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Originally published as MBC in Press, 10.1091/mbc.E07-04-0391 on September 26, 2007

Vol. 18, Issue 12, 4691-4697, December 2007

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Hypoxia Up-Regulates Hypoxia-Inducible Factor-1{alpha} Transcription by Involving Phosphatidylinositol 3-Kinase and Nuclear Factor {kappa}B in Pulmonary Artery Smooth Muscle Cells

Rachida S. BelAiba*, Steve Bonello*, Christian Zähringer*, Stefanie Schmidt*, John Hess*, Thomas Kietzmann{dagger}, and Agnes Görlach*

*Experimental Pediatric Cardiology, Department of Pediatric Cardiology and Congenital Heart Disease, German Heart Center Munich at the Technical University Munich, D-80636 Munich, Germany; and {dagger}Faculty of Chemistry/Biochemistry, University of Kaiserslautern, D-67663 Kaiserslautern, Germany

Submitted April 30, 2007; Revised August 7, 2007; Accepted September 17, 2007
Monitoring Editor: Carl-Henrik Heldin

The oxygen sensitive {alpha}-subunit of the hypoxia-inducible factor-1 (HIF-1) is a major trigger of the cellular response to hypoxia. Although the posttranslational regulation of HIF-1{alpha} by hypoxia is well known, its transcriptional regulation by hypoxia is still under debate. We, therefore, investigated the regulation of HIF-1{alpha} mRNA in response to hypoxia in pulmonary artery smooth muscle cells. Hypoxia rapidly enhanced HIF-1{alpha} mRNA levels and HIF-1{alpha} promoter activity. Furthermore, inhibition of the phosphatidylinositol 3-kinase (PI3K)/AKT but not extracellular signal-regulated kinase 1/2 pathway blocked the hypoxia-dependent induction of HIF-1{alpha} mRNA and HIF-1{alpha} promoter activity, suggesting involvement of a PI3K/AKT-regulated transcription factor. Interestingly, hypoxia also induced nuclear factor-{kappa}B (NF{kappa}B) nuclear translocation and activity. In line, expression of the NF{kappa}B subunits p50 and p65 enhanced HIF-1{alpha} mRNA levels, whereas blocking of NF{kappa}B by an inhibitor of nuclear factor-{kappa}B attenuated HIF-1{alpha} mRNA induction by hypoxia. Reporter gene assays revealed the presence of an NF{kappa}B site within the HIF-1{alpha} promoter, and mutation of this site abolished induction by hypoxia. In line, gel shift analysis and chromatin immunoprecipitation confirmed binding of p50 and p65 NF{kappa}B subunits to the HIF-1{alpha} promoter under hypoxia. Together, these findings provide a novel mechanism in which hypoxia induces HIF-1{alpha} mRNA expression via the PI3K/AKT pathway and activation of NF{kappa}B.


This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E07-04-0391) on September 26, 2007.

Address correspondence to: Agnes Görlach (goerlach{at}dhm.mhn.de).




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