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首页> 外文期刊>American Journal of Physiology >Hypoxia induces epithelial amphiregulin gene expression in a CREB-dependent manner.
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Hypoxia induces epithelial amphiregulin gene expression in a CREB-dependent manner.

机译：缺氧以CREB依赖性方式诱导上皮两性调节蛋白基因表达。

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摘要

Hypoxia occurs during a number of conditions in which altered epithelial proliferation is critical, including tumor development. Microarray analysis of colon-derived epithelial cells revealed a hypoxia-dependent increase in the expression of amphiregulin, an EGF receptor (EGFR) ligand that activates epithelial proliferation and has been associated with the development of colonic tumors. Amphiregulin expression was also induced in tissues from mice exposed to whole animal hypoxia. The hypoxic upregulation of amphiregulin was independent of the classic transcriptional response mediated via hypoxia-inducible factor (HIF)-1alpha. Transfection of HeLa cells with truncated amphiregulin promoter reporter constructs revealed that a 37-bp segment upstream from the TATA box retained hypoxic sensitivity. This sequence contains an evolutionarily conserved cAMP response element (CRE) that constitutively binds the CRE binding protein (CREB). Deletion of the CRE abolished sensitivity to hypoxia. Thus hypoxia promotesintestinal epithelial amphiregulin expression in a CRE-dependent manner, an event that may contribute to increased proliferation. These data also further support a role for CREB as an HIF-independent hypoxia-responsive transcription factor in the regulation of intestinal epithelial gene expression.
机译：缺氧发生在许多情况下，其中上皮细胞增殖的改变至关重要，包括肿瘤的发展。结肠来源的上皮细胞的微阵列分析显示，缺氧依赖性的两性调节蛋白表达增加，这是一种激活上皮细胞增殖的EGF受体（EGFR）配体，与结肠肿瘤的发生有关。在暴露于整个动物缺氧的小鼠组织中也诱导了双调蛋白表达。 ampregregulin的缺氧上调独立于通过缺氧诱导因子（HIF）-1alpha介导的经典转录反应。用截短的双调蛋白启动子报告子构建体转染HeLa细胞显示，TATA盒上游的37 bp片段保留了低氧敏感性。该序列包含组成性结合CRE结合蛋白（CREB）的进化保守的cAMP反应元件（CRE）。 CRE的删除消除了对缺氧的敏感性。因此，缺氧以CRE依赖的方式促进肠上皮两性调节蛋白的表达，这一事件可能有助于增加增殖。这些数据还进一步支持了CREB作为独立于HIF的缺氧应答转录因子在肠上皮基因表达调控中的作用。

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