppressant drug rapamycin blocks progression of the cell cycle at the G1 phase in mammalian cells and yeast. Here we show that rapamycin inhibits cap-dependent, but not cap-independent, translation in NIH 3T3 cells. Cap-dependent translation is also specifically reduced in extracts from rapamycin-treated cells, as determined by in vitro translation experiments. This inhibition is causally related to the dephosphorylation and consequent activation of 4E-BP1, a protein recently identified as a repressor of the cap-binding protein, eIF-4E, function. These effects of rapamycin are specific as FK506, a structural analogue of rapamycin, had no effect on either cap-dependent translation or 4E-BP1 phosphorylation. The rapamycin-FK506 binding protein complex is the effector of the inhibition of 4E-BP1 phosphorylation as excess of FK506 over rapamycin reversed the rapamycin-mediated inhibition of 4E-BP1 phosphorylation. Thus, inactivation of eIF-4E is, at least in part, responsible for inhibition of cap-dependent translation in rapamycin-treated cells. Furthermore, these results suggest that 4E-BP1 phosphorylation is mediated by the FRAP/TOR signalling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Carrier Proteins*
  • Cell Cycle Proteins
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factors
  • Immunosuppressive Agents / pharmacology*
  • In Vitro Techniques
  • Mice
  • Peptide Chain Initiation, Translational / drug effects
  • Peptide Initiation Factors / metabolism
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Polyenes / pharmacology*
  • RNA Caps / genetics
  • RNA Caps / metabolism
  • Sirolimus
  • Tumor Cells, Cultured

Substances

  • Carrier Proteins
  • Cell Cycle Proteins
  • Eif4ebp1 protein, mouse
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factors
  • Immunosuppressive Agents
  • Peptide Initiation Factors
  • Phosphoproteins
  • Polyenes
  • RNA Caps
  • Sirolimus