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AHR  -  aryl hydrocarbon receptor

Homo sapiens

Synonyms: Ah receptor, AhR, Aryl hydrocarbon receptor, BHLHE76, Class E basic helix-loop-helix protein 76, ...
 
 
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Disease relevance of AHR

  • Variability in the human AHR affinity exists, but differences in human risk of toxicity or cancer related to AHR activation remain unproven [1].
  • In conclusion, the female reproductive tract expresses mRNA for the transcription factors AHR and ARNT, and changes in their expression at select target sites in specific pathological conditions such as endometriosis and uterine leiomyomas suggest a potential role for these factors in the pathogenesis of these conditions [2].
  • However, there were no changes in the expression of AHR or ARNT mRNA in ovarian cancer [2].
  • Leiomyomas expressed significantly less AHR and ARNT mRNA compared with normal myometrium [2].
  • Endometriotic ovarian cysts expressed more AHR but not more ARNT mRNA compared with healthy ovarian tissue [2].
  • These findings suggest that AHR polymorphisms and potential gene-smoking interaction may be involved in the etiology of lung cancer [3].
 

Psychiatry related information on AHR

 

High impact information on AHR

  • Reconstitution of STAT6 only in epithelial cells was sufficient for IL-13-induced AHR and mucus production in the absence of inflammation, fibrosis or other lung pathology [8].
  • In animal models of allergic asthma, blockade of IL-13 markedly inhibits allergen-induced AHR, mucus production and eosinophilia [8].
  • The requirement for this factor distinguishes the Ah receptor from the glucocorticoid receptor, to which the Ah receptor has been presumed to be similar [9].
  • The ability of the AhR to bind and be activated by a range of structurally divergent chemicals suggests that the AhR contains a rather promiscuous ligand binding site [10].
  • Two regulatory proteins, the aromatic (aryl) hydrocarbon receptor (AhR) and the AhR nuclear translocator (Arnt), mediate induction [11].
 

Chemical compound and disease context of AHR

 

Biological context of AHR

  • Specific transcriptional activation mediated by AHR/ARNT heterodimer, which is a functional indicator of receptor expression, was assessed by beta-galactosidase activity produced from a reporter plasmid [17].
  • Sequential two-step ChIP assays were performed which demonstrate that AHR and ER alpha are present together at the same time on the Cyp1a1 enhancer during transrepression [18].
  • AHR target gene activation can be repressed by estrogen and estrogen-like compounds [18].
  • In conclusion, these results demonstrate the existence of AHR- and CYP1A1-independent mechanisms of PAH metabolic activation in mouse liver, a phenomenon that may have important implications for PAH-mediated carcinogenesis [19].
  • Thus, no polymorphisms in the AHR, ARNT or CYP1A1 genes were identified that could be responsible for the non/low inducibility phenotype observed [20].
 

Anatomical context of AHR

  • The LS180 cell line should constitute a good model for further mechanistic studies on AHR-regulated CYP1A2 expression [21].
  • However, post-menopausal women on continuous hormone replacement therapy had greater expression of AHR but not of ARNT in the endometrium and myometrium when compared with women not taking hormones [2].
  • Transfection in HuH7 human liver cells confirmed previously reported ERalpha enhancement of AhR activity [22].
  • We studied the AhR-dependent pathway in lymphocytes from 62 subjects randomly sampled from the highest exposed zones and 59 subjects from the surrounding non-contaminated area, frequency matched for age, gender and smoking [23].
  • Identification of BCRP as transporter of benzo[a]pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists [24].
  • In human placentas, the AhR was primarily present in syncytiotrophoblasts and also in endothelium of large blood vessels in villi and endothelium of umbilical cord arteries and veins. In fetal tissues (from 4 to 7 months), the AhR was localized in lung, kidney, esophagus, pancreas, liver, testicle, thymus gland, retina, and choroid, mainly in epithelial cells, whereas it was absent in heart, brain, sclera, and thoracic aorta [25].
 

Associations of AHR with chemical compounds

  • In contrast, strains with an intact pathway for tryptophan biosynthesis responded to AHR agonists and had lower levels of background beta-galactosidase activity [17].
  • Indole-3-carbinol was an exceptionally potent AHR agonist (EC50 approximately 10 microM) in yeast [17].
  • Tryptophan, indole, indole acetic acid, and tryptamine activated transcription in yeast coexpressing AHR and ARNT (EC50 values approximately 300 microM) [17].
  • Hexachlorobenzene, benzo(a)pyrene, and beta-naphthoflavone were effective AHR agonists in the yeast system, and had EC50 values of 200, 40, and 20 nM, respectively, for beta-galactosidase activity induction [17].
  • Transfection studies with a plasmid containing a luciferase reporter gene under control of two dioxin-responsive elements indicate an effect on AHR protein expression [26].
  • Taken together, our studies show that recruitment of ARNT to the AhR after dioxin treatment can account for the antiestrogenic effect of dioxins [27].
 

Physical interactions of AHR

  • This yeast system is useful for the study of AHR/ARNT protein complexes, and may be generally applicable to the investigation of other multiprotein complexes [17].
  • Altogether, our data indicate that the RIP140 gene exhibits a complex structure with several noncoding exons and supports transcriptional cross-talk and feedback involving the ERalpha and AhR nuclear receptors [28].
  • Nuclear receptor coactivator SRC-1 interacts with the Q-rich subdomain of the AhR and modulates its transactivation potential [29].
  • We also report that AHR interacts with COUP-TF in transfected CV-1 cells [30].
  • Indeed, some xenobiotics do activate CYP1A1 gene expression in spite of their inability to compete with TCDD for binding to the AhR [31].
  • Inactivation or silencing of HDAC6 also led to reduced binding of ligand to the AhR and decreased translocation of the AhR from cytosol to nucleus in response to ligand [32].
 

Regulatory relationships of AHR

  • The aryl hydrocarbon (or dioxin) receptor (AhR) is a ligand-activated basic helix-loop-helix (bHLH) protein that heterodimerizes with the bHLH protein AhR nuclear translocator (ARNT) to form a complex that binds to xenobiotic regulatory elements in the enhancers of target genes [33].
  • CONCLUSIONS: In the absence of exogenous AhR ligands (such as cigarette smoke components), AhR overexpression up-regulated the expression of CYP1B1 in the early stage of lung adenocarcinoma [34].
  • Individuals with at least one copy of the G1721A AhR variant allele showed a significantly higher level of induced CYP1A1 activity compared with individuals negative for the polymorphism (P = 0.0001) [35].
  • The induction of BCRP (mRNA and protein expression) by indolo[3,2-b]carbazole was inhibited in Caco-2 cells by co-incubation with the AhR antagonist PD98059 (2'-amino-3'-methoxyflavone) [24].
  • Aryl hydrocarbon receptor agonists directly activate estrogen receptor alpha in MCF-7 breast cancer cells [36].
  • Binding of PDE2A to XAP2 inhibited TCDD- and cAMP-induced nuclear translocation of AhR in Hepa1c1c7 hepatocytes [37].
 

Other interactions of AHR

 

Analytical, diagnostic and therapeutic context of AHR

References

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  2. Uterine and ovarian aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) mRNA expression in benign and malignant gynaecological conditions. Khorram, O., Garthwaite, M., Golos, T. Mol. Hum. Reprod. (2002) [Pubmed]
  3. Association of human aryl hydrocarbon receptor gene polymorphisms with risk of lung cancer among cigarette smokers in a Chinese population. Chen, D., Tian, T., Wang, H., Liu, H., Hu, Z., Wang, Y., Liu, Y., Ma, H., Fan, W., Miao, R., Sun, W., Wang, Y., Qian, J., Jin, L., Wei, Q., Shen, H., Huang, W., Lu, D. Pharmacogenet. Genomics (2009) [Pubmed]
  4. Interindividual difference in expression of human Ah receptor and related P450 genes. Hayashi, S., Watanabe, J., Nakachi, K., Eguchi, H., Gotoh, O., Kawajiri, K. Carcinogenesis (1994) [Pubmed]
  5. Regulatory interaction between arylhydrocarbon receptor and SIM1, two basic helix-loop-helix PAS proteins involved in the control of food intake. Yang, C., Boucher, F., Tremblay, A., Michaud, J.L. J. Biol. Chem. (2004) [Pubmed]
  6. Polymorphism of alpha-estrogen receptor and aryl hydrocarbon receptor genes in dementia patients in Shanghai suburb. Lin, G.F., Ma, Q.W., Zhang, D.S., Zha, Y.L., Lou, K.J., Shen, J.H. Acta Pharmacol. Sin. (2003) [Pubmed]
  7. Genetic differences in alcohol drinking preference between inbred strains of mice. He, X.X., Nebert, D.W., Vasiliou, V., Zhu, H., Shertzer, H.G. Pharmacogenetics (1997) [Pubmed]
  8. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Kuperman, D.A., Huang, X., Koth, L.L., Chang, G.H., Dolganov, G.M., Zhu, Z., Elias, J.A., Sheppard, D., Erle, D.J. Nat. Med. (2002) [Pubmed]
  9. Cloning of a factor required for activity of the Ah (dioxin) receptor. Hoffman, E.C., Reyes, H., Chu, F.F., Sander, F., Conley, L.H., Brooks, B.A., Hankinson, O. Science (1991) [Pubmed]
  10. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Denison, M.S., Nagy, S.R. Annu. Rev. Pharmacol. Toxicol. (2003) [Pubmed]
  11. Induction of cytochrome P4501A1. Whitlock, J.P. Annu. Rev. Pharmacol. Toxicol. (1999) [Pubmed]
  12. Curcumin activates the aryl hydrocarbon receptor yet significantly inhibits (-)-benzo(a)pyrene-7R-trans-7,8-dihydrodiol bioactivation in oral squamous cell carcinoma cells and oral mucosa. Rinaldi, A.L., Morse, M.A., Fields, H.W., Rothas, D.A., Pei, P., Rodrigo, K.A., Renner, R.J., Mallery, S.R. Cancer Res. (2002) [Pubmed]
  13. For dioxin-induced birth defects, mouse or human CYP1A2 in maternal liver protects whereas mouse CYP1A1 and CYP1B1 are inconsequential. Dragin, N., Dalton, T.P., Miller, M.L., Shertzer, H.G., Nebert, D.W. J. Biol. Chem. (2006) [Pubmed]
  14. Aryl hydrocarbon receptor mediates sensitivity of MCF-7 breast cancer cells to antitumor agent 2-(4-amino-3-methylphenyl) benzothiazole. Loaiza-Pérez, A.I., Trapani, V., Hose, C., Singh, S.S., Trepel, J.B., Stevens, M.F., Bradshaw, T.D., Sausville, E.A. Mol. Pharmacol. (2002) [Pubmed]
  15. Estrogen and aryl hydrocarbon receptor expression and crosstalk in human Ishikawa endometrial cancer cells. Wormke, M., Castro-Rivera, E., Chen, I., Safe, S. J. Steroid Biochem. Mol. Biol. (2000) [Pubmed]
  16. CYP1A1 and CYP1B1 expressions in medulloblastoma cells are AhR-independent and have no direct link with resveratrol-induced differentiation and apoptosis. Wu, M.L., Li, H., Wu, D.C., Wang, X.W., Chen, X.Y., Kong, Q.Y., Ma, J.X., Gao, Y., Liu, J. Neurosci. Lett. (2005) [Pubmed]
  17. Expression of the human aryl hydrocarbon receptor complex in yeast. Activation of transcription by indole compounds. Miller, C.A. J. Biol. Chem. (1997) [Pubmed]
  18. ER alpha-AHR-ARNT protein-protein interactions mediate estradiol-dependent transrepression of dioxin-inducible gene transcription. Beischlag, T.V., Perdew, G.H. J. Biol. Chem. (2005) [Pubmed]
  19. Polycyclic aromatic hydrocarbon-inducible DNA adducts: evidence by 32P-postlabeling and use of knockout mice for Ah receptor-independent mechanisms of metabolic activation in vivo. Kondraganti, S.R., Fernandez-Salguero, P., Gonzalez, F.J., Ramos, K.S., Jiang, W., Moorthy, B. Int. J. Cancer (2003) [Pubmed]
  20. An uncommon phenotype of poor inducibility of CYP1A1 in human lung is not ascribable to polymorphisms in the AHR, ARNT, or CYP1A1 genes. Anttila, S., Lei, X.D., Elovaara, E., Karjalainen, A., Sun, W., Vainio, H., Hankinson, O. Pharmacogenetics (2000) [Pubmed]
  21. Regulation of cytochrome P450 enzymes by aryl hydrocarbon receptor in human cells: CYP1A2 expression in the LS180 colon carcinoma cell line after treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin or 3-methylcholanthrene. Li, W., Harper, P.A., Tang, B.K., Okey, A.B. Biochem. Pharmacol. (1998) [Pubmed]
  22. Aryl hydrocarbon receptor-mediated transcription: ligand-dependent recruitment of estrogen receptor alpha to 2,3,7,8-tetrachlorodibenzo-p-dioxin-responsive promoters. Matthews, J., Wihlén, B., Thomsen, J., Gustafsson, J.A. Mol. Cell. Biol. (2005) [Pubmed]
  23. TCDD-mediated alterations in the AhR-dependent pathway in Seveso, Italy, 20 years after the accident. Landi, M.T., Bertazzi, P.A., Baccarelli, A., Consonni, D., Masten, S., Lucier, G., Mocarelli, P., Needham, L., Caporaso, N., Grassman, J. Carcinogenesis (2003) [Pubmed]
  24. Identification of BCRP as transporter of benzo[a]pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists. Ebert, B., Seidel, A., Lampen, A. Carcinogenesis (2005) [Pubmed]
  25. Expression of aryl hydrocarbon receptor in human placentas and fetal tissues. Jiang, Y.Z., Wang, K., Fang, R., Zheng, J. J. Histochem. Cytochem. (2010) [Pubmed]
  26. Effect of transforming growth factor-beta1 on expression of aryl hydrocarbon receptor and genes of Ah gene battery: clues for independent down-regulation in A549 cells. Döhr, O., Sinning, R., Vogel, C., Münzel, P., Abel, J. Mol. Pharmacol. (1997) [Pubmed]
  27. The transcription factor aryl hydrocarbon receptor nuclear translocator functions as an estrogen receptor beta-selective coactivator, and its recruitment to alternative pathways mediates antiestrogenic effects of dioxin. Rüegg, J., Swedenborg, E., Wahlström, D., Escande, A., Balaguer, P., Pettersson, K., Pongratz, I. Mol. Endocrinol. (2008) [Pubmed]
  28. Transcriptional regulation of the human NRIP1/RIP140 gene by estrogen is modulated by dioxin signalling. Augereau, P., Badia, E., Fuentes, M., Rabenoelina, F., Corniou, M., Derocq, D., Balaguer, P., Cavailles, V. Mol. Pharmacol. (2006) [Pubmed]
  29. Nuclear receptor coactivator SRC-1 interacts with the Q-rich subdomain of the AhR and modulates its transactivation potential. Kumar, M.B., Perdew, G.H. Gene Expr. (1999) [Pubmed]
  30. The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TFI and ERRalpha1. Klinge, C.M., Kaur, K., Swanson, H.I. Arch. Biochem. Biophys. (2000) [Pubmed]
  31. Is CYP1A1 induction always related to AHR signaling pathway? Delescluse, C., Lemaire, G., de Sousa, G., Rahmani, R. Toxicology (2000) [Pubmed]
  32. HDAC6 modulates Hsp90 chaperone activity and regulates activation of aryl hydrocarbon receptor signaling. Kekatpure, V.D., Dannenberg, A.J., Subbaramaiah, K. J. Biol. Chem. (2009) [Pubmed]
  33. Trans-activation by the human aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator proteins: direct interactions with basal transcription factors. Rowlands, J.C., McEwan, I.J., Gustafsson, J.A. Mol. Pharmacol. (1996) [Pubmed]
  34. Requirement of Aryl Hydrocarbon Receptor Overexpression for CYP1B1 Up-Regulation and Cell Growth in Human Lung Adenocarcinomas. Chang, J.T., Chang, H., Chen, P.H., Lin, S.L., Lin, P. Clin. Cancer Res. (2007) [Pubmed]
  35. Variation in induced CYP1A1 levels: relationship to CYP1A1, Ah receptor and GSTM1 polymorphisms. Smart, J., Daly, A.K. Pharmacogenetics (2000) [Pubmed]
  36. Aryl hydrocarbon receptor agonists directly activate estrogen receptor alpha in MCF-7 breast cancer cells. Liu, S., Abdelrahim, M., Khan, S., Ariazi, E., Jordan, V.C., Safe, S. Biol. Chem. (2006) [Pubmed]
  37. Phosphodiesterase 2A forms a complex with the co-chaperone XAP2 and regulates nuclear translocation of the aryl hydrocarbon receptor. de Oliveira, S.K., Hoffmeister, M., Gambaryan, S., Müller-Esterl, W., Guimaraes, J.A., Smolenski, A.P. J. Biol. Chem. (2007) [Pubmed]
  38. Recruitment of the NCoA/SRC-1/p160 family of transcriptional coactivators by the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator complex. Beischlag, T.V., Wang, S., Rose, D.W., Torchia, J., Reisz-Porszasz, S., Muhammad, K., Nelson, W.E., Probst, M.R., Rosenfeld, M.G., Hankinson, O. Mol. Cell. Biol. (2002) [Pubmed]
  39. Involvement of the xenobiotic response element (XRE) in Ah receptor-mediated induction of human UDP-glucuronosyltransferase 1A1. Yueh, M.F., Huang, Y.H., Hiller, A., Chen, S., Nguyen, N., Tukey, R.H. J. Biol. Chem. (2003) [Pubmed]
  40. Differential recruitment of coactivator RIP140 by Ah and estrogen receptors. Absence of a role for LXXLL motifs. Kumar, M.B., Tarpey, R.W., Perdew, G.H. J. Biol. Chem. (1999) [Pubmed]
  41. Expression of the aryl hydrocarbon receptor (AhR) and the aryl hydrocarbon receptor nuclear translocator (ARNT) in fetal, benign hyperplastic, and malignant prostate. Kashani, M., Steiner, G., Haitel, A., Schaufler, K., Thalhammer, T., Amann, G., Kramer, G., Marberger, M., Schöller, A. Prostate (1998) [Pubmed]
 
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