Institute of Molecular Medicine, Peking University, Beijing 100871, China.
J Biol Chem. 2011 Jun 24;286(25):22699-705. doi: 10.1074/jbc.M111.237024. Epub 2011 May 2.
The amount of available hypoxia-inducible factor (HIF)-1α has been considered to be largely a consequence of post-translational modification by multiple ubiquitin-proteasome pathways. However, the role of transcriptional regulation of HIF-1α is less certain, and the mechanisms of transcriptional regulation of HIF-1α require further investigation. Here we report that related transcriptional enhancer factor-1 (RTEF-1), a member of the TEF transcriptional factor family, transcriptionally regulates the HIF-1α gene under normoxic and hypoxic conditions. The expression of HIF-1α mRNA was decreased in endothelial cells in which RTEF-1 was knocked down with siRNA. Sequential deletional analysis of the HIF-1α promoter revealed that the MCAT-like element in the HIF-1α promoter was essential for HIF-1α transcription. Binding of RTEF-1 to the MCAT-like element was confirmed by ChIP. Treatment of endothelial cells with a HIF-1 inhibitor resulted in retardation of RTEF-1-induced proliferation and tube formation. Moreover, increased HIF-1α expression was observed in transgenic mice expressing RTEF-1 under the VE-cadherin promoter (VE-Cad/RTEF-1). VE-Cad/RTEF-1 mice subjected to hindlimb ischemia demonstrated increased levels of HIF-1α, accelerated recovery of blood flow, and increased capillary density compared with littermate controls. These results identify RTEF-1 as a regulator of HIF-1α transcription, which results in up-regulation of HIF-1α and acceleration of recovery from ischemia.
缺氧诱导因子 (HIF)-1α 的含量在很大程度上被认为是多种泛素蛋白酶体途径对其进行翻译后修饰的结果。然而，HIF-1α 的转录调控作用尚不确定，HIF-1α 的转录调控机制需要进一步研究。在这里，我们报告称，TEF 转录因子家族的成员相关转录增强因子-1（RTEF-1）在常氧和缺氧条件下转录调控 HIF-1α 基因。用 siRNA 敲低内皮细胞中的 RTEF-1 后，HIF-1α mRNA 的表达降低。对 HIF-1α 启动子的连续缺失分析表明，HIF-1α 启动子中的 MCAT 样元件对于 HIF-1α 转录是必需的。ChIP 证实了 RTEF-1 与 MCAT 样元件的结合。用 HIF-1 抑制剂处理内皮细胞可导致 RTEF-1 诱导的增殖和管状形成的延迟。此外，在 VE-钙粘蛋白启动子（VE-Cad/RTEF-1）下表达 RTEF-1 的转基因小鼠中观察到 HIF-1α 表达增加。与同窝对照相比，后肢缺血的 VE-Cad/RTEF-1 小鼠表现出更高水平的 HIF-1α、更快的血流恢复和更高的毛细血管密度。这些结果表明 RTEF-1 是 HIF-1α 转录的调节剂，导致 HIF-1α 的上调并加速从缺血中恢复。
