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ARYL HYDROCARBON RECEPTOR; AHR

Gene map locus 7p15

TEXT

DESCRIPTION

Halogenated aromatic hydrocarbons, represented by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are environmental pollutants that are produced by minor side-reactions in chemical manufacturing processes and by combustion of waste materials. These chemicals cause potent and pleiotropic toxicity, including teratogenesis, immune suppression, epithelial disorders, and tumor production in experimental animals. At the molecular level, aldehyde dehydrogenase, quinone reductase, and various drug-metabolizing enzymes are induced by the chemicals in some cultured cells and some tissues of experimental animals. All these biologic effects are thought to be mediated by an intracellular aryl hydrocarbon receptor (AHR).

CLONING

Ema et al. (1994) isolated human cDNA for the AHR gene, using mouse cDNA as a labeled probe. The deduced primary structure of human AHR showed an overall amino acid similarity of 72.5% with that of the mouse counterpart. Protein encoded by the AHR cDNA bound the inducer, TCDD, with a high affinity in a 9S complex form.

GENE FUNCTION

A heterodimer of the dioxin receptor (AHR) and ARNT (126110), which are basic helix-loop-helix/PAS family transcription factors, mediates most of the toxic effects of dioxins. Ohtake et al. (2003) demonstrated that the agonist-activated AHR/ARNT heterodimer directly associates with the estrogen receptors ER-alpha (133430) and ER-beta (601663). They showed that this association results in the recruitment of unliganded estrogen receptor and the coactivator p300 (602700) to estrogen-responsive gene promoters, leading to activation of transcription and estrogenic effects. The function of liganded estrogen receptor was found to be attenuated. Estrogenic actions of AHR agonists were detected in wildtype ovariectomized mouse uteri, but were absent in Ahr -/- or Er-alpha -/- ovariectomized mice. Ohtake et al. (2003) concluded that their findings suggest a novel mechanism by which estrogen receptor-mediated estrogen signaling is modulated by a coregulatory-like function of activated AHR/ARNT, giving rise to adverse estrogen-related actions of dioxin-type environmental contaminants.

Ohtake et al. (2007) characterized a fat-soluble ligand-dependent ubiquitin ligase complex in human cell lines, in which AHR is integrated as a component of a novel cullin-4B (300304) ubiquitin ligase complex, CUL4B(AHR). Complex assembly and ubiquitin ligase activity of CUL4B(AHR) in vitro and in vivo are dependent on the AHR ligand. In the CUL4B(AHR) complex, ligand-activated AHR acts as a substrate-specific adaptor component that targets sex steroid receptors for degradation. Ohtake et al. (2007) concluded that their findings uncovered a function for AHR as an atypical component of the ubiquitin ligase complex and demonstrated a nongenomic signaling pathway in which fat-soluble ligands regulate target protein-selective degradation through a ubiquitin ligase complex.

MAPPING

By fluorescence in situ hybridization and by DNA blot hybridization using human/mouse or human/Chinese hamster hybrid cell DNAs, Ema et al. (1994) assigned the AHR gene to 7p21.

By use of PCR analysis of somatic cell hybrids and fluorescence in situ hybridization of metaphase cells, Le Beau et al. (1994) localized the AHR gene to 7p21-p15. Micka et al. (1997) localized the AHR gene to 7p15 using fluorescence in situ hybridization. Performing linkage analysis in a 3-generation family, they showed with good probability that the high CYP1A1 (108330) inducibility phenotype segregates with the 7p15 region.

MOLECULAR GENETICS

Micka et al. (1997) sequenced 93 nucleotides (corresponding to 31 amino acids) of exon 9 of the human AHR gene, which is the region corresponding to that containing the mouse ala375-to-val polymorphism, and found no nucleotide differences; val381 was present in all 5 individuals examined, 2 of whom showed 'high' and 3 of whom 'low' CYP1A1 inducibility.

ANIMAL MODEL

To determine whether the aryl hydrocarbon receptor plays a role in modulating carcinogenesis through the induction of xenobiotic-metabolizing enzymes, Shimizu et al. (2000) studied Ahr-deficient mice exposed to benzo(a)pyrene, a widely distributed environmental carcinogen. They found that the carcinogenicity of this agent was lost in Ahr-deficient mice. Shimizu et al. (2000) concluded that the carcinogenic action of benzo(a)pyrene can be determined primarily by AHR, a transcriptional regulator of the gene for CYP1A1.

Polycyclic aromatic hydrocarbons (PAHs) are toxic chemicals released into the environment by fossil fuel combustion. Oocyte destruction and ovarian failure occur in PAH-treated mice, and cigarette smoking causes early menopause in women. In many cells, PAHs activate the AHR, a member of the Per-Arnt-Sim family of transcription factors. The AHR is also activated by dioxin, one of the most intensively studied environmental contaminants. Matikainen et al. (2001) demonstrated that an exposure of mice to PAHs induces the expression of Bax (600040) in oocytes, followed by apoptosis. Ovarian damage caused by PAHs is prevented by Ahr or Bax inactivation. Oocytes microinjected with a Bax promoter-reporter construct show Ahr-dependent transcriptional activation after PAH, but not dioxin, treatment, consistent with findings that dioxin is not cytotoxic to oocytes. This difference in the action of PAHs versus dioxin is conveyed by a single basepair flanking each Ahr response element in the Bax promoter. Oocytes in human ovarian biopsies grafted into immunodeficient mice also accumulated Bax and underwent apoptosis after PAH exposure in vivo. Thus, Matikainen et al. (2001) concluded that AHR-driven Bax transcription is a novel and evolutionarily conserved cell-death signaling pathway responsible for environmental toxicant-induced ovarian failure.

Environmental pollutants, notably polychlorinated dioxins and biphenyls, represent well-characterized AHR ligands. The dioxin/AHR functions as a ligand-activated transcription factor regulating transcription of a battery of genes encoding xenobiotic metabolizing enzymes. Loss-of-function (gene-disruption) studies in mice had demonstrated that AHR is involved in toxic effects of dioxins but had not yielded unequivocal results concerning the physiologic function of the receptor. To unravel the biologic functions of AHR, Andersson et al. (2002) performed gain-of-function studies. 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.

By targeted disruption of the Ahr gene in mice, Walisser et al. (2005) demonstrated that Ahr signaling in endothelial/hematopoietic cells is necessary for developmental closure of the ductus venosus, whereas Ahr signaling in hepatocytes is necessary to generate adaptive and toxic responses to dioxin exposure. They concluded that cell-specific receptor signaling generates distinct AHR-dependent physiologic outcomes.

REFERENCES

1. Andersson, P.; McGuire, J.; Rubio, C.; Gradin, K.; Whitelaw, M. L.; Pettersson, S.; Hanberg, A.; Poellinger, L. :

A constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors. Proc. Nat. Acad. Sci. 99: 9990-9995, 2002.
PubMed ID : 12107286

2. Ema, M.; Matsushita, N.; Sogawa, K.; Ariyama, T.; Inazawa, J.; Nemoto, T.; Ota, M.; Oshimura, M.; Fujii-Kuriyama, Y. :

Human arylhydrocarbon receptor: functional expression and chromosomal assignment to 7p21. J. Biochem. 116: 845-851, 1994.
PubMed ID : 7883760

3. Le Beau, M. M.; Carver, L. A.; Espinosa, R., III; Schmidt, J. V.; Bradfield, C. A. :

Chromosomal localization of the human AHR locus encoding the structural gene for the Ah receptor to 7p21-p15. Cytogenet. Cell Genet. 66: 172-176, 1994.
PubMed ID : 8125016

4. Matikainen, T.; Perez, G. I.; Jurisicova, A.; Pru, J. K.; Schlezinger, J. J.; Ryu, H.-Y.; Laine, J.; Sakai, T.; Korsmeyer, S. J.; Casper, R. F.; Sherr, D. H.; Tilly, J. L. :

Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nature Genet. 28: 355-360, 2001.
PubMed ID : 11455387

5. Micka, J.; Milatovich, A.; Menon, A.; Grabowski, G. A.; Puga, A.; Nebert, D. W. :

Human Ah receptor (AHR) gene: localization to 7p15 and suggestive correlation of polymorphism with CYP1A1 inducibility. Pharmacogenetics 7: 95-101, 1997.
PubMed ID : 9170146

6. Ohtake, F.; Baba, A.; Takada, I.; Okada, M.; Iwasaki, K.; Miki, H.; Takahashi, S.; Kouzmenko, A.; Nohara, K.; Chiba, T.; Fujii-Kuriyama, Y.; Kato, S. :

Dioxin receptor is a ligand-dependent E3 ubiquitin ligase. Nature 446: 562-566, 2007.
PubMed ID : 17392787

7. Ohtake, F.; Takeyama, K.; Matsumoto, T.; Kitagawa, H.; Yamamoto, Y.; Nohara, K.; Tohyama, C.; Krust, A.; Mimura, J.; Chambon, P.; Yanagisawa, J.; Fujii-Kuriyama, Y.; Kato, S. :

Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. Nature 423: 545-550, 2003.
PubMed ID : 12774124

8. Shimizu, Y.; Nakatsuru, Y.; Ichinose, M.; Takahashi, Y.; Kume, H.; Mimura, J.; Fujii-Kuriyama, Y.; Ishikawa, T. :

Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proc. Nat. Acad. Sci. 97: 779-782, 2000.
PubMed ID : 10639156

9. Walisser, J. A.; Glover, E.; Pande, K.; Liss, A. L.; Bradfield, C. A. :

Aryl hydrocarbon receptor-dependent liver development and hepatotoxicity are mediated by different cell types. Proc. Nat. Acad. Sci. 102: 17858-17863, 2005.
PubMed ID : 16301529

CONTRIBUTORS

Ada Hamosh - updated : 4/12/2007
Patricia A. Hartz - updated : 1/27/2006
Ada Hamosh - updated : 5/29/2003
Victor A. McKusick - updated : 9/20/2002
Ada Hamosh - updated : 7/13/2001
Victor A. McKusick - updated : 2/9/2000
Victor A. McKusick - updated : 8/19/1997

CREATION DATE

Victor A. McKusick : 12/20/1994

EDIT HISTORY

alopez : 4/12/2007
mgross : 2/2/2006
terry : 1/27/2006
mgross : 5/30/2003
mgross : 5/30/2003
terry : 5/29/2003
cwells : 9/24/2002
carol : 9/20/2002
alopez : 10/29/2001
alopez : 10/15/2001
alopez : 7/16/2001
terry : 7/13/2001
carol : 1/17/2001
mgross : 3/1/2000
terry : 2/9/2000
jenny : 8/22/1997
terry : 8/19/1997
carol : 1/17/1995
carol : 12/21/1994
terry : 12/20/1994

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