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

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.

Differential expression of Myc1 and Myc2 isoforms in cells transformed by eIF4E: evidence for internal ribosome repositioning in the human c-myc 5′UTR

“…The fact that the translation of cmyc is highly dependent on eIF4E is also inferred by its activation upon stimulation of the FRAP/mTOR pathway, which leads to the dissociation of the inhibitory proteins, 4E-BPs, from eIF4E (Mendez et al, 1997). This was recently con®rmed by a group who initially postulated the existence of the IRES in c-myc (West et al, 1998).…”

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

“…Phosphoinositide 3-kinase (PI3K) and the downstream Akt/mammalian target of rapamycin (mTOR) pathway have essential roles in modulating cellular functions, activating molecules like ribosomal protein S6 kinase and the eukaryotic translation initiation factor 4E (eIF4E)-binding protein (4E-BP1), which contribute to the regulation of cell size, proliferation, and survival. 1,2 Therefore, the Akt/mTOR pathway is regarded as oncogenic and has the potential to be a therapeutic target. Several previous studies have demonstrated activation of the Akt/mTOR pathway and its contribution to cell survival and proliferation in SS cell lines [3][4][5][6] as well as the effects of the clinical application of therapeutic agents targeting mTOR in soft tissue sarcoma (STS).…”

Members of the poly (rC) binding protein family stimulate the activity of the c-myc internal ribosome entry segment in vitro and in vivo

“…It is not surprising therefore that the expression of c-myc is controlled at multiple levels including transcription, protein stability, RNA stability and translation (Eisenman, 2001). The translational regulation of c-myc is complex and the synthesis of this protein can be initiated via two mechanisms (Nanbru et al, 1997;Stoneley et al, 1998;West et al, 1998). c-myc mRNA translation initiation can occur by cap-dependent scanning, which requires the binding of the multimeric complex eIF4F (which is comprised of the cap-binding protein eIF4E, the DEAD-box helicase eIF4A and the scaffold protein eIF4G) to the 7-methyl-G cap structure of the mRNA, followed by recruitment of the 40S ribosomal subunit, and scanning to the first AUG codon, which is in an adequate context (Gray and Wickens, 1998).…”