| Autor: |
Pagé EL; Centre de Recherche de L'Hôtel-Dieu de Québec, Canada., Robitaille GA, Pouysségur J, Richard DE |
| Jazyk: |
angličtina |
| Zdroj: |
The Journal of biological chemistry [J Biol Chem] 2002 Dec 13; Vol. 277 (50), pp. 48403-9. Date of Electronic Publication: 2002 Oct 11. |
| DOI: |
10.1074/jbc.M209114200 |
| Abstrakt: |
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-1alpha, 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-1alpha by Ang II in VSMC is dependent on active transcription and ongoing translation. We demonstrate that stimulation of VSMC by Ang II strongly increases HIF-1alpha gene expression. The activation of diacylglycerol-sensitive protein kinase C (PKC) plays a major role in the increase of HIF-1alpha gene transcription. We also demonstrate that Ang II relies on ongoing translation to maintain elevated HIF-1alpha protein levels. Ang II increases HIF-1alpha translation by a reactive oxygen species (ROS)-dependent activation of the phosphatidylinositol 3-kinase pathway, which acts on the 5'-untranslated region of HIF-1alpha 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-1alpha 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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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