Translational induction of the c-myc oncogene via activation of the FRAP/TOR signalling pathway.
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.
Department of Biochemistry, University of Leicester, UK.
M J
MJ
West
M
M
Stoneley
A E
AE
Willis
D048868:Adaptor Proteins, Signal Transducing; D000730:Androstadienes / Q000494:pharmacology; D001402:B-Lymphocytes / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020104:Immunophilins; D010750:Phosphoproteins; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor); D011090:Polyenes / Q000494:pharmacology; D014176:Protein Biosynthesis; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000077191:Wortmannin
D048868:Adaptor Proteins, Signal Transducing; D000730:Androstadienes; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C000715470:MAS1 protein, human; D010750:Phosphoproteins; D011090:Polyenes; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020104:Immunophilins; D020123:Sirolimus; D000077191:Wortmannin