title: 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-1α) 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-β-dependent transcription factor SMAD4 cooperates with HIF-1α to fully activate 4E-BP1 gene transcription under hypoxia. These data therefore suggest that HIF-1α contributes to 4E-BP1 gene expression under different conditions.
authors.affiliation: Institut national de la santé et de la recherche medicale (INSERM) U1037, BP 84225, Toulouse 31432, France.
authors.forename: Rania
authors.initials: R
authors.lastname: Azar
authors.forename: Charline
authors.initials: C
authors.lastname: Lasfargues
authors.forename: Corinne
authors.initials: C
authors.lastname: Bousquet
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pyronnet
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015870:Gene Expression; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D051793:Hypoxia-Inducible Factor 1; D010750:Phosphoproteins