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Hypoxia up-regulates hypoxia-inducible factor-1alpha transcription by involving phosphatidylinositol 3-kinase and nuclear factor kappaB in pulmonary artery smooth muscle cells.
- Source :
-
Molecular biology of the cell [Mol Biol Cell] 2007 Dec; Vol. 18 (12), pp. 4691-7. Date of Electronic Publication: 2007 Sep 26. - Publication Year :
- 2007
-
Abstract
- 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.
- Subjects :
- Animals
Arteries metabolism
Base Sequence
Cells, Cultured
Humans
Hypoxia genetics
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Mice
Mice, Inbred C57BL
Proto-Oncogene Proteins c-akt
RNA, Messenger genetics
Signal Transduction
Hypoxia metabolism
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Myocytes, Smooth Muscle metabolism
NF-kappa B metabolism
Phosphatidylinositol 3-Kinases metabolism
Transcription, Genetic genetics
Up-Regulation genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1059-1524
- Volume :
- 18
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Molecular biology of the cell
- Publication Type :
- Academic Journal
- Accession number :
- 17898080
- Full Text :
- https://doi.org/10.1091/mbc.e07-04-0391