Hypoxia up-regulates hypoxia-inducible factor-1alpha transcription by involving phosphatidylinositol 3-kinase and nuclear factor kappaB in pulmonary artery smooth muscle cells
| Autor: | John Hess, Agnes Görlach, Rachida S. BelAiba, Stefanie Schmidt, Christian Zähringer, Thomas Kietzmann, Steve Bonello |
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| Rok vydání: | 2007 |
| Předmět: |
Transcription
Genetic Myocytes Smooth Muscle Biology Mice Phosphatidylinositol 3-Kinases Transcriptional regulation medicine Animals Humans Post-translational regulation RNA Messenger Hypoxia Molecular Biology Protein kinase B Transcription factor PI3K/AKT/mTOR pathway Cells Cultured Base Sequence NF-kappa B Cell Biology Arteries Articles Hypoxia (medical) Hypoxia-Inducible Factor 1 alpha Subunit Molecular biology Up-Regulation Mice Inbred C57BL Hypoxia-inducible factors Signal transduction medicine.symptom Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Molecular biology of the cell. 18(12) |
| ISSN: | 1059-1524 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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