Induction of Hypoxia-inducible Factor-1α by Transcriptional and Translational Mechanisms

Elisabeth L. Pagé, Geneviève A. Robitaille, Jacques Pouysségur, Darren E. Richard
2002 Journal of Biological Chemistry  
Hypoxia-inducible factor-1 (HIF-1) regulates the transcription of many genes induced by low oxygen conditions. Recent studies have demonstrated that non-hypoxic stimuli can also activate HIF-1 in a cell-specific manner. Here, we define two key mechanisms that are implicated in increasing the active subunit of the HIF-1 complex, HIF-1␣, following the stimulation of vascular smooth muscle cells (VSMC) with angiotensin II (Ang II). We show that, in contrast to hypoxia, the induction of HIF-1␣ by
more » ... g II in VSMC is dependent on active transcription and ongoing translation. We demonstrate that stimulation of VSMC by Ang II strongly increases HIF-1␣ gene expression. The activation of diacylglycerol-sensitive protein kinase C (PKC) plays a major role in the increase of HIF-1␣ gene transcription. We also demonstrate that Ang II relies on ongoing translation to maintain elevated HIF-1␣ protein levels. Ang II increases HIF-1␣ translation by a reactive oxygen species (ROS)-dependent activation of the phosphatidylinositol 3-kinase pathway, which acts on the 5-untranslated region of HIF-1␣ mRNA. These results establish that the non-hypoxic induction of the HIF-1 transcription factor via vasoactive hormones (Ang II and thrombin) is triggered by a dual mechanism, i.e. a PKC-mediated transcriptional action and a ROS-dependent increase in HIF-1␣ protein expression. Elucidation of these signaling pathways that up-regulate the vascular endothelial growth factor (VEGF) could have a strong impact on different aspects of vascular biology.
doi:10.1074/jbc.m209114200 pmid:12379645 fatcat:udvb4w3mxfdrtaaggdtw4id72e