Hypoxia Up-Regulates Hypoxia-Inducible Factor-1α Transcription by Involving Phosphatidylinositol 3-Kinase and Nuclear Factor κB in Pulmonary Artery Smooth Muscle Cells
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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.
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HIF1 in humans responds transcriptionally to hypoxia, but its activity is primarily post-translationally regulated.
“However, HIF1 in humans also responds transcriptionally to hypoxia, but its activity is primarily post-translationally regulated [62],[63].”
From A Sterol-Regulatory Element Binding Protein Is Required for Cell Polarity, Hypoxia Adaptation, Azole Drug Resistance, and Virulence in Aspergillus fumigatus (2008) · cites this paper as [63]
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- Authors
- BelAiba, R. S., Bonello, S., Zähringer, C., Schmidt, S., Hess, J., Kietzmann, T., & Görlach, A.
- Affiliations
- Deutsches Herzzentrum München (DE)
- University of Kaiserslautern (DE)
- Venue
- Molecular Biology of the Cell
- Published
- 2007-12
- Volume
- 18
- Issue
- 12
- Pages
- 4691-4697
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC2096613
- OpenAlex
- W2002008095
- Cited by
- 423
- References
- 50
- Citations by year
- 2026: 15 · 2025: 18 · 2024: 13 · 2023: 27 · 2022: 16 · 2021: 24 · 2020: 17 · 2019: 20 · 2018: 26 · 2017: 28 · 2016: 24 · 2015: 26 · 2014: 24 · 2013: 33 · 2012: 11
- FWCI
- 9.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Biology of the Cell (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Fondation Leducq
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- hypoxia, hypoxia-inducible factor-1α, pulmonary artery smooth muscle cells, PI3K/Akt signaling, NF-κB, NF-kappaB binding site, transcriptional regulation
- MeSH terms
- Animals, Hypoxia, Arteries, Base Sequence, Cells, Cultured, Humans, Mice, Inbred C57BL, RNA, Messenger, Transcription, Genetic, Signal Transduction, Up-Regulation, NF-kappa B, Phosphatidylinositol 3-Kinases, Myocytes, Smooth Muscle, Proto-Oncogene Proteins c-akt, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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