Contribution of HIF-1α in 4E-BP1 Gene Expression
Contribution of HIF-1α in 4E-BP1 Gene Expression
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DOI：
10.1158/1541-7786.mcr-12-0095
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发表时间：
2013-01-01
影响因子：
5.2
通讯作者：
Pyronnet, Stephane
中科院分区：
文献类型：
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作者：
Azar, Rania;Lasfargues, Charline;Pyronnet, Stephane
真核翻译起始因子 4E (eIF4E) 对于加帽 mRNA 翻译成蛋白质是必需的。然而，帽依赖性 mRNA 翻译可被 eIF4E 结合蛋白 1 (4E-BP1) 抑制。 4E-BP1 的低磷酸化形式确实隔离了 eIF4E，从而阻断翻译起始和随后的蛋白质合成。不同的报道表明，除了低磷酸化之外，4E-BP1的功能也可以在蛋白质表达水平上受到调节。这是接触抑制细胞或暴露于缺氧的细胞中的情况。然而，在这些条件下导致 4E-BP1 蛋白积累的分子机制仍然未知。在本研究中，我们发现4E-BP1基因启动子含有缺氧反应元件（HRE），通过缺氧诱导因子1α（HIF-1α）转录因子介导4E-BP1基因上调。基因报告分析随后表明，4E-BP1 基因启动子中此类 HRE 的存在参与了接触抑制细胞和暴露于缺氧的细胞中 4E-BP1 的积累。我们还发现，TGF-β依赖性转录因子SMAD4与HIF-1α配合，在缺氧条件下完全激活4E-BP1基因转录。因此，这些数据表明 HIF-1 α 在不同条件下有助于 4E-BP1 基因表达。摩尔癌症研究中心； 11(1)； 54-61。 (c) 2012 年 AACR。
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-1 alpha) 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-beta-dependent transcription factor SMAD4 cooperates with HIF-1 alpha to fully activate 4E-BP1 gene transcription under hypoxia. These data therefore suggest that HIF-1 alpha contributes to 4E-BP1 gene expression under different conditions. Mol Cancer Res; 11(1); 54-61. (c) 2012 AACR.