| Autor: |
Pagé EL; Centre de recherche de L'Hôtel-Dieu de Québec, Department of Medicine, Université Laval, Québec, QC, G1R 2J6, Canada., Chan DA, Giaccia AJ, Levine M, Richard DE |
| Jazyk: |
angličtina |
| Zdroj: |
Molecular biology of the cell [Mol Biol Cell] 2008 Jan; Vol. 19 (1), pp. 86-94. Date of Electronic Publication: 2007 Oct 17. |
| DOI: |
10.1091/mbc.e07-06-0612 |
| Abstrakt: |
Hypoxia-inducible factor-1 (HIF-1) is a decisive element for the transcriptional regulation of many genes induced under low oxygen conditions. Under normal oxygen conditions, HIF-1alpha, the active subunit of HIF-1, is hydroxylated on proline residues by specific HIF prolyl-hydroxylases, leading to ubiquitination and degradation by the proteasome. In hypoxia, hydroxylation and ubiquitination are blocked and HIF-1alpha accumulates in cells. Recent studies have shown that in normal oxygen conditions G-protein-coupled receptor agonists, including angiotensin (Ang) II and thrombin, potently induce and activate HIF-1 in vascular smooth muscle cells. The current study identifies HIF-1alpha protein stabilization as a key mechanism for HIF-1 induction by Ang II. We show that hydroxylation on proline 402 is altered by Ang II, decreasing pVHL binding to HIF-1alpha and allowing HIF-1alpha protein to escape subsequent ubiquitination and degradation mechanisms. We show that HIF-1alpha stability is mediated through the Ang II-mediated generation of hydrogen peroxide and a subsequent decrease in ascorbate levels, leading to decreased HIF prolyl-hydroxylase activity and HIF-1alpha stabilization. These findings identify novel and intricate signaling mechanisms involved in HIF-1 complex activation and will lead to the elucidation of the importance of HIF-1 in different Ang II-related cell responses. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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