Tumor Necrosis Factor-α Causes Accumulation of a Ubiquitinated Form of Hypoxia Inducible Factor-1α through a Nuclear Factor-κB-Dependent Pathway
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Hypoxia-inducible factor-1 (HIF-1) is a regulator of metabolic adaptation to hypoxia. It is now appreciated that HIF-1α accumulation is achieved under normoxic conditions by various factors, such as TNF-α. Here, it was our intention to gain insight into the signaling mechanisms used by TNF-α to stimulate HIF-1α. In tubular LLC-PK 1 or human embryonic kidney cells, TNF-α induced accumulation of HIF-1α protein but not HIF-1α mRNA. Blocking nuclear factor (NF)-κB with sulfasalazine or expression of an IκB superrepressor attenuated HIF-1α accumulation, whereas transfection of active p50/p65-NF-κB subunits mimicked a TNF-α response. Experiments with actinomycin D and cycloheximide also pointed to a transcriptional and translational process in facilitating the TNF-α response. Interestingly, and in contrast to established hypoxic signaling concepts, TNF-α elicited HIF-1α accumulation in a ubiquitinated form that still bound the von Hippel-Lindau (pVHL) protein. These data indicate that HIF-1α accumulation by TNF-α demands the NF-κB pathway, preserves ubiquitination of HIF-1α, and allows the HIF-1α-pVHL interaction.
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Adam17 and Arg2 proteins affect Hif-1α stability and activity by regulating production of tumor necrosis factor α (TNF-α) and nitric oxide, respectively, whereas Mmp3 has key roles in numerous physiological processes.
“The Adam17 and Arg2 proteins affect Hif-1α stability and activity by regulating production of tumor necrosis factor α (TNF-α) 31,32 and nitric oxide, respectively 33,34 , whereas Mmp3 has key roles in numerous physiological processes 35 .”
From The yak genome and adaptation to life at high altitude (2012) · cites this paper as [32]
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- Authors
- Zhou, J., Schmid, T., & Brüne, B.
- Affiliations
- University of Kaiserslautern (DE)
- Venue
- Molecular Biology of the Cell
- Published
- 2003-06
- Volume
- 14
- Issue
- 6
- Pages
- 2216-2225
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC194872
- OpenAlex
- W2171610971
- Cited by
- 177
- References
- 36
- Citations by year
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- FWCI
- 4.23
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular Biology of the Cell (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fonds der Chemischen Industrie
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- TNF-α, hypoxia-inducible factor-1α, NF-κB signaling, ubiquitination, von Hippel-Lindau protein, tubular epithelial cells, sulfasalazine
- MeSH terms
- Humans, Transcription Factors, Transfection, Tumor Necrosis Factor-alpha, NF-kappa B, Ubiquitin, Hypoxia-Inducible Factor 1, alpha Subunit
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