Abstract
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.
Highlights
The MAX network of transcription factors is composed of a group of basic helix-loop-helix and leucine-zipper proteins that form heterodimers with the bHLH-Zip protein MAX [1]
We show that the role of c-Myc during cell growth and proliferation is linked to an increase in eukaryotic initiation factor 4F (eIF4F) activity in a feedforward relationship, providing a possible molecular mechanism of cell transformation by c-Myc
RNA extracted from serum-deprived cells at various time points after MycER activation was analyzed by Northern blotting. eukaryotic initiation factor 4E (eIF4E), eIF4AI, and eIF4GI mRNA expression was induced upon MycER activation, but not eIF4AII or eIF4B (Fig. 1A)
Summary
The MAX network of transcription factors is composed of a group of basic helix-loop-helix and leucine-zipper (bHLH-Zip) proteins that form heterodimers with the bHLH-Zip protein MAX [1]. These proteins include the Myc family of activators and the Mad family of repressors. Both Myc and Mad family members bind DNA to E-box sequence motifs (5¶CACGTG3¶ and related sequences), thereby modulating the transcriptional activity of genes that play critical roles in the regulation of cell growth, proliferation, differentiation, and apoptosis [1]. In contrast to c-Myc, Mad protein members are expressed in differentiating and resting cells and are negative regulators of cell growth. Mad inhibits cell cycle progression, apoptosis, and transformation of tumor cells [2]
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