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

Mol Biol Cell. 2007 Dec;18(12):4691-7. doi: 10.1091/mbc.e07-04-0391. Epub 2007 Sep 26.


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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arteries / metabolism
  • Base Sequence
  • Cells, Cultured
  • Humans
  • Hypoxia / genetics
  • Hypoxia / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Smooth Muscle / metabolism*
  • NF-kappa B / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger / genetics
  • Signal Transduction
  • Transcription, Genetic / genetics*
  • Up-Regulation / genetics*


  • Hypoxia-Inducible Factor 1, alpha Subunit
  • NF-kappa B
  • RNA, Messenger
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt