Translational induction of the c-myc oncogene via activation of the FRAP/TOR signalling pathway

Oncogene. 1998 Aug 13;17(6):769-80. doi: 10.1038/sj.onc.1201990.

Abstract

Previous studies on the regulation of c-myc have focused on the transcriptional control of this proto-oncogene. We have investigated the signalling pathways involved under circumstances in which there is a translational upregulation in the levels of c-myc protein. We have demonstrated an up to tenfold serum-dependent increase of c-myc protein levels in Epstein-Barr virus immortalized B-cell lines 2-4 h after disruption of cellular aggregates, which is not accompanied by an equivalent increase in mRNA. Overall protein synthesis rates only increased threefold suggesting that the c-myc message was being selectively translated. We observed increases in the phosphorylation of p70 and p85 S6 kinases and of initiation factor eIF-4E binding protein 1 (4E-BP1) 1-2 h after stimulation, suggesting activation of the FRAP/TOR signalling pathway. The increased phosphorylation of 4E-BP1 led to a decrease in its association with eIF-4E and an increase in its association with the eIF-4G component of the eIF-4F initiation complex. The signalling inhibitors rapamycin and wortmannin blocked the phosphorylation of 4E-BP1 and abolished the translational component of the c-myc response. Our data suggest that dissociation of eIF-4E from 4E-BP1, leading to an increase in the formation of the eIF-4F initiation complex, relieves the translation repression imposed on the c-myc mRNA by its structured 5'UTR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Androstadienes / pharmacology
  • B-Lymphocytes / metabolism
  • Carrier Proteins / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunophilins*
  • Phosphoproteins
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor)*
  • Polyenes / pharmacology
  • Protein Biosynthesis*
  • Proto-Oncogene Proteins c-myc / biosynthesis*
  • Ribosomal Protein S6 Kinases
  • Signal Transduction
  • Sirolimus
  • TOR Serine-Threonine Kinases
  • Wortmannin

Substances

  • Adaptor Proteins, Signal Transducing
  • Androstadienes
  • Carrier Proteins
  • EIF4EBP1 protein, human
  • Phosphoproteins
  • Polyenes
  • Proto-Oncogene Proteins c-myc
  • Phosphotransferases (Alcohol Group Acceptor)
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases
  • Immunophilins
  • Sirolimus
  • Wortmannin