A constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors
Open accessAbstract
The dioxin/aryl hydrocarbon receptor (AhR) functions as a ligand-activated transcription factor regulating transcription of a battery of genes encoding xenobiotic metabolizing enzymes. Known receptor ligands are environmental pollutants including polycyclic aromatic hydrocarbons and polychlorinated dioxins. Loss-of-function (gene-disruption) studies in mice have demonstrated that the AhR is involved in toxic effects of dioxins but have not yielded unequivocal results concerning the physiological function of the receptor. Gain-of-function studies therefore were performed to unravel the biological functions of the AhR. A constitutively active AhR expressed in transgenic mice reduced the life span of the mice and induced tumors in the glandular part of the stomach, demonstrating the oncogenic potential of the AhR and implicating the receptor in regulation of cell proliferation.
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AHR mutants lacking the PAS B domain constitutively dimerize with ARNT, bind AHREs, and induce AHRE-driven genes independently of ligand.
“Early evidence from domain mapping studies demonstrated that Ahr mutants lacking the PAS B domain constitutively dimerize with ARNT, bind to AHREs, and induce transcription of AHRE-driven genes in a manner that is independent of ligand binding (Andersson et al., 2002; J. McGuire et al., 2001).”
From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Andersson et al., 2002
The Results report that an AhR mutant lacking amino acids 288–421 of the ligand-binding domain cannot bind ligand but constitutively activates a reporter gene; they also report induction of AhR target genes. Our copy does not identify the deleted portion as PAS B or show that the mutant constitutively dimerizes with ARNT or binds AHREs. (LLM, conf=0.86)
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Cites
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Definition of a Dioxin Receptor Mutant That Is a Constitutive Activator of Transcription
McGuire, J., Okamoto, K., Whitelaw, M. L., Tanaka, H., & Poellinger, L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105607200 · Cited by 102 · see citing works
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“An important aspect of AHR activation is the necessity for negative feedback regulation as prolonged stimulation has detrimental effects (Andersson et al., 2002; Mitchell and Elferink, 2009).”
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Rodent Genetic Models of Ah Receptor Signaling
Wilson, R. H., & Bradfield, C. A. (2021) · Drug Metabolism Reviews · doi:10.1080/03602532.2021.1955916 · Cited by 16 · see citing works
“Early evidence from domain mapping studies demonstrated that Ahr mutants lacking the PAS B domain constitutively dimerize with ARNT, bind to AHREs, and induce transcription of AHREdriven genes in a manner that is independent of ligand binding (McGuire et al. 2001; Andersson et al. 2002).”
Background
- Authors
- Andersson, P., McGuire, J., Rubio, C., Gradin, K., Whitelaw, M. L., Pettersson, S., Hanberg, A., & Poellinger, L.
- Affiliations
- Karolinska Institutet (SE)
- Department of Cell and Molecular Biology, Institute of Environmental Medicine, Department of Oncology-Pathology, and Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77 Stockholm, Sweden; and Department of Biochemistry, University of Adelaide, South Australia 5005, Australia
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2002-07-09
- Volume
- 99
- Issue
- 15
- Pages
- 9990-9995
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC126612
- OpenAlex
- W2007225446
- Cited by
- 310
- References
- 2
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 4 · 2023: 11 · 2022: 12 · 2021: 13 · 2020: 14 · 2019: 19 · 2018: 15 · 2017: 13 · 2016: 17 · 2015: 11 · 2014: 12 · 2013: 18 · 2012: 15
- FWCI
- 8.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- 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 › Carcinogens and Genotoxicity Assessment
- Keywords
- aryl hydrocarbon receptor, constitutively active receptor, stomach neoplasms, gastric cancer, oncogenicity, transgenic mice, xenobiotic metabolism, cell proliferation, polychlorinated dibenzo-p-dioxins, polycyclic aromatic hydrocarbons, transcription factors
- MeSH terms
- Polychlorinated Dibenzodioxins, Animals, Carcinogens, Cloning, Molecular, Cricetinae, Intestinal Neoplasms, Liver, Male, Mice, Inbred CBA, Mice, Inbred C57BL, Recombinant Proteins, Stomach Neoplasms, Thymus Gland, Transfection, CHO Cells, Receptors, Aryl Hydrocarbon, Gene Expression Regulation, Developmental, Cytochrome P-450 CYP1A1, Mice
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