Hypoxia up-regulates hypoxia-inducible factor-1α transcription by involving phosphatidylinositol 3-kinase and nuclear factor κB in pulmonary artery smooth muscle cells

Rachida S. BelAiba, Steve Bonello, Christian Zähringer, Stefanie Schmidt, John Hess, Thomas Kietzmann, Agnes Görlach

Research output: Contribution to journalArticlepeer-review

360 Scopus citations

Abstract

The oxygen sensitive α-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-1α by hypoxia is well known, its transcriptional regulation by hypoxia is still under debate. We, therefore, investigated the regulation of HIF-1α mRNA in response to hypoxia in pulmonary artery smooth muscle cells. Hypoxia rapidly enhanced HIF-1α mRNA levels and HIF-1α 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-1α mRNA and HIF-1α promoter activity, suggesting involvement of a PI3K/AKT-regulated transcription factor. Interestingly, hypoxia also induced nuclear factor-κB (NFκB) nuclear translocation and activity. In line, expression of the NFκB subunits p50 and p65 enhanced HIF-1α mRNA levels, whereas blocking of NFκB by an inhibitor of nuclear factor-κB attenuated HIF-1α mRNA induction by hypoxia. Reporter gene assays revealed the presence of an NFκB site within the HIF-1α promoter, and mutation of this site abolished induction by hypoxia. In line, gel shift analysis and chromatin immunoprecipitation confirmed binding of p50 and p65 NFκB subunits to the HIF-1α promoter under hypoxia. Together, these findings provide a novel mechanism in which hypoxia induces HIF-1α mRNA expression via the PI3K/AKT pathway and activation of NFκB.

Original languageEnglish
Pages (from-to)4691-4697
Number of pages7
JournalMolecular Biology of the Cell
Volume18
Issue number12
DOIs
StatePublished - Dec 2007

Fingerprint

Dive into the research topics of 'Hypoxia up-regulates hypoxia-inducible factor-1α transcription by involving phosphatidylinositol 3-kinase and nuclear factor κB in pulmonary artery smooth muscle cells'. Together they form a unique fingerprint.

Cite this