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Gene Review

Ahr  -  aryl-hydrocarbon receptor

Mus musculus

Synonyms: Ah, Ah receptor, AhR, Ahh, Ahre, ...
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Disease relevance of Ahr

  • We found that unliganded AhR shows a predominantly cytoplasmic diffuse distribution in mouse hepatoma cells [1].
  • The dioxin-inducible mouse [Ah] battery contains at least six genes that "cross-talk" with one another and are believed to play important roles in reproduction and development, and in environmental toxicity, cancer, and oxidative stress [2].
  • The AhR-ligand complex is known to mediate a range of biological responses, such as developmental toxicity, induction of cleft palate, and hydronephrosis [3].
  • Concomitant treatment of cultures with hypoxia (1% O2) and 3-methylcholanthrene (an AhR ligand) did not significantly alter HIF target gene expression [4].
  • We found that AhR(-/-) mice develop significant cardiac hypertrophy at 5 mo [5].

Psychiatry related information on Ahr

  • AhR protein levels peaked between postnatal day (PND) 3-10, a critical period for granule neuroblast growth and maturation [6].
  • We conclude that the alcohol drinking preference between the B6 and D2 inbred mouse strains is independent of the Ah receptor-but is genetically determined, in part, by the level of brain catalase activity which, in turn, regulates brain acetaldehyde concentrations [7].

High impact information on Ahr

  • Thus, Ahr-driven Bax transcription is a novel and evolutionarily conserved cell-death signaling pathway responsible for environmental toxicant-induced ovarian failure [8].
  • The Ahr is also activated by dioxin, one of the most intensively studied environmental contaminants [8].
  • Mice lacking either Ahr or the pro-apoptotic protein Bax have an increased number of primordial follicles, and these mutant oocytes are resistant to PAH toxicity [9].
  • 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 [8].
  • This difference in the action of PAHs versus dioxin is conveyed by a single base pair flanking each Ahr response element in the Bax promoter [8].

Chemical compound and disease context of Ahr


Biological context of Ahr

  • Histomorphometric analysis of serial ovarian sections revealed a two-fold higher number of primordial follicles in Ahr-null versus wild-type females at day 4 postpartum [13].
  • We present gene expression profiles of smooth muscle cells from wild type and Ahr(-/-) mice that show significant changes in the RNA levels of the transforming growth factor-beta3 (Tgfb3) gene and genes involved in the modulation and processing of TGF-beta [14].
  • All AhR-positive male mice of both +/+ and +/- genotypes that received subcutaneous injection of B[a]P (2 mg) on the first and the eighth days had developed subcutaneous tumors at the site of injection at the end of the 18-week experiment [15].
  • AHR content did not affect staurosporine- or doxorubicin-induced apoptosis [10].
  • Such cross-talk between coexpressed bHLH/PAS factors can occur through competition for ARNT, which we find evident in SIM repression of DR-induced transcription from a xenobiotic response element reporter gene [16].

Anatomical context of Ahr


Associations of Ahr with chemical compounds

  • Gestational exposure of Ahr and Arnt hypomorphs to dioxin rescues vascular development [21].
  • Dioxin treatment increased mitochondrial glutathione levels in the wt, Cyp1a1(-/-), and Cyp1a2(-/-) mice, but not in Ahr(-/-) mice [22].
  • The level of mitochondrial H(2)O(2) production in vehicle-treated Ahr(-/-) mice was one fifth that found in vehicle-treated wt mice [22].
  • Whereas dioxin caused a rise in succinate-stimulated mitochondrial H(2)O(2) production in the wt, Cyp1a1(-/-), and Cyp1a2(-/-) mice, this increase did not occur with the Ahr(-/-) knockout [22].
  • A heterodimer of the dioxin receptor (AhR) and Arnt, which are basic helix-loop-helix/PAS-family transcription factors, mediates most of the toxic effects of dioxins [17].
  • AhR KO mice challenged with inhaled endotoxin, which does not contain AhR ligands, also developed greater lung neutrophilia than controls, and bronchoalveolar lavage cells from AhR KO mice produced elevated levels of tumor necrosis factor-alpha and interleukin-6 when treated with endotoxin in vitro [23].
  • Serum levels of IL-6, MCP-1, IFN-gamma, and TNF-alpha were comparable between L. monocytogenes-infected AhR(-/-) and AhR(+/-) mice [24].
  • AHR activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) mediated the induction of cytochrome p450 1A1 and cycloxygenase-2 protein levels [25].
  • In vivo treatment with an antisense oligonucleotide for AhR increased TGFbeta signaling and improved re-epithelialization in wounds of wild-type mice [26].

Physical interactions of Ahr

  • Herein, we have investigated the subcellular distribution of the AhR/ARNT complex in response to ligand stimulation, by using live-cell confocal and high-resolution deconvolution microscopy [1].
  • The reduction in Cyp1a gene transcription by TPA could be accounted for by reduced DNA binding of the dioxin receptor to the xenobiotic-responsive element (XRE) sequences, as measured by gel-retardation analysis [27].
  • This study indicates that the effects of TCDD on EGF receptor ligand binding are mediated by the Ah receptor [28].
  • At the two lowest doses used in the enzyme induction study, 5 and 10 ng/kg, the levels of specifically bound nuclear Ah receptor complex liganded with [3H]TCDD were 2.3 and 2.5 fmol/mg protein [29].
  • We also provided evidence implicating the ubiquitin ligase protein C-terminal hsp70-interacting protein (CHIP) in the degradation of the DR, and we demonstrated that this degradation can be overcome by overexpression of XAP2 [30].

Enzymatic interactions of Ahr

  • In order to minimize any artificial steric hindrances to dimerization and XRE binding, each Ahr mutant was also tested with an equivalently deleted Arnt mutant [31].

Co-localisations of Ahr


Regulatory relationships of Ahr


Other interactions of Ahr

  • 5. These findings define the temporal regulation of receptor activation during normal ontogeny and provide evidence to support the idea that receptor activation and AHR-ARNT heterodimerization are essential for normal vascular development [21].
  • In contrast, Cyp1a2 gene expression was positive in liver irrespective of the presence or absence of the AhR gene, or B[a]P treatment, although its inducibility was lost in the AhR(-/-) mouse [15].
  • Taken together, these data suggest that the AHR cross talks with the EGFR signaling pathway by directly inducing the expression of growth factors that are important for EGFR signaling in the developing mouse ureter [33].
  • Here, we report the tissue distribution of AhRR in AhR deficient and wild type C57BL/6 mice [34].
  • These studies establish a critical role for ARNT in AHR and HIF-1alpha signal transduction in the intact mouse [36].

Analytical, diagnostic and therapeutic context of Ahr


  1. Recruitment of dioxin receptor to active transcription sites. Elbi, C., Misteli, T., Hager, G.L. Mol. Biol. Cell (2002) [Pubmed]
  2. How knockout mouse lines will be used to study the role of drug-metabolizing enzymes and their receptors during reproduction and development, and in environmental toxicity, cancer, and oxidative stress. Nebert, D.W., Duffy, J.J. Biochem. Pharmacol. (1997) [Pubmed]
  3. Developmental expression of two members of a new class of transcription factors: II. Expression of aryl hydrocarbon receptor nuclear translocator in the C57BL/6N mouse embryo. Abbott, B.D., Probst, M.R. Dev. Dyn. (1995) [Pubmed]
  4. Hypoxic inhibition of 3-methylcholanthrene-induced CYP1A1 expression is independent of HIF-1alpha. Allen, J.W., Johnson, R.S., Bhatia, S.N. Toxicol. Lett. (2005) [Pubmed]
  5. Aryl hydrocarbon receptor null mice develop cardiac hypertrophy and increased hypoxia-inducible factor-1alpha in the absence of cardiac hypoxia. Thackaberry, E.A., Gabaldon, D.M., Walker, M.K., Smith, S.M. Cardiovasc. Toxicol. (2002) [Pubmed]
  6. Aryl hydrocarbon receptor expression and activity in cerebellar granule neuroblasts: implications for development and dioxin neurotoxicity. Williamson, M.A., Gasiewicz, T.A., Opanashuk, L.A. Toxicol. Sci. (2005) [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. Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. 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. Nat. Genet. (2001) [Pubmed]
  9. Eggs in the balance. Matzuk, M.M. Nat. Genet. (2001) [Pubmed]
  10. Aryl hydrocarbon receptor regulation of ceramide-induced apoptosis in murine hepatoma 1c1c7 cells. A function independent of aryl hydrocarbon receptor nuclear translocator. Reiners, J.J., Clift, R.E. J. Biol. Chem. (1999) [Pubmed]
  11. Down-regulation of aryl hydrocarbon receptor-regulated genes by tumor necrosis factor-alpha and lipopolysaccharide in murine hepatoma Hepa 1c1c7 cells. Gharavi, N., El-Kadi, A.O. Journal of pharmaceutical sciences. (2005) [Pubmed]
  12. The aryl hydrocarbon receptor mediates degradation of estrogen receptor alpha through activation of proteasomes. Wormke, M., Stoner, M., Saville, B., Walker, K., Abdelrahim, M., Burghardt, R., Safe, S. Mol. Cell. Biol. (2003) [Pubmed]
  13. The aryl hydrocarbon receptor, a basic helix-loop-helix transcription factor of the PAS gene family, is required for normal ovarian germ cell dynamics in the mouse. Robles, R., Morita, Y., Mann, K.K., Perez, G.I., Yang, S., Matikainen, T., Sherr, D.H., Tilly, J.L. Endocrinology (2000) [Pubmed]
  14. Expression of genes in the TGF-beta signaling pathway is significantly deregulated in smooth muscle cells from aorta of aryl hydrocarbon receptor knockout mice. Guo, J., Sartor, M., Karyala, S., Medvedovic, M., Kann, S., Puga, A., Ryan, P., Tomlinson, C.R. Toxicol. Appl. Pharmacol. (2004) [Pubmed]
  15. Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Shimizu, Y., Nakatsuru, Y., Ichinose, M., Takahashi, Y., Kume, H., Mimura, J., Fujii-Kuriyama, Y., Ishikawa, T. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  16. Differential activities of murine single minded 1 (SIM1) and SIM2 on a hypoxic response element. Cross-talk between basic helix-loop-helix/per-Arnt-Sim homology transcription factors. Woods, S.L., Whitelaw, M.L. J. Biol. Chem. (2002) [Pubmed]
  17. Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. 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. Nature (2003) [Pubmed]
  18. The aryl hydrocarbon receptor predisposes hepatocytes to Fas-mediated apoptosis. Park, K.T., Mitchell, K.A., Huang, G., Elferink, C.J. Mol. Pharmacol. (2005) [Pubmed]
  19. The aryl-hydrocarbon receptor, but not the aryl-hydrocarbon receptor nuclear translocator protein, is rapidly depleted in hepatic and nonhepatic culture cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Pollenz, R.S. Mol. Pharmacol. (1996) [Pubmed]
  20. The aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator protein show distinct subcellular localizations in Hepa 1c1c7 cells by immunofluorescence microscopy. Pollenz, R.S., Sattler, C.A., Poland, A. Mol. Pharmacol. (1994) [Pubmed]
  21. Gestational exposure of Ahr and Arnt hypomorphs to dioxin rescues vascular development. Walisser, J.A., Bunger, M.K., Glover, E., Bradfield, C.A. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  22. Mitochondrial reactive oxygen production is dependent on the aromatic hydrocarbon receptor. Senft, A.P., Dalton, T.P., Nebert, D.W., Genter, M.B., Puga, A., Hutchinson, R.J., Kerzee, J.K., Uno, S., Shertzer, H.G. Free Radic. Biol. Med. (2002) [Pubmed]
  23. Aryl hydrocarbon receptor-deficient mice develop heightened inflammatory responses to cigarette smoke and endotoxin associated with rapid loss of the nuclear factor-kappaB component RelB. Thatcher, T.H., Maggirwar, S.B., Baglole, C.J., Lakatos, H.F., Gasiewicz, T.A., Phipps, R.P., Sime, P.J. Am. J. Pathol. (2007) [Pubmed]
  24. The aryl hydrocarbon receptor is required for optimal resistance to Listeria monocytogenes infection in mice. Shi, L.Z., Faith, N.G., Nakayama, Y., Suresh, M., Steinberg, H., Czuprynski, C.J. J. Immunol. (2007) [Pubmed]
  25. Environmental toxicants may modulate osteoblast differentiation by a mechanism involving the aryl hydrocarbon receptor. Ryan, E.P., Holz, J.D., Mulcahey, M., Sheu, T.J., Gasiewicz, T.A., Puzas, J.E. J. Bone Miner. Res. (2007) [Pubmed]
  26. Loss of dioxin-receptor expression accelerates wound healing in vivo by a mechanism involving TGFbeta. Carvajal-Gonzalez, J.M., Roman, A.C., Cerezo-Guisado, M.I., Rico-Leo, E.M., Martin-Partido, G., Fernandez-Salguero, P.M. J. Cell. Sci. (2009) [Pubmed]
  27. Phorbol esters inhibit the dioxin receptor-mediated transcriptional activation of the mouse Cyp1a-1 and Cyp1a-2 genes by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Okino, S.T., Pendurthi, U.R., Tukey, R.H. J. Biol. Chem. (1992) [Pubmed]
  28. Influence of the Ah locus on the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the hepatic epidermal growth factor receptor. Lin, F.H., Clark, G., Birnbaum, L.S., Lucier, G.W., Goldstein, J.A. Mol. Pharmacol. (1991) [Pubmed]
  29. Relative sensitivities of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced Cyp1a-1 and Cyp1a-2 gene expression and immunotoxicity in female B6C3F1 mice. Narasimhan, T.R., Craig, A., Arellano, L., Harper, N., Howie, L., Menache, M., Birnbaum, L., Safe, S. Fundamental and applied toxicology : official journal of the Society of Toxicology. (1994) [Pubmed]
  30. Defining the role for XAP2 in stabilization of the dioxin receptor. Lees, M.J., Peet, D.J., Whitelaw, M.L. J. Biol. Chem. (2003) [Pubmed]
  31. Identification of functional domains of the aryl hydrocarbon receptor. Fukunaga, B.N., Probst, M.R., Reisz-Porszasz, S., Hankinson, O. J. Biol. Chem. (1995) [Pubmed]
  32. Liver portal fibrosis in dioxin receptor-null mice that overexpress the latent transforming growth factor-beta-binding protein-1. Corchero, J., Martín-Partido, G., Dallas, S.L., Fernández-Salguero, P.M. International journal of experimental pathology. (2004) [Pubmed]
  33. In Utero Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Amphiregulin Gene Expression in the Developing Mouse Ureter. Choi, S.S.h., Miller, M.A., Harper, P.A. Toxicol. Sci. (2006) [Pubmed]
  34. Tissue distribution and function of the Aryl hydrocarbon receptor repressor (AhRR) in C57BL/6 and Aryl hydrocarbon receptor deficient mice. Bernshausen, T., Jux, B., Esser, C., Abel, J., Fritsche, E. Arch. Toxicol. (2006) [Pubmed]
  35. Comparison of expression of aldehyde dehydrogenase 3 and CYP1A1 in dominant and recessive aryl hydrocarbon hydroxylase-deficient mutant mouse hepatoma cells. Korkalainen, M.K., Törrönen, A.R., Kärenlampi, S.O. Chem. Biol. Interact. (1995) [Pubmed]
  36. Conditional disruption of the aryl hydrocarbon receptor nuclear translocator (Arnt) gene leads to loss of target gene induction by the aryl hydrocarbon receptor and hypoxia-inducible factor 1alpha. Tomita, S., Sinal, C.J., Yim, S.H., Gonzalez, F.J. Mol. Endocrinol. (2000) [Pubmed]
  37. Structure and expression of the Ah receptor repressor gene. Baba, T., Mimura, J., Gradin, K., Kuroiwa, A., Watanabe, T., Matsuda, Y., Inazawa, J., Sogawa, K., Fujii-Kuriyama, Y. J. Biol. Chem. (2001) [Pubmed]
  38. Determination of aryl hydrocarbon receptor nuclear translocator protein concentration and subcellular localization in hepatic and nonhepatic cell culture lines: development of quantitative Western blotting protocols for calculation of aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator protein in total cell lysates. Holmes, J.L., Pollenz, R.S. Mol. Pharmacol. (1997) [Pubmed]
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