Functional Interference between Hypoxia and Dioxin Signal Transduction Pathways: Competition for Recruitment of the Arnt Transcription Factor
Open accessAbstract
Hypoxia-inducible factor 1 alpha (HIF-1 alpha) and the intracellular dioxin receptor mediate hypoxia and dioxin signalling, respectively. Both proteins are conditionally regulated basic helix-loop-helix (bHLH) transcription factors that, in addition to the bHLH motif, share a Per-Arnt-Sim (PAS) region of homology and form heterodimeric complexes with the common bHLH/PAS partner factor Arnt. Here we demonstrate that HIF-1 alpha required Arnt for DNA binding in vitro and functional activity in vivo. Both the bHLH and PAS motifs of Arnt were critical for dimerization with HIF-1 alpha. Strikingly, HIF-1 alpha exhibited very high affinity for Arnt in coimmunoprecipitation assays in vitro, resulting in competition with the ligand-activated dioxin receptor for recruitment of Arnt. Consistent with these observations, activation of HIF-1 alpha function in vivo or overexpression of HIF-1 alpha inhibited ligand-dependent induction of DNA binding activity by the dioxin receptor and dioxin receptor function on minimal reporter gene constructs. However, HIF-1 alpha- and dioxin receptor-mediated signalling pathways were not mutually exclusive, since activation of dioxin receptor function did not impair HIF-1 alpha-dependent induction of target gene expression. Both HIF-1 alpha and Arnt mRNAs were expressed constitutively in a large number of human tissues and cell lines, and these steady-state expression levels were not affected by exposure to hypoxia. Thus, HIF-1 alpha may be conditionally regulated by a mechanism that is distinct from induced expression levels, the prevalent model of activation of HIF-1 alpha function. Interestingly, we observed that HIF-1 alpha was associated with the molecular chaperone hsp90. Given the critical role of hsp90 for ligand binding activity and activation of the dioxin receptor, it is therefore possible that HIF-1 alpha is regulated by a similar mechanism, possibly by binding an as yet unknown class of ligands.
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ARNT dimerizes with HIFs and is essential for hypoxia response, glucose metabolism, blood cell development, and angiogenesis.
“Notably, ARNT is now known to dimerize with HIFs, and through these interactions is essential in biological processes including the hypoxia response, glucose metabolism, blood cell development, and angiogenesis (Gradin et al., 1996; McIntosh et al., 2010).”
From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Gradin et al., 1996
The Results and Discussion (page numbers unavailable) demonstrate that ARNT dimerizes with HIF-1α and is required for HIF-1α-mediated hypoxic gene regulation. They examine genes relevant to glucose metabolism, blood cell development, and angiogenesis, but do not establish that ARNT is essential for those biological processes as a whole; VEGF induction was only partially impaired when ARNT was deficient. The paper also tests HIF-1α, not HIFs generally. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHsp90 can stabilize HIF-1α against non-VHL dependent degradation.
“In addition, Hsp90 can stabilize HIF-1α against its non-VHL dependent degradation.”
From HIF-1α pathway: role, regulation and intervention for cancer therapy (2015) · cites this paper as [43]
The “Mechanism of activation of HIF-1α” section reports that HIF-1α associates with hsp90 in vitro and speculates that hsp90 may help maintain a repressed form of HIF-1α. It does not establish that hsp90 prevents HIF-1α degradation or identify a non-VHL-dependent degradation pathway. Page numbers were not available in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredMice homozygous for AhrTer383 are a phenocopy of null mice for the DV endpoint and may help identify other ARNT-dependent signaling events mediated by partners such as HIFs.
“Finally, it is important to note that mice homozygous for this allele are a phenocopy of null mice for the DV endpoint and may be useful in identifying other ARNT dependent signaling events mediated by partners such as hypoxia inducible factors (HIFs) (Chan et al., 1999; Gradin et al., 1996; McIntosh et al., 2010).”
From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Gradin et al., 1996
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“Notably, ARNT is now known to dimerize with HIFs, and through these interactions are essential in biological processes including the hypoxia response, glucose metabolism, blood cell development, and angiogenesis (Gradin et al. 1996; McIntosh et al. 2010).”
Background
- Authors
- Gradin, K., McGuire, J., Wenger, R. H., Kvietikova, I., Whitelaw, M. L., Toftgård, R., Tora, L., Gassmann, M., & Poellinger, L.
- Affiliations
- Karolinska Institutet (SE)
- University of Zurich (CH)
- The University of Adelaide (AU)
- Institut de Géneétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM, F-67404 Illkirch Cedex, France
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1996-10-01
- Volume
- 16
- Issue
- 10
- Pages
- 5221-5231
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC231522
- OpenAlex
- W2133193034
- Cited by
- 470
- References
- 4
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 2 · 2023: 10 · 2022: 23 · 2021: 9 · 2020: 7 · 2019: 11 · 2018: 9 · 2017: 15 · 2016: 11 · 2015: 15 · 2014: 13 · 2013: 6 · 2012: 13
- FWCI
- 12.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Cancerfonden
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Keywords
- hypoxia-inducible factor-1α, aryl hydrocarbon receptor, ARNT, PAS domain, bHLH domain, signaling crosstalk, HSP90, DNA binding, ligand-independent transcriptional activation
- MeSH terms
- Cobalt, Dioxins, DNA-Binding Proteins, Female, HeLa Cells, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Luciferases, Male, Nuclear Proteins, Organ Specificity, Recombinant Fusion Proteins, RNA, Messenger, Transcription Factors, Transfection, Tumor Cells, Cultured, Signal Transduction, Cell Hypoxia, Mutagenesis, Sequence Deletion, Genes, Reporter, Helix-Loop-Helix Motifs, Receptors, Aryl Hydrocarbon, HSP90 Heat-Shock Proteins, Cytochrome P-450 CYP1A1, Aryl Hydrocarbon Receptor Nuclear Translocator, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit
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