c-Myc and eIF4F are components of a feedforward loop that links transcription and translation.
The Myc/Max/Mad family of transcription factors and the eukaryotic initiation factor 4F (eIF4F) complex play fundamental roles in regulating cell growth, proliferation, differentiation, and oncogenic transformation. eIF4F is involved in the recruitment of ribosomes to mRNAs and is thought to generally be the rate-limiting phase of translation. Here, we show that c-Myc directly activates transcription of the three subunits of eIF4F (eIF4E, eIF4AI, and eIF4GI). These transcriptional effects are mediated through canonical E-boxes (5'CACGTG3') present in the promoters of these genes. In addition, the c-Myc antagonist Mad1 down-regulates the expression of eIF4F subunits. We also show that MycER activation stimulates protein synthesis at the level of translation initiation. Increased eIF4F levels result in stimulation of c-Myc mRNA translation specifically, as assessed by quantitative reverse transcription-PCR. We use a murine model of lymphomagenesis to show the expression of eIF4F subunits is also up-regulated by c-Myc in vivo. Our results suggest the presence of a feedforward loop involving c-Myc and eIF4F that serves to link transcription and translation and that could contribute to the effects of c-Myc on cell proliferation and neoplastic growth.
Lin
Chen-Ju
CJ
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Cencic
Regina
R
Mills
John R
JR
Robert
Francis
F
Pelletier
Jerry
J
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000502:physiology; D039601:Eukaryotic Initiation Factor-4A / Q000235:genetics; D039562:Eukaryotic Initiation Factor-4F / Q000235:genetics / Q000502:physiology*; D039603:Eukaryotic Initiation Factor-4G; D025461:Feedback, Physiological / Q000502:physiology*; D005786:Gene Expression Regulation; D018922:HL-60 Cells; D006801:Humans; D008223:Lymphoma / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D041681:NIH 3T3 Cells; D010446:Peptide Fragments / Q000235:genetics; D010448:Peptide Initiation Factors / Q000235:genetics; D014176:Protein Biosynthesis / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*; D014162:Transfection; D014183:Transplantation, Heterologous
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C491908:Eif4g1 protein, mouse; D039562:Eukaryotic Initiation Factor-4F; D039603:Eukaryotic Initiation Factor-4G; C489427:MYC protein, human; C499479:Mad protein, mouse; D010446:Peptide Fragments; D010448:Peptide Initiation Factors; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D039601:Eukaryotic Initiation Factor-4A