School of Medicine and Medical Science and UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
Mol Cell Biol. 2011 Oct;31(19):4087-96. doi: 10.1128/MCB.01276-10. Epub 2011 Aug 1.
The hypoxia-inducible factor (HIF) is a key regulator of the transcriptional response to hypoxia. While the mechanism underpinning HIF activation is well understood, little is known about its resolution. Both the protein and the mRNA levels of HIF-1α (but not HIF-2α) were decreased in intestinal epithelial cells exposed to prolonged hypoxia. Coincident with this, microRNA (miRNA) array analysis revealed multiple hypoxia-inducible miRNAs. Among these was miRNA-155 (miR-155), which is predicted to target HIF-1α mRNA. We confirmed the hypoxic upregulation of miR-155 in cultured cells and intestinal tissue from mice exposed to hypoxia. Furthermore, a role for HIF-1α in the induction of miR-155 in hypoxia was suggested by the identification of hypoxia response elements in the miR-155 promoter and confirmed experimentally. Application of miR-155 decreased the HIF-1α mRNA, protein, and transcriptional activity in hypoxia, and neutralization of endogenous miR-155 reversed the resolution of HIF-1α stabilization and activity. Based on these data and a mathematical model of HIF-1α suppression by miR-155, we propose that miR-155 induction contributes to an isoform-specific negative-feedback loop for the resolution of HIF-1α activity in cells exposed to prolonged hypoxia, leading to oscillatory behavior of HIF-1α-dependent transcription.
缺氧诱导因子 (HIF) 是对缺氧反应的转录调节的关键调节剂。虽然 HIF 激活的机制已被充分理解，但对其解决机制知之甚少。在暴露于长时间缺氧的肠上皮细胞中，HIF-1α 的蛋白和 mRNA 水平均降低（但 HIF-2α 没有）。与此巧合的是，miRNA（miRNA）芯片分析显示出多种缺氧诱导的 miRNA。其中之一是 miRNA-155（miR-155），其被预测靶向 HIF-1α mRNA。我们证实了 miR-155 在培养细胞和暴露于缺氧的小鼠肠组织中的缺氧上调。此外，通过鉴定 miR-155 启动子中的缺氧反应元件，并通过实验证实，HIF-1α 在缺氧诱导 miR-155 中的作用得到了证实。miR-155 的应用降低了缺氧条件下 HIF-1α mRNA、蛋白和转录活性，而内源性 miR-155 的中和作用则逆转了 HIF-1α 稳定和活性的解决。基于这些数据和 miR-155 抑制 HIF-1α 的数学模型，我们提出 miR-155 的诱导有助于在长时间暴露于缺氧的细胞中 HIF-1α 活性的同型特异性负反馈回路，导致 HIF-1α 依赖性转录的振荡行为。
