Contribution of HIF-1α in 4E-BP1 Gene Expression

Abstract

The eukaryotic translation initiation factor 4E (eIF4E) is necessary for the translation of capped mRNAs into proteins. Cap-dependent mRNA translation can be however inhibited by the eIF4E-binding protein 1 (4E-BP1). The hypophosphorylated forms of 4E-BP1 indeed sequester eIF4E and thus block translation initiation and consequent protein synthesis. Different reports indicate that, in addition to hypophosphorylation, 4E-BP1 function can be also regulated at the level of protein expression. This is the case in contact-inhibited cells or in cells exposed to hypoxia. The molecular mechanisms responsible for 4E-BP1 protein accumulation in these conditions remain however unknown. In the present study, we found that 4E-BP1 gene promoter contains a hypoxia-responsive element (HRE) that mediates 4E-BP1 gene upregulation via the hypoxia-inducible factor-1 alpha (HIF-1a) transcription factor. Gene reporter assays then revealed that the presence of such HRE in the promoter of 4E-BP1 gene is involved in 4E-BP1 accumulation in contact-inhibited cells and in cells exposed to hypoxia. We also reveal that the TGF-b-dependent transcription factor SMAD4 cooperates with HIF-1a to fully activate 4E-BP1 gene transcription under hypoxia. These data therefore suggest that HIF-1a contributes to 4E-BP1

Deep computational analysis of human cancer and non-cancer tissues details dysregulation of eIF4F components and their interactions in human cancers

“…The constant 1:1 ratio for EIF4G1:EIF4A1 and 8:1 for EIF4G1:EIF4E in healthy tissues confirm a previous report that transcription of EIF4F subunits for CDTI is highly coordinated (Lin et al, 2008). Furthermore, the EIF4E promoter contains hypoxia-responsive elements (HREs) that can be directly regulated by HIF1α under hypoxic conditions (Azar et al, 2013;Yi et al, 2013). Since HREs overlap the E-box motifs in EIF4E promoter, c-Myc and HIF1α compete for the transcription regulation of EIF4E (Gordan et al, 2007), which may perturb the coordinated transcription between EIF4G1 and EIF4E.…”

Eukaryotic Translation Initiation Factor 4E Is a Feed-Forward Translational Coactivator of Transforming Growth Factor β Early Protransforming Events in Breast Epithelial Cells

“…They also showed that the loss of Smad4, an oncogenic driver in human pancreatic cancer, results in the loss of 4E-BP1 expression and promotes prooncogenic unopposed eIF4E activity, which can be blocked by enforced reexpression of 4E-BP1 (80,81). Intriguingly, HIF1␣ was found to coassociate Smad3/4 and to increase the level of hypoxia-dependent transcription of 4E-BP1, thereby implicating the loss of Smad4 in the failure of pancreatic cancer cells to inhibit protein synthesis during hypoxia (82). Other studies whose findings are consistent with those of our work include those that have observed that overexpression of eIF4E, in concert with certain TGF-␤ pathway single nucleotide polymorphisms in colon cancer cells, is associated with increased TGF-␤ stimulation of adhesion molecule expression (83).…”

Cell type–specific abundance of 4EBP1 primes prostate cancer sensitivity or resistance to PI3K pathway inhibitors

“…Thus, contrary to the expected outcome of increased PI3K signaling resulting in equivalent eIF4E activation across all cell prostate epithelial types, our data uncovered cell-type specificity in 4EBP1 transcript abundance that primes cells for drug sensitivity or resistance. In the future, it will be interesting to determine the molecular basis for the increased 4EBP1 expression in luminal epithelial cells compared to basal epithelial cells and whether these differences arise from transcription factor promoter binding (26, 27), chromatin remodeling, or mRNA degradation rates.…”