Cross-talk between the Aryl Hydrocarbon Receptor and Hypoxia Inducible Factor Signaling Pathways
Open accessAbstract
The aryl hydrocarbon receptor (AHR) and the alpha-class hypoxia inducible factors (HIF1alpha, HIF2alpha, and HIF3alpha) are basic helix-loop-helix PAS (bHLH-PAS) proteins that heterodimerize with ARNT. In response to 2,3,7,8-tetrachlorodibenzo-p-dioxin, the AHR. ARNT complex binds to "dioxin responsive enhancers" (DREs) and activates genes involved in the metabolism of xenobiotics, e.g. cytochrome P4501A1 (Cyp1a1). The HIF1alpha.ARNT complex binds to "hypoxia responsive enhancers" and activates the transcription of genes that regulate adaptation to low oxygen, e.g. erythropoietin (Epo). We postulated that activation of one pathway would inhibit the other due to competition for ARNT or other limiting cellular factors. Using pathway specific reporters in transient transfection assays, we observed that DRE driven transcription was markedly inhibited by hypoxia and that hypoxia responsive enhancer driven transcription was inhibited by AHR agonists. When we attempted to support this cross-talk model using endogenous loci, we observed that activation of the hypoxia pathway inhibited Cyp1a1 up-regulation, but that activation of the AHR actually enhanced the induction of Epo by hypoxia. To explain this unexpected additivity, we examined the Epo gene and found that its promoter harbors DREs immediately upstream of its transcriptional start site. These experiments outline conditions where inhibitory and additive cross-talk occur between the hypoxia and dioxin signal transduction pathways and identify Epo as an AHR-regulated gene.
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Mice 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 Chan et al., 1999
The paper’s Discussion (page unavailable in our copy) supports the HIF portion: it describes HIF-1α–ARNT signaling and cross-talk with AHR. It does not report that mice homozygous for AhrTer383 phenocopy null mice for the DV endpoint, or test whether that allele can identify other ARNT-dependent events. (LLM, conf=0.87)
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References 32 · Cited by 221
Research works printed but not linked: 5
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- Wang, G. L., Jiang, B. H., Rue, E. A., and Semenza, G. L. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 5510 -5514
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- Authors
- Chan, W. K., Yao, G., Gu, Y.-Z., & Bradfield, C. A.
- Affiliations
- University of the Pacific (US)
- University of Wisconsin–Madison (US)
- Corresponding author
- Bradfield, Christopher A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1999-04
- Volume
- 274
- Issue
- 17
- Pages
- 12115-12123
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2050968841
- Cited by
- 221
- References
- 32
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 13 · 2021: 6 · 2020: 5 · 2019: 9 · 2018: 6 · 2017: 5 · 2016: 5 · 2015: 5 · 2014: 7 · 2013: 8 · 2012: 8
- FWCI
- 9.26
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p30ca007175-36)
- National Cancer Institute (P30 CA 07175, T32-CA098681)
- National Institute of Environmental Health Sciences (R01-ES05703, R01ES005703)
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- aryl hydrocarbon receptor, hypoxia-inducible factor, HIF-1α, HIF-2α, ARNT, transcriptional crosstalk, CYP1A1, erythropoietin, 2,3,7,8-tetrachlorodibenzo-p-dioxin, transcriptional regulation, bHLH-PAS proteins
- MeSH terms
- Base Sequence, Binding, Competitive, Cobalt, Dioxins, DNA, Enhancer Elements, Genetic, Erythropoietin, Molecular Sequence Data, Promoter Regions, Genetic, RNA, Messenger, Transcription Factors, Tumor Cells, Cultured, Signal Transduction, Gene Expression Regulation, Enzymologic, Receptors, Aryl Hydrocarbon, Cytochrome P-450 CYP1A1, Receptor Cross-Talk
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