Aryl hydrocarbon receptor: Difference between revisions

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{{Redirect|AHR||Ahr (disambiguation)}}
{{Redirect|AHR||Ahr (disambiguation)}}
{{Infobox_gene}}
{{Infobox_gene}}
The '''aryl hydrocarbon receptor''' ('''AhR''' or '''AHR''' or '''ahr''' or '''ahR''') is a [[protein]] that in humans is encoded by the AHR [[gene]]. The aryl hydrocarbon receptor is a [[transcription factor]] that regulates gene expression. It was originally thought to function primarily as a sensor of [[xenobiotic]] chemicals and also as the regulator of enzymes such as [[cytochrome P450s]] that metabolize these chemicals.  The most notable of these xenobiotic chemicals are [[aromatic hydrocarbon|aromatic (aryl) hydrocarbon]]s from which the receptor derives its name.


The '''aryl hydrocarbon receptor''' ('''AhR''' or '''AHR''' or '''ahr''' or '''ahR''') is a [[protein]] that in humans is encoded by the AHR [[gene]]. The aryl hydrocarbon receptor is a ligand-activated [[transcription factor]] involved in the regulation of biological responses to planar [[aromatic hydrocarbon|aromatic (aryl) hydrocarbon]]s. This receptor has been shown to regulate [[xenobiotic]]-metabolizing enzymes such as [[cytochrome P450]].
More recently, it has been discovered that AhR is activated (or deactivated) by a number of [[endogenous]] [[indole]] derivatives such as [[kynurenine]].  In addition to regulating metabolism enzymes, the AhR has roles in regulating immunity, [[stem cell]] maintenance, and [[cellular differentiation]].<ref name="Esser_2016">{{Cite book | vauthors = Esser C | title = The Aryl Hydrocarbon Receptor in Immunity: Tools and Potential | journal = Methods in Molecular Biology | volume = 1371 | issue = | pages = 239–57 | date = 2016 | pmid = 26530806 | doi = 10.1007/978-1-4939-3139-2_16 | isbn = 978-1-4939-3138-5 }}</ref><ref name="Kawajiri_2017">{{cite journal | vauthors = Kawajiri K, Fujii-Kuriyama Y | title = The aryl hydrocarbon receptor: a multifunctional chemical sensor for host defense and homeostatic maintenance | journal = Experimental Animals | volume = 66 | issue = 2 | pages = 75–89 | date = May 2017 | pmid = 27980293 | pmc = 5411294 | doi = 10.1538/expanim.16-0092 }}</ref><ref name="Gutiérrez-Vázquez_2018">{{cite journal | vauthors = Gutiérrez-Vázquez C, Quintana FJ | title = Regulation of the Immune Response by the Aryl Hydrocarbon Receptor | journal = Immunity | volume = 48 | issue = 1 | pages = 19–33 | date = January 2018 | pmid = 29343438 | pmc = 5777317 | doi = 10.1016/j.immuni.2017.12.012 }}</ref>


The aryl hydrocarbon receptor is a member of the family of [[basic helix-loop-helix]] [[transcription factor]]s.  AHR binds several exogenous ligands such as natural plant [[flavonoid]]s, [[polyphenolic]]s and [[indole]]s, as well as synthetic polycyclic aromatic hydrocarbons and [[Dioxins and dioxin-like compounds|dioxin-like compounds]]. AhR is a cytosolic transcription factor that is normally inactive, bound to several [[co-chaperone]]s. Upon [[agonist|ligand]] binding to chemicals such as [[2,3,7,8-Tetrachlorodibenzodioxin|2,3,7,8-tetrachlorodibenzo-''p''-dioxin]] (TCDD), the chaperones [[Dissociation (chemistry)|dissociate]] resulting in AhR translocating into the [[cell nucleus|nucleus]] and [[protein dimer|dimer]]izing with ARNT [[Aryl hydrocarbon receptor nuclear translocator|(''AhR nuclear translocator'')]], leading to changes in [[gene]] [[Transcription (genetics)|transcription]].
The aryl hydrocarbon receptor is a member of the family of [[basic helix-loop-helix]] [[transcription factor]]s.  AHR binds several exogenous ligands such as natural plant [[flavonoid]]s, [[polyphenolic]]s and [[indole]]s, as well as synthetic polycyclic aromatic hydrocarbons and [[Dioxins and dioxin-like compounds|dioxin-like compounds]]. AhR is a cytosolic transcription factor that is normally inactive, bound to several [[co-chaperone]]s. Upon [[agonist|ligand]] binding to chemicals such as [[2,3,7,8-Tetrachlorodibenzodioxin|2,3,7,8-tetrachlorodibenzo-''p''-dioxin]] (TCDD), the chaperones [[Dissociation (chemistry)|dissociate]] resulting in AhR translocating into the [[cell nucleus|nucleus]] and [[protein dimer|dimer]]izing with ARNT [[Aryl hydrocarbon receptor nuclear translocator|(''AhR nuclear translocator'')]], leading to changes in [[gene]] [[Transcription (genetics)|transcription]].
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==Protein functional domains==
==Protein functional domains==
[[File:AHR functional domains.svg|right|400px|thumb| '''AhR Functional Domains''']]
[[File:AHR functional domains.svg|right|400px|thumb| '''AhR Functional Domains''']]
The AhR [[protein]] contains several domains critical for function and is classified as a member of the [[basic helix-loop-helix]]/[[PAS domain|Per-Arnt-Sim]] (bHLH/PAS) family of [[transcription factors]].<ref name="pmid1325649">{{cite journal | vauthors = Burbach KM, Poland A, Bradfield CA | title = Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 89 | issue = 17 | pages = 8185–9 | year = 1992 | pmid = 1325649 | pmc = 49882 | doi = 10.1073/pnas.89.17.8185 }}</ref><ref name="pmid7493958">{{cite journal | vauthors = Fukunaga BN, Probst MR, Reisz-Porszasz S, Hankinson O | title = Identification of functional domains of the aryl hydrocarbon receptor | journal = J. Biol. Chem. | volume = 270 | issue = 49 | pages = 29270–8 | year = 1995 | pmid = 7493958 | doi = 10.1074/jbc.270.49.29270 }}</ref> The bHLH motif is located in the [[N-terminal]] of the protein and is a common entity in a variety of [[transcription factors]].<ref name="pmid15186484">{{cite journal | vauthors = Jones S | title = An overview of the basic helix-loop-helix proteins | journal = Genome Biol. | volume = 5 | issue = 6 | pages = 226 | year = 2004 | pmid = 15186484 | pmc = 463060 | doi = 10.1186/gb-2004-5-6-226 }}</ref> Members of the bHLH superfamily have two functionally distinctive and highly conserved domains. The first is the basic-region (b), which is involved in the binding of the transcription factor to [[DNA]]. The second is the helix-loop-helix (HLH) region, which facilitates protein-protein interactions. Also contained with the AhR are two PAS domains, PAS-A and PAS-B, which are stretches of 200-350 [[amino acids]] that exhibit a high sequence homology to the protein domains that were originally found in the [[Drosophila]] genes period (Per) and single-minded (Sim) and in AhR’s dimerization partner the [[aryl hydrocarbon receptor nuclear translocator]] (ARNT).<ref name="pmid1314586">{{cite journal | vauthors = Ema M, Sogawa K, Watanabe N, Chujoh Y, Matsushita N, Gotoh O, Funae Y, Fujii-Kuriyama Y | title = cDNA cloning and structure of mouse putative Ah receptor | journal = Biochem. Biophys. Res. Commun. | volume = 184 | issue = 1 | pages = 246–53 | year = 1992 | pmid = 1314586 | doi = 10.1016/0006-291X(92)91185-S }}</ref> The PAS domains support specific secondary interactions with other PAS domain containing proteins, as is the case with AhR and ARNT, so that dimeric and heteromeric protein complexes can form. The ligand binding site of AhR is contained within the PAS-B domain<ref name="pmid7559670">{{cite journal | vauthors = Coumailleau P, Poellinger L, Gustafsson JA, Whitelaw ML | title = Definition of a minimal domain of the dioxin receptor that is associated with Hsp90 and maintains wild type ligand binding affinity and specificity | journal = J. Biol. Chem. | volume = 270 | issue = 42 | pages = 25291–300 | year = 1995 | pmid = 7559670 | doi = 10.1074/jbc.270.42.25291 }}</ref> and contains several conserved residues critical for ligand binding.<ref name="pmid17227672">{{cite journal | vauthors = Goryo K, Suzuki A, Del Carpio CA, Siizaki K, Kuriyama E, Mikami Y, Kinoshita K, Yasumoto K, Rannug A, Miyamoto A, Fujii-Kuriyama Y, Sogawa K | title = Identification of amino acid residues in the Ah receptor involved in ligand binding | journal = Biochem. Biophys. Res. Commun. | volume = 354 | issue = 2 | pages = 396–402 | year = 2007 | pmid = 17227672 | doi = 10.1016/j.bbrc.2006.12.227 }}</ref> Finally, a [[glutamine]]-rich (Q-rich) domain is located in the [[C-terminal]] region of the protein and is involved in co-activator recruitment and transactivation.<ref name="pmid11551916">{{cite journal | vauthors = Kumar MB, Ramadoss P, Reen RK, Vanden Heuvel JP, Perdew GH | title = The Q-rich subdomain of the human Ah receptor transactivation domain is required for dioxin-mediated transcriptional activity | journal = J. Biol. Chem. | volume = 276 | issue = 45 | pages = 42302–10 | year = 2001 | pmid = 11551916 | doi = 10.1074/jbc.M104798200 }}</ref>
The AhR [[protein]] contains several domains critical for function and is classified as a member of the [[basic helix-loop-helix]]/[[PAS domain|Per-Arnt-Sim]] (bHLH/PAS) family of [[transcription factors]].<ref name="pmid1325649">{{cite journal | vauthors = Burbach KM, Poland A, Bradfield CA | title = Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 17 | pages = 8185–9 | date = September 1992 | pmid = 1325649 | pmc = 49882 | doi = 10.1073/pnas.89.17.8185 }}</ref><ref name="pmid7493958">{{cite journal | vauthors = Fukunaga BN, Probst MR, Reisz-Porszasz S, Hankinson O | title = Identification of functional domains of the aryl hydrocarbon receptor | journal = The Journal of Biological Chemistry | volume = 270 | issue = 49 | pages = 29270–8 | date = December 1995 | pmid = 7493958 | doi = 10.1074/jbc.270.49.29270 }}</ref> The bHLH motif is located in the [[N-terminal]] of the protein and is a common entity in a variety of [[transcription factors]].<ref name="pmid15186484">{{cite journal | vauthors = Jones S | title = An overview of the basic helix-loop-helix proteins | journal = Genome Biology | volume = 5 | issue = 6 | pages = 226 | year = 2004 | pmid = 15186484 | pmc = 463060 | doi = 10.1186/gb-2004-5-6-226 }}</ref> Members of the bHLH superfamily have two functionally distinctive and highly conserved domains. The first is the basic-region (b), which is involved in the binding of the transcription factor to [[DNA]]. The second is the helix-loop-helix (HLH) region, which facilitates protein-protein interactions. Also contained with the AhR are two PAS domains, PAS-A and PAS-B, which are stretches of 200-350 [[amino acids]] that exhibit a high sequence homology to the protein domains that were originally found in the [[Drosophila]] genes period (Per) and single-minded (Sim) and in AhR’s dimerization partner the [[aryl hydrocarbon receptor nuclear translocator]] (ARNT).<ref name="pmid1314586">{{cite journal | vauthors = Ema M, Sogawa K, Watanabe N, Chujoh Y, Matsushita N, Gotoh O, Funae Y, Fujii-Kuriyama Y | title = cDNA cloning and structure of mouse putative Ah receptor | journal = Biochemical and Biophysical Research Communications | volume = 184 | issue = 1 | pages = 246–53 | date = April 1992 | pmid = 1314586 | doi = 10.1016/0006-291X(92)91185-S }}</ref> The PAS domains support specific secondary interactions with other PAS domain containing proteins, as is the case with AhR and ARNT, so that dimeric and heteromeric protein complexes can form. The ligand binding site of AhR is contained within the PAS-B domain<ref name="pmid7559670">{{cite journal | vauthors = Coumailleau P, Poellinger L, Gustafsson JA, Whitelaw ML | title = Definition of a minimal domain of the dioxin receptor that is associated with Hsp90 and maintains wild type ligand binding affinity and specificity | journal = The Journal of Biological Chemistry | volume = 270 | issue = 42 | pages = 25291–300 | date = October 1995 | pmid = 7559670 | doi = 10.1074/jbc.270.42.25291 }}</ref> and contains several conserved residues critical for ligand binding.<ref name="pmid17227672">{{cite journal | vauthors = Goryo K, Suzuki A, Del Carpio CA, Siizaki K, Kuriyama E, Mikami Y, Kinoshita K, Yasumoto K, Rannug A, Miyamoto A, Fujii-Kuriyama Y, Sogawa K | title = Identification of amino acid residues in the Ah receptor involved in ligand binding | journal = Biochemical and Biophysical Research Communications | volume = 354 | issue = 2 | pages = 396–402 | date = March 2007 | pmid = 17227672 | doi = 10.1016/j.bbrc.2006.12.227 }}</ref> Finally, a [[glutamine]]-rich (Q-rich) domain is located in the [[C-terminal]] region of the protein and is involved in co-activator recruitment and transactivation.<ref name="pmid11551916">{{cite journal | vauthors = Kumar MB, Ramadoss P, Reen RK, Vanden Heuvel JP, Perdew GH | title = The Q-rich subdomain of the human Ah receptor transactivation domain is required for dioxin-mediated transcriptional activity | journal = The Journal of Biological Chemistry | volume = 276 | issue = 45 | pages = 42302–10 | date = November 2001 | pmid = 11551916 | doi = 10.1074/jbc.M104798200 }}</ref>


==Ligands==
==Ligands==
AhR ligands have been generally classified into two categories, synthetic or naturally occurring. The first ligands to be discovered were synthetic and members of the halogenated aromatic hydrocarbons ([[polychlorinated dibenzodioxin]]s, [[Polychlorinated dibenzofurans|dibenzofurans]] and [[Polychlorinated biphenyl|biphenyls]]) and [[polycyclic aromatic hydrocarbon]]s ([[3-methylcholanthrene]], [[benzo(a)pyrene|benzo[''a'']pyrene]], [[Tetracene|benzanthracenes]] and [[beta-Naphthoflavone|benzoflavones]]).<ref name="pmid12213382">{{cite journal | vauthors = Denison MS, Pandini A, Nagy SR, Baldwin EP, Bonati L | title = Ligand binding and activation of the Ah receptor | journal = Chem. Biol. Interact. | volume = 141 | issue = 1–2 | pages = 3–24 | year = 2002 | pmid = 12213382 | doi = 10.1016/S0009-2797(02)00063-7 }}</ref><ref name="pmid12540743">{{cite journal | vauthors = Denison MS, Nagy SR | title = Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals | journal = Annu. Rev. Pharmacol. Toxicol. | volume = 43 | issue =  | pages = 309–34 | year = 2003 | pmid = 12540743 | doi = 10.1146/annurev.pharmtox.43.100901.135828 }}</ref>
AhR ligands have been generally classified into two categories, synthetic or naturally occurring. The first ligands to be discovered were synthetic and members of the halogenated aromatic hydrocarbons ([[polychlorinated dibenzodioxin]]s, [[Polychlorinated dibenzofurans|dibenzofurans]] and [[Polychlorinated biphenyl|biphenyls]]) and [[polycyclic aromatic hydrocarbon]]s ([[3-methylcholanthrene]], [[benzo(a)pyrene|benzo[''a'']pyrene]], [[Tetracene|benzanthracenes]] and [[beta-Naphthoflavone|benzoflavones]]).<ref name="pmid12213382">{{cite journal | vauthors = Denison MS, Pandini A, Nagy SR, Baldwin EP, Bonati L | title = Ligand binding and activation of the Ah receptor | journal = Chemico-Biological Interactions | volume = 141 | issue = 1–2 | pages = 3–24 | date = September 2002 | pmid = 12213382 | doi = 10.1016/S0009-2797(02)00063-7 | url = http://www.escholarship.org/uc/item/1c68w9nb | type = Submitted manuscript }}</ref><ref name="pmid12540743">{{cite journal | vauthors = Denison MS, Nagy SR | title = Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals | journal = Annual Review of Pharmacology and Toxicology | volume = 43 | issue =  | pages = 309–34 | year = 2003 | pmid = 12540743 | doi = 10.1146/annurev.pharmtox.43.100901.135828 }}</ref>


Research has focused on naturally occurring compounds with the hope of identifying an endogenous ligand. Naturally occurring compounds that have been identified as ligands of Ahr include derivatives of [[tryptophan]] such as [[indigo dye]] and [[indirubin]],<ref name="pmid11425848">{{cite journal | vauthors = Adachi J, Mori Y, Matsui S, Takigami H, Fujino J, Kitagawa H, Miller CA, Kato T, Saeki K, Matsuda T | title = Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine | journal = J. Biol. Chem. | volume = 276 | issue = 34 | pages = 31475–8 | date = August 2001 | pmid = 11425848 | doi = 10.1074/jbc.C100238200 }}</ref> [[tetrapyrrole]]s such as [[bilirubin]],<ref name="pmid9380021">{{cite journal | vauthors = Sinal CJ, Bend JR | title = Aryl hydrocarbon receptor-dependent induction of cyp1a1 by bilirubin in mouse hepatoma hepa 1c1c7 cells | journal = Mol. Pharmacol. | volume = 52 | issue = 4 | pages = 590–9 | year = 1997 | pmid = 9380021 | doi =  }}</ref> the [[arachidonic acid]] metabolites [[Lipoxin|lipoxin A4]] and [[Prostaglandin|prostaglandin G]],<ref name="pmid11673847">{{cite journal | vauthors = Seidel SD, Winters GM, Rogers WJ, Ziccardi MH, Li V, Keser B, Denison MS | title = Activation of the Ah receptor signaling pathway by prostaglandins | journal = J. Biochem. Mol. Toxicol. | volume = 15 | issue = 4 | pages = 187–96 | year = 2001 | pmid = 11673847 | doi = 10.1002/jbt.16 }}</ref> modified [[low-density lipoprotein]]<ref name="pmid17227852">{{cite journal | vauthors = McMillan BJ, Bradfield CA | title = The aryl hydrocarbon receptor is activated by modified low-density lipoprotein | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 104 | issue = 4 | pages = 1412–7 | year = 2007 | pmid = 17227852 | pmc = 1783125 | doi = 10.1073/pnas.0607296104 }}</ref> and several dietary [[carotenoid]]s.<ref name="pmid12540743"/> One assumption made in the search for an endogenous ligand is that the ligand will be a receptor [[agonist]]. However, work by Savouret ''et al.'' has shown this may not be the case since their findings demonstrate that 7-ketocholesterol competitively inhibits Ahr signal transduction.<ref name="pmid11042205">{{cite journal | vauthors = Savouret JF, Antenos M, Quesne M, Xu J, Milgrom E, Casper RF | title = 7-ketocholesterol is an endogenous modulator for the arylhydrocarbon receptor | journal = J. Biol. Chem. | volume = 276 | issue = 5 | pages = 3054–9 | year = 2001 | pmid = 11042205 | doi = 10.1074/jbc.M005988200 }}</ref>
Research has focused on naturally occurring compounds with the hope of identifying an endogenous ligand. Naturally occurring compounds that have been identified as ligands of Ahr include derivatives of [[tryptophan]] such as [[indigo dye]] and [[indirubin]],<ref name="pmid11425848">{{cite journal | vauthors = Adachi J, Mori Y, Matsui S, Takigami H, Fujino J, Kitagawa H, Miller CA, Kato T, Saeki K, Matsuda T | title = Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine | journal = The Journal of Biological Chemistry | volume = 276 | issue = 34 | pages = 31475–8 | date = August 2001 | pmid = 11425848 | doi = 10.1074/jbc.C100238200 }}</ref> [[tetrapyrrole]]s such as [[bilirubin]],<ref name="pmid9380021">{{cite journal | vauthors = Sinal CJ, Bend JR | title = Aryl hydrocarbon receptor-dependent induction of cyp1a1 by bilirubin in mouse hepatoma hepa 1c1c7 cells | journal = Molecular Pharmacology | volume = 52 | issue = 4 | pages = 590–9 | date = October 1997 | pmid = 9380021 | doi =  }}</ref> the [[arachidonic acid]] metabolites [[Lipoxin|lipoxin A4]] and [[Prostaglandin|prostaglandin G]],<ref name="pmid11673847">{{cite journal | vauthors = Seidel SD, Winters GM, Rogers WJ, Ziccardi MH, Li V, Keser B, Denison MS | title = Activation of the Ah receptor signaling pathway by prostaglandins | journal = Journal of Biochemical and Molecular Toxicology | volume = 15 | issue = 4 | pages = 187–96 | year = 2001 | pmid = 11673847 | doi = 10.1002/jbt.16 }}</ref> modified [[low-density lipoprotein]]<ref name="pmid17227852">{{cite journal | vauthors = McMillan BJ, Bradfield CA | title = The aryl hydrocarbon receptor is activated by modified low-density lipoprotein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 4 | pages = 1412–7 | date = January 2007 | pmid = 17227852 | pmc = 1783125 | doi = 10.1073/pnas.0607296104 }}</ref> and several dietary [[carotenoid]]s.<ref name="pmid12540743"/> One assumption made in the search for an endogenous ligand is that the ligand will be a receptor [[agonist]]. However, work by Savouret ''et al.'' has shown this may not be the case since their findings demonstrate that 7-ketocholesterol competitively inhibits Ahr signal transduction.<ref name="pmid11042205">{{cite journal | vauthors = Savouret JF, Antenos M, Quesne M, Xu J, Milgrom E, Casper RF | title = 7-ketocholesterol is an endogenous modulator for the arylhydrocarbon receptor | journal = The Journal of Biological Chemistry | volume = 276 | issue = 5 | pages = 3054–9 | date = February 2001 | pmid = 11042205 | doi = 10.1074/jbc.M005988200 }}</ref>
 
[[Carbidopa]] is a selective aryl hydrocarbon receptor modulator (SAhRM).<ref>{{cite journal | doi = 10.1042/BCJ20170728| pmid = 29109131| title = Carbidopa: A selective Ah receptor modulator (SAhRM)| journal = Biochemical Journal| volume = 474| issue = 22| pages = 3763–3765| year = 2017| last1 = Safe| first1 = Stephen}} </ref>
 
ICZ{{Expand acronym|date=November 2018}} is one of the strongest non-halogenated agonists for AHR in vitro reported.{{cn|date=November 2018}}


==Signaling pathway==
==Signaling pathway==
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===Cytosolic complex===
===Cytosolic complex===
Non-ligand bound Ahr is retained in the [[cytoplasm]] as an inactive [[protein]] complex consisting of a dimer of [[Hsp90]],<ref name="pmid2844180">{{cite journal | vauthors = Denis M, Cuthill S, Wikström AC, Poellinger L, Gustafsson JA | title = Association of the dioxin receptor with the Mr 90,000 heat shock protein: a structural kinship with the glucocorticoid receptor | journal = Biochem. Biophys. Res. Commun. | volume = 155 | issue = 2 | pages = 801–7 | year = 1988 | pmid = 2844180 | doi = 10.1016/S0006-291X(88)80566-7 }}</ref><ref name="pmid2843537">{{cite journal | vauthors = Perdew GH | title = Association of the Ah receptor with the 90-kDa heat shock protein | journal = J. Biol. Chem. | volume = 263 | issue = 27 | pages = 13802–5 | year = 1988 | pmid = 2843537 | doi =  }}</ref> [[PTGES3|prostaglandin E synthase 3]] (PTGES3, p23)<ref name="pmid15270073">{{cite journal | vauthors = Cox MB, Miller CA | title = Cooperation of heat shock protein 90 and p23 in aryl hydrocarbon receptor signaling | journal = Cell Stress Chaperones | volume = 9 | issue = 1 | pages = 4–20 | year = 2004 | pmid = 15270073 | pmc = 1065305 | doi = 10.1379/460.1 }}</ref><ref name="pmid10224120">{{cite journal | vauthors = Kazlauskas A, Poellinger L, Pongratz I | title = Evidence that the co-chaperone p23 regulates ligand responsiveness of the dioxin (Aryl hydrocarbon) receptor | journal = J. Biol. Chem. | volume = 274 | issue = 19 | pages = 13519–24 | year = 1999 | pmid = 10224120 | doi = 10.1074/jbc.274.19.13519 }}</ref><ref name="pmid11259606">{{cite journal | vauthors = Kazlauskas A, Sundström S, Poellinger L, Pongratz I | title = The hsp90 chaperone complex regulates intracellular localization of the dioxin receptor | journal = Mol. Cell. Biol. | volume = 21 | issue = 7 | pages = 2594–607 | year = 2001 | pmid = 11259606 | pmc = 86890 | doi = 10.1128/MCB.21.7.2594-2607.2001 }}</ref><ref name="pmid12623125">{{cite journal | vauthors = Shetty PV, Bhagwat BY, Chan WK | title = P23 enhances the formation of the aryl hydrocarbon receptor-DNA complex | journal = Biochem. Pharmacol. | volume = 65 | issue = 6 | pages = 941–8 | year = 2003 | pmid = 12623125 | doi = 10.1016/S0006-2952(02)01650-7 }}</ref> and a single molecule of the [[immunophilin]]-like [[AH receptor-interacting protein]], also known as hepatitis B virus X-associated protein 2 (XAP2),<ref name="pmid9447995">{{cite journal | vauthors = Meyer BK, Pray-Grant MG, Vanden Heuvel JP, Perdew GH | title = Hepatitis B virus X-associated protein 2 is a subunit of the unliganded aryl hydrocarbon receptor core complex and exhibits transcriptional enhancer activity | journal = Mol. Cell. Biol. | volume = 18 | issue = 2 | pages = 978–88 | year = 1998 | pmid = 9447995 | pmc = 108810 | doi =  }}</ref> AhR interacting protein (AIP),<ref name="pmid9083006">{{cite journal | vauthors = Ma Q, Whitlock JP | title = A novel cytoplasmic protein that interacts with the Ah receptor, contains tetratricopeptide repeat motifs, and augments the transcriptional response to 2,3,7,8-tetrachlorodibenzo-p-dioxin | journal = J. Biol. Chem. | volume = 272 | issue = 14 | pages = 8878–84 | year = 1997 | pmid = 9083006 | doi = 10.1074/jbc.272.14.8878 }}</ref> and AhR-activated 9 (ARA9).<ref name="pmid9111057">{{cite journal | vauthors = Carver LA, Bradfield CA | title = Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo | journal = J. Biol. Chem. | volume = 272 | issue = 17 | pages = 11452–6 | year = 1997 | pmid = 9111057 | doi = 10.1074/jbc.272.17.11452 }}</ref> The dimer of Hsp90, along with PTGES3 (p23), has a multifunctional role in the protection of the receptor from proteolysis, constraining the receptor in a conformation receptive to ligand binding and preventing the premature binding of ARNT.<ref name="pmid7559670"/><ref name="pmid10224120"/><ref name="pmid12623125"/><ref name="pmid7982913">{{cite journal | vauthors = Carver LA, Jackiw V, Bradfield CA | title = The 90-kDa heat shock protein is essential for Ah receptor signaling in a yeast expression system | journal = J. Biol. Chem. | volume = 269 | issue = 48 | pages = 30109–12 | year = 1994 | pmid = 7982913 | doi =  }}</ref><ref name="pmid1320028">{{cite journal | vauthors = Pongratz I, Mason GG, Poellinger L | title = Dual roles of the 90-kDa heat shock protein hsp90 in modulating functional activities of the dioxin receptor. Evidence that the dioxin receptor functionally belongs to a subclass of nuclear receptors that require hsp90 both for ligand-binding activity and repression of intrinsic DNA binding activity | journal = J. Biol. Chem. | volume = 267 | issue = 19 | pages = 13728–34 | year = 1992 | pmid = 1320028 | doi =  }}</ref><ref name="pmid8384309">{{cite journal | vauthors = Whitelaw M, Pongratz I, Wilhelmsson A, Gustafsson JA, Poellinger L | title = Ligand-dependent recruitment of the Arnt coregulator determines DNA recognition by the dioxin receptor | journal = Mol. Cell. Biol. | volume = 13 | issue = 4 | pages = 2504–14 | year = 1993 | pmid = 8384309 | pmc = 359572 | doi =  }}</ref> AIP interacts with carboxyl-terminal of Hsp90 and binds to the AhR [[Nuclear Localization sequence|nuclear localization sequence (NLS)]] preventing the inappropriate trafficking of the receptor into the nucleus.<ref name="pmid9837941">{{cite journal | vauthors = Carver LA, LaPres JJ, Jain S, Dunham EE, Bradfield CA | title = Characterization of the Ah receptor-associated protein, ARA9 | journal = J. Biol. Chem. | volume = 273 | issue = 50 | pages = 33580–7 | year = 1998 | pmid = 9837941 | doi = 10.1074/jbc.273.50.33580 }}</ref><ref name="pmid10986286">{{cite journal | vauthors = Petrulis JR, Hord NG, Perdew GH | title = Subcellular localization of the aryl hydrocarbon receptor is modulated by the immunophilin homolog hepatitis B virus X-associated protein 2 | journal = J. Biol. Chem. | volume = 275 | issue = 48 | pages = 37448–53 | year = 2000 | pmid = 10986286 | doi = 10.1074/jbc.M006873200 }}</ref><ref name="pmid12431985">{{cite journal | vauthors = Petrulis JR, Kusnadi A, Ramadoss P, Hollingshead B, Perdew GH | title = The hsp90 Co-chaperone AIP alters importin beta recognition of the bipartite nuclear localization signal of the Ah receptor and represses transcriptional activity | journal = J. Biol. Chem. | volume = 278 | issue = 4 | pages = 2677–85 | year = 2003 | pmid = 12431985 | doi = 10.1074/jbc.M209331200 }}</ref>
Non-ligand bound Ahr is retained in the [[cytoplasm]] as an inactive [[protein]] complex consisting of a dimer of [[Hsp90]],<ref name="pmid2844180">{{cite journal | vauthors = Denis M, Cuthill S, Wikström AC, Poellinger L, Gustafsson JA | title = Association of the dioxin receptor with the Mr 90,000 heat shock protein: a structural kinship with the glucocorticoid receptor | journal = Biochemical and Biophysical Research Communications | volume = 155 | issue = 2 | pages = 801–7 | date = September 1988 | pmid = 2844180 | doi = 10.1016/S0006-291X(88)80566-7 }}</ref><ref name="pmid2843537">{{cite journal | vauthors = Perdew GH | title = Association of the Ah receptor with the 90-kDa heat shock protein | journal = The Journal of Biological Chemistry | volume = 263 | issue = 27 | pages = 13802–5 | date = September 1988 | pmid = 2843537 | doi =  }}</ref> [[PTGES3|prostaglandin E synthase 3]] (PTGES3, p23)<ref name="pmid15270073">{{cite journal | vauthors = Cox MB, Miller CA | title = Cooperation of heat shock protein 90 and p23 in aryl hydrocarbon receptor signaling | journal = Cell Stress & Chaperones | volume = 9 | issue = 1 | pages = 4–20 | date = March 2004 | pmid = 15270073 | pmc = 1065305 | doi = 10.1379/460.1 }}</ref><ref name="pmid10224120">{{cite journal | vauthors = Kazlauskas A, Poellinger L, Pongratz I | title = Evidence that the co-chaperone p23 regulates ligand responsiveness of the dioxin (Aryl hydrocarbon) receptor | journal = The Journal of Biological Chemistry | volume = 274 | issue = 19 | pages = 13519–24 | date = May 1999 | pmid = 10224120 | doi = 10.1074/jbc.274.19.13519 }}</ref><ref name="pmid11259606">{{cite journal | vauthors = Kazlauskas A, Sundström S, Poellinger L, Pongratz I | title = The hsp90 chaperone complex regulates intracellular localization of the dioxin receptor | journal = Molecular and Cellular Biology | volume = 21 | issue = 7 | pages = 2594–607 | date = April 2001 | pmid = 11259606 | pmc = 86890 | doi = 10.1128/MCB.21.7.2594-2607.2001 }}</ref><ref name="pmid12623125">{{cite journal | vauthors = Shetty PV, Bhagwat BY, Chan WK | title = P23 enhances the formation of the aryl hydrocarbon receptor-DNA complex | journal = Biochemical Pharmacology | volume = 65 | issue = 6 | pages = 941–8 | date = March 2003 | pmid = 12623125 | doi = 10.1016/S0006-2952(02)01650-7 }}</ref> and a single molecule of the [[immunophilin]]-like [[AH receptor-interacting protein]], also known as hepatitis B virus X-associated protein 2 (XAP2),<ref name="pmid9447995">{{cite journal | vauthors = Meyer BK, Pray-Grant MG, Vanden Heuvel JP, Perdew GH | title = Hepatitis B virus X-associated protein 2 is a subunit of the unliganded aryl hydrocarbon receptor core complex and exhibits transcriptional enhancer activity | journal = Molecular and Cellular Biology | volume = 18 | issue = 2 | pages = 978–88 | date = February 1998 | pmid = 9447995 | pmc = 108810 | doi =  }}</ref> AhR interacting protein (AIP),<ref name="pmid9083006">{{cite journal | vauthors = Ma Q, Whitlock JP | title = A novel cytoplasmic protein that interacts with the Ah receptor, contains tetratricopeptide repeat motifs, and augments the transcriptional response to 2,3,7,8-tetrachlorodibenzo-p-dioxin | journal = The Journal of Biological Chemistry | volume = 272 | issue = 14 | pages = 8878–84 | date = April 1997 | pmid = 9083006 | doi = 10.1074/jbc.272.14.8878 }}</ref><ref>{{cite journal | vauthors = Zhou Q, Lavorgna A, Bowman M, Hiscott J, Harhaj EW | title = Aryl Hydrocarbon Receptor Interacting Protein Targets IRF7 to Suppress Antiviral Signaling and the Induction of Type I Interferon | journal = The Journal of Biological Chemistry | volume = 290 | issue = 23 | pages = 14729–39 | date = June 2015 | pmid = 25911105 | doi = 10.1074/jbc.M114.633065 | url = http://www.jbc.org/content/290/23/14729 | pmc = 4505538 }}</ref> and AhR-activated 9 (ARA9).<ref name="pmid9111057">{{cite journal | vauthors = Carver LA, Bradfield CA | title = Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo | journal = The Journal of Biological Chemistry | volume = 272 | issue = 17 | pages = 11452–6 | date = April 1997 | pmid = 9111057 | doi = 10.1074/jbc.272.17.11452 }}</ref> The dimer of Hsp90, along with PTGES3 (p23), has a multifunctional role in the protection of the receptor from proteolysis, constraining the receptor in a conformation receptive to ligand binding and preventing the premature binding of ARNT.<ref name="pmid7559670"/><ref name="pmid10224120"/><ref name="pmid12623125"/><ref name="pmid7982913">{{cite journal | vauthors = Carver LA, Jackiw V, Bradfield CA | title = The 90-kDa heat shock protein is essential for Ah receptor signaling in a yeast expression system | journal = The Journal of Biological Chemistry | volume = 269 | issue = 48 | pages = 30109–12 | date = December 1994 | pmid = 7982913 | doi =  }}</ref><ref name="pmid1320028">{{cite journal | vauthors = Pongratz I, Mason GG, Poellinger L | title = Dual roles of the 90-kDa heat shock protein hsp90 in modulating functional activities of the dioxin receptor. Evidence that the dioxin receptor functionally belongs to a subclass of nuclear receptors which require hsp90 both for ligand binding activity and repression of intrinsic DNA binding activity | journal = The Journal of Biological Chemistry | volume = 267 | issue = 19 | pages = 13728–34 | date = July 1992 | pmid = 1320028 | doi = }}</ref><ref name="pmid8384309">{{cite journal | vauthors = Whitelaw M, Pongratz I, Wilhelmsson A, Gustafsson JA, Poellinger L | title = Ligand-dependent recruitment of the Arnt coregulator determines DNA recognition by the dioxin receptor | journal = Molecular and Cellular Biology | volume = 13 | issue = 4 | pages = 2504–14 | date = April 1993 | pmid = 8384309 | pmc = 359572 | doi =  }}</ref> AIP interacts with carboxyl-terminal of Hsp90 and binds to the AhR [[Nuclear Localization sequence|nuclear localization sequence (NLS)]] preventing the inappropriate trafficking of the receptor into the nucleus.<ref name="pmid9837941">{{cite journal | vauthors = Carver LA, LaPres JJ, Jain S, Dunham EE, Bradfield CA | title = Characterization of the Ah receptor-associated protein, ARA9 | journal = The Journal of Biological Chemistry | volume = 273 | issue = 50 | pages = 33580–7 | date = December 1998 | pmid = 9837941 | doi = 10.1074/jbc.273.50.33580 }}</ref><ref name="pmid10986286">{{cite journal | vauthors = Petrulis JR, Hord NG, Perdew GH | title = Subcellular localization of the aryl hydrocarbon receptor is modulated by the immunophilin homolog hepatitis B virus X-associated protein 2 | journal = The Journal of Biological Chemistry | volume = 275 | issue = 48 | pages = 37448–53 | date = December 2000 | pmid = 10986286 | doi = 10.1074/jbc.M006873200 }}</ref><ref name="pmid12431985">{{cite journal | vauthors = Petrulis JR, Kusnadi A, Ramadoss P, Hollingshead B, Perdew GH | title = The hsp90 Co-chaperone XAP2 alters importin beta recognition of the bipartite nuclear localization signal of the Ah receptor and represses transcriptional activity | journal = The Journal of Biological Chemistry | volume = 278 | issue = 4 | pages = 2677–85 | date = January 2003 | pmid = 12431985 | doi = 10.1074/jbc.M209331200 }}</ref>


===Receptor activation===
===Receptor activation===
Upon ligand binding to AhR, AIP is released resulting in exposure of the NLS, which is located in the bHLH region,<ref name="pmid9446600">{{cite journal | vauthors = Ikuta T, Eguchi H, Tachibana T, Yoneda Y, Kawajiri K | title = Nuclear localization and export signals of the human aryl hydrocarbon receptor | journal = J. Biol. Chem. | volume = 273 | issue = 5 | pages = 2895–904 | year = 1998 | pmid = 9446600 | doi = 10.1074/jbc.273.5.2895 }}</ref> leading to importation into the nucleus.<ref name="pmid10913191">{{cite journal | vauthors = Pollenz RS, Barbour ER | title = Analysis of the complex relationship between nuclear export and aryl hydrocarbon receptor-mediated gene regulation | journal = Mol. Cell. Biol. | volume = 20 | issue = 16 | pages = 6095–104 | year = 2000 | pmid = 10913191 | pmc = 86085 | doi = 10.1128/MCB.20.16.6095-6104.2000 }}</ref> It is presumed that once in the nucleus, Hsp90 dissociates exposing the two PAS domains allowing the binding of ARNT.<ref name="pmid8384309"/><ref name="pmid1852076">{{cite journal | vauthors = Hoffman EC, Reyes H, Chu FF, Sander F, Conley LH, Brooks BA, Hankinson O | title = Cloning of a factor required for activity of the Ah (dioxin) receptor | journal = Science | volume = 252 | issue = 5008 | pages = 954–8 | year = 1991 | pmid = 1852076 | doi = 10.1126/science.1852076 }}</ref><ref name="pmid8396713">{{cite journal | vauthors = Probst MR, Reisz-Porszasz S, Agbunag RV, Ong MS, Hankinson O | title = Role of the aryl hydrocarbon receptor nuclear translocator protein in aryl hydrocarbon (dioxin) receptor action | journal = Mol. Pharmacol. | volume = 44 | issue = 3 | pages = 511–8 | year = 1993 | pmid = 8396713 | doi =  }}</ref><ref name="pmid1317062">{{cite journal | vauthors = Reyes H, Reisz-Porszasz S, Hankinson O | title = Identification of the Ah receptor nuclear translocator protein (Arnt) as a component of the DNA binding form of the Ah receptor | journal = Science | volume = 256 | issue = 5060 | pages = 1193–5 | year = 1992 | pmid = 1317062 | doi = 10.1126/science.256.5060.1193 }}</ref> The activated AhR/ARNT heterodimer complex is then capable of either directly and indirectly interacting with DNA by binding to recognition sequences located in the 5’- regulatory region of dioxin-responsive genes.<ref name="pmid8384309"/><ref name="pmid8396713"/><ref name="pmid8397410">{{cite journal | vauthors = Dolwick KM, Swanson HI, Bradfield CA | title = In vitro analysis of Ah receptor domains involved in ligand-activated DNA recognition | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 90 | issue = 18 | pages = 8566–70 | year = 1993 | pmid = 8397410 | pmc = 47398 | doi = 10.1073/pnas.90.18.8566 }}</ref>
Upon ligand binding to AhR, AIP is released resulting in exposure of the NLS, which is located in the bHLH region,<ref name="pmid9446600">{{cite journal | vauthors = Ikuta T, Eguchi H, Tachibana T, Yoneda Y, Kawajiri K | title = Nuclear localization and export signals of the human aryl hydrocarbon receptor | journal = The Journal of Biological Chemistry | volume = 273 | issue = 5 | pages = 2895–904 | date = January 1998 | pmid = 9446600 | doi = 10.1074/jbc.273.5.2895 }}</ref> leading to import into the nucleus.<ref name="pmid10913191">{{cite journal | vauthors = Pollenz RS, Barbour ER | title = Analysis of the complex relationship between nuclear export and aryl hydrocarbon receptor-mediated gene regulation | journal = Molecular and Cellular Biology | volume = 20 | issue = 16 | pages = 6095–104 | date = August 2000 | pmid = 10913191 | pmc = 86085 | doi = 10.1128/MCB.20.16.6095-6104.2000 }}</ref> It is presumed that once in the nucleus, Hsp90 dissociates exposing the two PAS domains allowing the binding of ARNT.<ref name="pmid8384309"/><ref name="pmid1852076">{{cite journal | vauthors = Hoffman EC, Reyes H, Chu FF, Sander F, Conley LH, Brooks BA, Hankinson O | title = Cloning of a factor required for activity of the Ah (dioxin) receptor | journal = Science | volume = 252 | issue = 5008 | pages = 954–8 | date = May 1991 | pmid = 1852076 | doi = 10.1126/science.1852076 }}</ref><ref name="pmid8396713">{{cite journal | vauthors = Probst MR, Reisz-Porszasz S, Agbunag RV, Ong MS, Hankinson O | title = Role of the aryl hydrocarbon receptor nuclear translocator protein in aryl hydrocarbon (dioxin) receptor action | journal = Molecular Pharmacology | volume = 44 | issue = 3 | pages = 511–8 | date = September 1993 | pmid = 8396713 | doi =  }}</ref><ref name="pmid1317062">{{cite journal | vauthors = Reyes H, Reisz-Porszasz S, Hankinson O | title = Identification of the Ah receptor nuclear translocator protein (Arnt) as a component of the DNA binding form of the Ah receptor | journal = Science | volume = 256 | issue = 5060 | pages = 1193–5 | date = May 1992 | pmid = 1317062 | doi = 10.1126/science.256.5060.1193 }}</ref> The activated AhR/ARNT heterodimer complex is then capable of either directly and indirectly interacting with DNA by binding to recognition sequences located in the 5’- regulatory region of dioxin-responsive genes.<ref name="pmid8384309"/><ref name="pmid8396713"/><ref name="pmid8397410">{{cite journal | vauthors = Dolwick KM, Swanson HI, Bradfield CA | title = In vitro analysis of Ah receptor domains involved in ligand-activated DNA recognition | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 18 | pages = 8566–70 | date = September 1993 | pmid = 8397410 | pmc = 47398 | doi = 10.1073/pnas.90.18.8566 }}</ref>


===DNA binding (xenobiotic response element – XRE)===
===DNA binding (xenobiotic response element – XRE)===
The classical recognition motif of the AhR/ARNT complex, referred to as either the AhR-, dioxin- or xenobiotic- responsive element (AHRE, DRE or XRE), contains the core sequence 5'-GCGTG-3'<ref name="pmid1313023">{{cite journal | vauthors = Shen ES, Whitlock JP | title = Protein-DNA interactions at a dioxin-responsive enhancer. Mutational analysis of the DNA-binding site for the liganded Ah receptor | journal = J. Biol. Chem. | volume = 267 | issue = 10 | pages = 6815–9 | year = 1992 | pmid = 1313023 | doi =  }}</ref> within the consensus sequence 5'-T/GNGCGTGA/CG/CA-3'<ref name="pmid8384216">{{cite journal | vauthors = Lusska A, Shen E, Whitlock JP | title = Protein-DNA interactions at a dioxin-responsive enhancer. Analysis of six bona fide DNA-binding sites for the liganded Ah receptor | journal = J. Biol. Chem. | volume = 268 | issue = 9 | pages = 6575–80 | year = 1993 | pmid = 8384216 | doi =  }}</ref><ref name="pmid1318077">{{cite journal | vauthors = Yao EF, Denison MS | title = DNA sequence determinants for binding of transformed Ah receptor to a dioxin-responsive enhancer | journal = Biochemistry | volume = 31 | issue = 21 | pages = 5060–7 | year = 1992 | pmid = 1318077 | doi = 10.1021/bi00136a019 }}</ref> in the [[Promoter (biology)|promoter region]] of AhR responsive genes. The AhR/ARNT heterodimer directly binds the AHRE/DRE/XRE core sequence in an asymmetric manner such that ARNT binds to 5'-GTG-3' and AhR binding 5'-TC/TGC-3'.<ref name="pmid7821222">{{cite journal | vauthors = Wharton KA, Franks RG, Kasai Y, Crews ST | title = Control of CNS midline transcription by asymmetric E-box-like elements: similarity to xenobiotic responsive regulation | journal = Development | volume = 120 | issue = 12 | pages = 3563–9 | year = 1994 | pmid = 7821222 | doi =  }}</ref><ref name="pmid7700240">{{cite journal | vauthors = Bacsi SG, Reisz-Porszasz S, Hankinson O | title = Orientation of the heterodimeric aryl hydrocarbon (dioxin) receptor complex on its asymmetric DNA recognition sequence | journal = Mol. Pharmacol. | volume = 47 | issue = 3 | pages = 432–8 | year = 1995 | pmid = 7700240 | doi =  }}</ref><ref name="pmid7592839">{{cite journal | vauthors = Swanson HI, Chan WK, Bradfield CA | title = DNA binding specificities and pairing rules of the Ah receptor, ARNT, and SIM proteins | journal = J. Biol. Chem. | volume = 270 | issue = 44 | pages = 26292–302 | year = 1995 | pmid = 7592839 | doi = 10.1074/jbc.270.44.26292 }}</ref> Recent research suggests that a second type of element termed AHRE-II, 5'-CATG(N6)C[T/A]TG-3', is capable of indirectly acting with the AhR/ARNT complex.<ref name="pmid15358164">{{cite journal | vauthors = Boutros PC, Moffat ID, Franc MA, Tijet N, Tuomisto J, Pohjanvirta R, Okey AB | title = Dioxin-responsive AHRE-II gene battery: identification by phylogenetic footprinting | journal = Biochem. Biophys. Res. Commun. | volume = 321 | issue = 3 | pages = 707–15 | year = 2004 | pmid = 15358164 | doi = 10.1016/j.bbrc.2004.06.177 }}</ref><ref name="pmid15144902">{{cite journal | vauthors = Sogawa K, Numayama-Tsuruta K, Takahashi T, Matsushita N, Miura C, Nikawa J, Gotoh O, Kikuchi Y, Fujii-Kuriyama Y | title = A novel induction mechanism of the rat CYP1A2 gene mediated by Ah receptor-Arnt heterodimer | journal = Biochem. Biophys. Res. Commun. | volume = 318 | issue = 3 | pages = 746–55 | year = 2004 | pmid = 15144902 | doi = 10.1016/j.bbrc.2004.04.090 }}</ref> Regardless of the response element, the end result is a variety of differential changes in gene expression.
The classical recognition motif of the AhR/ARNT complex, referred to as either the AhR-, dioxin- or xenobiotic- responsive element (AHRE, DRE or XRE), contains the core sequence 5'-GCGTG-3'<ref name="pmid1313023">{{cite journal | vauthors = Shen ES, Whitlock JP | title = Protein-DNA interactions at a dioxin-responsive enhancer. Mutational analysis of the DNA-binding site for the liganded Ah receptor | journal = The Journal of Biological Chemistry | volume = 267 | issue = 10 | pages = 6815–9 | date = April 1992 | pmid = 1313023 | doi =  }}</ref> within the consensus sequence 5'-T/GNGCGTGA/CG/CA-3'<ref name="pmid8384216">{{cite journal | vauthors = Lusska A, Shen E, Whitlock JP | title = Protein-DNA interactions at a dioxin-responsive enhancer. Analysis of six bona fide DNA-binding sites for the liganded Ah receptor | journal = The Journal of Biological Chemistry | volume = 268 | issue = 9 | pages = 6575–80 | date = March 1993 | pmid = 8384216 | doi =  }}</ref><ref name="pmid1318077">{{cite journal | vauthors = Yao EF, Denison MS | title = DNA sequence determinants for binding of transformed Ah receptor to a dioxin-responsive enhancer | journal = Biochemistry | volume = 31 | issue = 21 | pages = 5060–7 | date = June 1992 | pmid = 1318077 | doi = 10.1021/bi00136a019 }}</ref> in the [[Promoter (biology)|promoter region]] of AhR responsive genes. The AhR/ARNT heterodimer directly binds the AHRE/DRE/XRE core sequence in an asymmetric manner such that ARNT binds to 5'-GTG-3' and AhR binding 5'-TC/TGC-3'.<ref name="pmid7821222">{{cite journal | vauthors = Wharton KA, Franks RG, Kasai Y, Crews ST | title = Control of CNS midline transcription by asymmetric E-box-like elements: similarity to xenobiotic responsive regulation | journal = Development | volume = 120 | issue = 12 | pages = 3563–9 | date = December 1994 | pmid = 7821222 | doi =  }}</ref><ref name="pmid7700240">{{cite journal | vauthors = Bacsi SG, Reisz-Porszasz S, Hankinson O | title = Orientation of the heterodimeric aryl hydrocarbon (dioxin) receptor complex on its asymmetric DNA recognition sequence | journal = Molecular Pharmacology | volume = 47 | issue = 3 | pages = 432–8 | date = March 1995 | pmid = 7700240 | doi =  }}</ref><ref name="pmid7592839">{{cite journal | vauthors = Swanson HI, Chan WK, Bradfield CA | title = DNA binding specificities and pairing rules of the Ah receptor, ARNT, and SIM proteins | journal = The Journal of Biological Chemistry | volume = 270 | issue = 44 | pages = 26292–302 | date = November 1995 | pmid = 7592839 | doi = 10.1074/jbc.270.44.26292 }}</ref> Recent research suggests that a second type of element termed AHRE-II, 5'-CATG(N6)C[T/A]TG-3', is capable of indirectly acting with the AhR/ARNT complex.<ref name="pmid15358164">{{cite journal | vauthors = Boutros PC, Moffat ID, Franc MA, Tijet N, Tuomisto J, Pohjanvirta R, Okey AB | title = Dioxin-responsive AHRE-II gene battery: identification by phylogenetic footprinting | journal = Biochemical and Biophysical Research Communications | volume = 321 | issue = 3 | pages = 707–15 | date = August 2004 | pmid = 15358164 | doi = 10.1016/j.bbrc.2004.06.177 }}</ref><ref name="pmid15144902">{{cite journal | vauthors = Sogawa K, Numayama-Tsuruta K, Takahashi T, Matsushita N, Miura C, Nikawa J, Gotoh O, Kikuchi Y, Fujii-Kuriyama Y | title = A novel induction mechanism of the rat CYP1A2 gene mediated by Ah receptor-Arnt heterodimer | journal = Biochemical and Biophysical Research Communications | volume = 318 | issue = 3 | pages = 746–55 | date = June 2004 | pmid = 15144902 | doi = 10.1016/j.bbrc.2004.04.090 }}</ref> Regardless of the response element, the end result is a variety of differential changes in gene expression.


==Functional role in physiology and toxicology==
==Functional role in physiology and toxicology==


===Role in development===
===Role in development===
In terms of evolution, the oldest physiological role of Ahr is in development. Ahr is presumed to have evolved from [[invertebrates]] where it served a ligand-independent role in normal development processes.<ref name="pmid16902966">{{cite journal |vauthors=Hahn ME, Karchner SI, Evans BR, Franks DG, Merson RR, Lapseritis JM |title=Unexpected diversity of aryl hydrocarbon receptors in non-mammalian vertebrates: insights from comparative genomics |journal=J. Exp. Zoolog. Part a Comp. Exp. Biol. |volume=305 |issue=9 |pages=693–706 |year=2006 |pmid=16902966 |doi=10.1002/jez.a.323}}</ref> The Ahr homolog in ''[[Drosophila]], spineless ''(ss) is necessary for development of the distal segments of the antenna and leg.<ref name="pmid9573046">{{cite journal |vauthors=Duncan DM, Burgess EA, Duncan I |title=Control of distal antennal identity and tarsal development in Drosophila by spineless-aristapedia, a homolog of the mammalian dioxin receptor |journal=Genes Dev. |volume=12 |issue=9 |pages=1290–303 |year=1998 |pmid=9573046 |pmc=316766 |doi=10.1101/gad.12.9.1290}}</ref><ref name="pmid10433921">{{cite journal |vauthors=Emmons RB, Duncan D, Estes PA, Kiefel P, Mosher JT, Sonnenfeld M, Ward MP, Duncan I, Crews ST |title=The spineless-aristapedia and tango bHLH-PAS proteins interact to control antennal and tarsal development in Drosophila |journal=Development |volume=126 |issue=17 |pages=3937–45 |date=September 1999 |pmid=10433921 |doi= }}</ref> ''Ss'' dimerizes with ''tango ''(tgo), which is the homolog to the mammalian Arnt, to initiate gene transcription. [[Evolution]] of the receptor in [[vertebrates]] resulted in the ability to bind ligand and might have helped humans evolve to tolerate smoke of fires. In developing vertebrates, Ahr seemingly plays a role in cellular proliferation and differentiation.<ref name="pmid16214954">{{cite journal |vauthors=Tijet N, Boutros PC, Moffat ID, Okey AB, Tuomisto J, Pohjanvirta R |title=Aryl hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries |journal=Mol. Pharmacol. |volume=69 |issue=1 |pages=140–53 |year=2006 |pmid=16214954 |doi=10.1124/mol.105.018705}}</ref> Despite lacking a clear endogenous ligand, AHR appears to play a role in the differentiation of many developmental pathways, including hematopoiesis,<ref name="pmid19896476">{{cite journal |vauthors=Gasiewicz TA, Singh KP, Casado FL |title=The aryl hydrocarbon receptor has an important role in the regulation of hematopoiesis: implications for benzene-induced hematopoietic toxicity |journal=Chem. Biol. Interact. |volume=184 |issue=1–2 |pages=246–51 |date=March 2010 |pmid=19896476 |pmc=2846208 |doi=10.1016/j.cbi.2009.10.019}}</ref> lymphoid systems,<ref name="pmid22033518">{{cite journal |vauthors=Kiss EA, Vonarbourg C, Kopfmann S, Hobeika E, Finke D, Esser C, Diefenbach A |title=Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles |journal=Science |volume=334 |issue=6062 |pages=1561–5 |date=December 2011 |pmid=22033518 |doi=10.1126/science.1214914}}</ref><ref name="Li_2012">{{cite journal |vauthors=Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR, Grigorieva EF, Wilhelm C, Veldhoen M |title=Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation |journal=Cell |volume=147 |issue=3 |pages=629–40 |date=October 2011 |pmid=21999944 |doi=10.1016/j.cell.2011.09.025}}</ref> T-cells,<ref name="pmid18362915">{{cite journal |vauthors=Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, Caccamo M, Oukka M, Weiner HL |title=Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor |journal=Nature |volume=453 |pages=65–71 |year=2008 |pmid=18362915 |doi=10.1038/nature06880}}</ref> neurons,<ref name="pmid16956419">{{cite journal |vauthors=Akahoshi E, Yoshimura S, Ishihara-Sugano M |title=Over-expression of AhR (aryl hydrocarbon receptor) induces neural differentiation of Neuro2a cells: neurotoxicology study |journal=Environ Health. |volume=5 |page=24 |year=2006 |pmid=16956419 |pmc=1570454 |doi=10.1186/1476-069X-5-24}}</ref> and hepatocytes.<ref name="pmid16301529">{{cite journal |vauthors=Walisser JA, Glover E, Pande K, Liss AL, Bradfield CA |title=Aryl hydrocarbon receptor-dependent liver development and hepatotoxicity are mediated by different cell types |journal=Proc Natl Acad Sci U S A |volume=102 |issue=49 |pages=17858–63 |year=2005 |pmid=16301529 |pmc=1308889 |doi=10.1073/pnas.0504757102}}</ref> AhR has also been found to have an important function in hematopoietic stem cells: AhR antagonism promotes their self-renewal and ex-vivo expansion<ref name="pmid20688981">{{cite journal |vauthors=Boitano AE, Wang J, Romeo R, Bouchez LC, Parker AE, Sutton SE, Walker JR, Flaveny CA, Perdew GH, Denison MS, Schultz PG, Cooke MP |title=Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells |journal=Science |volume=329 |issue=5997 |pages=1345–8 |date=September 2010 |pmid=20688981 |pmc=3033342 |doi=10.1126/science.1191536}}</ref> and is involved in megakaryocyte differentiation.<ref name="pmid=21226706">{{cite journal |vauthors=Lindsey S, Papoutsakis ET |title=The aryl hydrocarbon receptor (AHR) transcription factor regulates megakaryocytic polyploidization |journal=Br J Haematol. |volume=152 |issue=4 |pages=469–84 |year=2011 |pmid=21226706 |pmc=3408620 |doi=10.1111/j.1365-2141.2010.08548.x}}</ref>
In terms of evolution, the oldest physiological role of Ahr is in development. Ahr is presumed to have evolved from [[invertebrates]] where it served a ligand-independent role in normal development processes.<ref name="pmid16902966">{{cite journal | vauthors = Hahn ME, Karchner SI, Evans BR, Franks DG, Merson RR, Lapseritis JM | title = Unexpected diversity of aryl hydrocarbon receptors in non-mammalian vertebrates: insights from comparative genomics | journal = Journal of Experimental Zoology Part A: Comparative Experimental Biology | volume = 305 | issue = 9 | pages = 693–706 | date = September 2006 | pmid = 16902966 | doi = 10.1002/jez.a.323 }}</ref> The Ahr homolog in ''[[Drosophila]], spineless ''(ss) is necessary for development of the distal segments of the antenna and leg.<ref name="pmid9573046">{{cite journal | vauthors = Duncan DM, Burgess EA, Duncan I | title = Control of distal antennal identity and tarsal development in Drosophila by spineless-aristapedia, a homolog of the mammalian dioxin receptor | journal = Genes & Development | volume = 12 | issue = 9 | pages = 1290–303 | date = May 1998 | pmid = 9573046 | pmc = 316766 | doi = 10.1101/gad.12.9.1290 }}</ref><ref name="pmid10433921">{{cite journal | vauthors = Emmons RB, Duncan D, Estes PA, Kiefel P, Mosher JT, Sonnenfeld M, Ward MP, Duncan I, Crews ST | title = The spineless-aristapedia and tango bHLH-PAS proteins interact to control antennal and tarsal development in Drosophila | journal = Development | volume = 126 | issue = 17 | pages = 3937–45 | date = September 1999 | pmid = 10433921 | doi = }}</ref> ''Ss'' dimerizes with ''tango ''(tgo), which is the homolog to the mammalian Arnt, to initiate gene transcription. [[Evolution]] of the receptor in [[vertebrates]] resulted in the ability to bind ligand and might have helped humans evolve to tolerate smoke of fires. In developing vertebrates, Ahr seemingly plays a role in cellular proliferation and differentiation.<ref name="pmid16214954">{{cite journal | vauthors = Tijet N, Boutros PC, Moffat ID, Okey AB, Tuomisto J, Pohjanvirta R | title = Aryl hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries | journal = Molecular Pharmacology | volume = 69 | issue = 1 | pages = 140–53 | date = January 2006 | pmid = 16214954 | doi = 10.1124/mol.105.018705 }}</ref> Despite lacking a clear endogenous ligand, AHR appears to play a role in the differentiation of many developmental pathways, including hematopoiesis,<ref name="pmid19896476">{{cite journal | vauthors = Gasiewicz TA, Singh KP, Casado FL | title = The aryl hydrocarbon receptor has an important role in the regulation of hematopoiesis: implications for benzene-induced hematopoietic toxicity | journal = Chemico-Biological Interactions | volume = 184 | issue = 1–2 | pages = 246–51 | date = March 2010 | pmid = 19896476 | pmc = 2846208 | doi = 10.1016/j.cbi.2009.10.019 }}</ref> lymphoid systems,<ref name="pmid22033518">{{cite journal | vauthors = Kiss EA, Vonarbourg C, Kopfmann S, Hobeika E, Finke D, Esser C, Diefenbach A | title = Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles | journal = Science | volume = 334 | issue = 6062 | pages = 1561–5 | date = December 2011 | pmid = 22033518 | doi = 10.1126/science.1214914 }}</ref><ref name="Li_2012">{{cite journal | vauthors = Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR, Grigorieva EF, Wilhelm C, Veldhoen M | title = Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation | journal = Cell | volume = 147 | issue = 3 | pages = 629–40 | date = October 2011 | pmid = 21999944 | doi = 10.1016/j.cell.2011.09.025 }}</ref> T-cells,<ref name="pmid18362915">{{cite journal | vauthors = Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, Caccamo M, Oukka M, Weiner HL | title = Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor | journal = Nature | volume = 453 | issue = 7191 | pages = 65–71 | date = May 2008 | pmid = 18362915 | doi = 10.1038/nature06880 }}</ref> neurons,<ref name="pmid16956419">{{cite journal | vauthors = Akahoshi E, Yoshimura S, Ishihara-Sugano M | title = Over-expression of AhR (aryl hydrocarbon receptor) induces neural differentiation of Neuro2a cells: neurotoxicology study | journal = Environmental Health | volume = 5 | pages = 24 | date = September 2006 | pmid = 16956419 | pmc = 1570454 | doi = 10.1186/1476-069X-5-24 }}</ref> and hepatocytes.<ref name="pmid16301529">{{cite journal | vauthors = Walisser JA, Glover E, Pande K, Liss AL, Bradfield CA | title = Aryl hydrocarbon receptor-dependent liver development and hepatotoxicity are mediated by different cell types | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 49 | pages = 17858–63 | date = December 2005 | pmid = 16301529 | pmc = 1308889 | doi = 10.1073/pnas.0504757102 }}</ref> AhR has also been found to have an important function in hematopoietic stem cells: AhR antagonism promotes their self-renewal and ex-vivo expansion<ref name="pmid20688981">{{cite journal | vauthors = Boitano AE, Wang J, Romeo R, Bouchez LC, Parker AE, Sutton SE, Walker JR, Flaveny CA, Perdew GH, Denison MS, Schultz PG, Cooke MP | title = Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells | journal = Science | volume = 329 | issue = 5997 | pages = 1345–8 | date = September 2010 | pmid = 20688981 | pmc = 3033342 | doi = 10.1126/science.1191536 }}</ref> and is involved in megakaryocyte differentiation.<ref name="pmid=21226706">{{cite journal | vauthors = Lindsey S, Papoutsakis ET | title = The aryl hydrocarbon receptor (AHR) transcription factor regulates megakaryocytic polyploidization | journal = British Journal of Haematology | volume = 152 | issue = 4 | pages = 469–84 | date = February 2011 | pmid = 21226706 | pmc = 3408620 | doi = 10.1111/j.1365-2141.2010.08548.x }}</ref>


===Adaptive and innate response===
===Adaptive and innate response===
The adaptive response is manifested as the induction of xenobiotic metabolizing enzymes. Evidence of this response was first observed from the induction of cytochrome P450, family 1, subfamily A, polypeptide 1 (Cyp1a1) resultant from TCDD exposure, which was determined to be directly related to activation of the Ahr signaling pathway.<ref name="pmid6885786">{{cite journal | vauthors = Israel DI, Whitlock JP | title = Induction of mRNA specific for cytochrome P1-450 in wild type and variant mouse hepatoma cells | journal = J. Biol. Chem. | volume = 258 | issue = 17 | pages = 10390–4 | year = 1983 | pmid = 6885786 | doi =  }}</ref><ref name="pmid6715350">{{cite journal | vauthors = Israel DI, Whitlock JP | title = Regulation of cytochrome P1-450 gene transcription by 2,3,7, 8-tetrachlorodibenzo-p-dioxin in wild type and variant mouse hepatoma cells | journal = J. Biol. Chem. | volume = 259 | issue = 9 | pages = 5400–2 | year = 1984 | pmid = 6715350 | doi =  }}</ref><ref name="pmid8524325">{{cite journal | vauthors = Ko HP, Okino ST, Ma Q, Whitlock JP | title = Dioxin-induced CYP1A1 transcription in vivo: the aromatic hydrocarbon receptor mediates transactivation, enhancer-promoter communication, and changes in chromatin structure | journal = Mol. Cell. Biol. | volume = 16 | issue = 1 | pages = 430–6 | year = 1996 | pmid = 8524325 | pmc = 231019 | doi =  }}</ref>  The search for other metabolizing genes induced by Ahr ligands, due to the presence of DREs, has led to the identification of an "Ahr gene battery" of Phase I and Phase II metabolizing enzymes consisting of [[CYP1A1]], [[CYP1A2]], [[CYP1B1]], NQO1, ALDH3A1, UGT1A2 and GSTA1.<ref name="pmid10605936">{{cite journal | vauthors = Nebert DW, Roe AL, Dieter MZ, Solis WA, Yang Y, Dalton TP | title = Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis | journal = Biochem. Pharmacol. | volume = 59 | issue = 1 | pages = 65–85 | year = 2000 | pmid = 10605936 | doi = 10.1016/S0006-2952(99)00310-X }}</ref> Presumably, vertebrates have this function to be able to detect a wide range of chemicals, indicated by the wide range of substrates Ahr is able to bind and facilitate their [[biotransformation]] and elimination. The AhR may also signal the presence of toxic chemicals in food and cause aversion of such foods.<ref name="pmid21458548">{{cite journal | vauthors = Lensu S, Tuomisto JT, Tuomisto J, Viluksela M, Niittynen M, Pohjanvirta R | title = Immediate and highly sensitive aversion response to a novel food item linked to AH receptor stimulation | journal = Toxicol. Lett. | volume = 203 | issue = 3 | pages = 252–7 | date = June 2011 | pmid = 21458548 | doi = 10.1016/j.toxlet.2011.03.025 }}</ref>
The adaptive response is manifested as the induction of xenobiotic metabolizing enzymes. Evidence of this response was first observed from the induction of cytochrome P450, family 1, subfamily A, polypeptide 1 (Cyp1a1) resultant from TCDD exposure, which was determined to be directly related to activation of the Ahr signaling pathway.<ref name="pmid6885786">{{cite journal | vauthors = Israel DI, Whitlock JP | title = Induction of mRNA specific for cytochrome P1-450 in wild type and variant mouse hepatoma cells | journal = The Journal of Biological Chemistry | volume = 258 | issue = 17 | pages = 10390–4 | date = September 1983 | pmid = 6885786 | doi =  }}</ref><ref name="pmid6715350">{{cite journal | vauthors = Israel DI, Whitlock JP | title = Regulation of cytochrome P1-450 gene transcription by 2,3,7, 8-tetrachlorodibenzo-p-dioxin in wild type and variant mouse hepatoma cells | journal = The Journal of Biological Chemistry | volume = 259 | issue = 9 | pages = 5400–2 | date = May 1984 | pmid = 6715350 | doi =  }}</ref><ref name="pmid8524325">{{cite journal | vauthors = Ko HP, Okino ST, Ma Q, Whitlock JP | title = Dioxin-induced CYP1A1 transcription in vivo: the aromatic hydrocarbon receptor mediates transactivation, enhancer-promoter communication, and changes in chromatin structure | journal = Molecular and Cellular Biology | volume = 16 | issue = 1 | pages = 430–6 | date = January 1996 | pmid = 8524325 | pmc = 231019 | doi =  }}</ref>  The search for other metabolizing genes induced by Ahr ligands, due to the presence of DREs, has led to the identification of an "Ahr gene battery" of Phase I and Phase II metabolizing enzymes consisting of [[CYP1A1]], [[CYP1A2]], [[CYP1B1]], NQO1, ALDH3A1, UGT1A2 and GSTA1.<ref name="pmid10605936">{{cite journal | vauthors = Nebert DW, Roe AL, Dieter MZ, Solis WA, Yang Y, Dalton TP | title = Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis | journal = Biochemical Pharmacology | volume = 59 | issue = 1 | pages = 65–85 | date = January 2000 | pmid = 10605936 | doi = 10.1016/S0006-2952(99)00310-X }}</ref> Presumably, vertebrates have this function to be able to detect a wide range of chemicals, indicated by the wide range of substrates Ahr is able to bind and facilitate their [[biotransformation]] and elimination. The AhR may also signal the presence of toxic chemicals in food and cause aversion of such foods.<ref name="pmid21458548">{{cite journal | vauthors = Lensu S, Tuomisto JT, Tuomisto J, Viluksela M, Niittynen M, Pohjanvirta R | title = Immediate and highly sensitive aversion response to a novel food item linked to AH receptor stimulation | journal = Toxicology Letters | volume = 203 | issue = 3 | pages = 252–7 | date = June 2011 | pmid = 21458548 | doi = 10.1016/j.toxlet.2011.03.025 }}</ref>


AhR activation seems to be also important for immunological responses and inhibiting inflammation <ref name="Li_2012"/> through upregulation of [[interleukin 22]] <ref name="pmid21600206">{{cite journal | vauthors = Monteleone I, Rizzo A, Sarra M, Sica G, Sileri P, Biancone L, MacDonald TT, Pallone F, Monteleone G | title = Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract | journal = Gastroenterology | volume = 141 | issue = 1 | pages = 237–48, 248.e1 | date = July 2011 | pmid = 21600206 | doi = 10.1053/j.gastro.2011.04.007 }}</ref> and downregulation of [[Th17]] response.<ref name=" pmid = 24514067 ">{{cite journal | vauthors = Wei P, Hu GH, Kang HY, Yao HB, Kou W, Liu H, Zhang C, Hong SL | title = An aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress the Th17 response in allergic rhinitis patients. | journal = Lab Invest. | volume = 94 | issue = 5 | pages = 528–35 | date = May 2014 | pmid = 24514067 | doi = 10.1038/labinvest.2014.8 }}</ref>
AhR activation seems to be also important for immunological responses and inhibiting inflammation <ref name="Li_2012"/> through upregulation of [[interleukin 22]] <ref name="pmid21600206">{{cite journal | vauthors = Monteleone I, Rizzo A, Sarra M, Sica G, Sileri P, Biancone L, MacDonald TT, Pallone F, Monteleone G | title = Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract | journal = Gastroenterology | volume = 141 | issue = 1 | pages = 237–48, 248.e1 | date = July 2011 | pmid = 21600206 | doi = 10.1053/j.gastro.2011.04.007 }}</ref> and downregulation of [[Th17]] response.<ref name=" pmid = 24514067 ">{{cite journal | vauthors = Wei P, Hu GH, Kang HY, Yao HB, Kou W, Liu H, Zhang C, Hong SL | title = An aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress the Th17 response in allergic rhinitis patients | journal = Laboratory Investigation; A Journal of Technical Methods and Pathology | volume = 94 | issue = 5 | pages = 528–35 | date = May 2014 | pmid = 24514067 | doi = 10.1038/labinvest.2014.8 }}</ref>
The Knockdown of AHR mostly downregulates the expression of innate immunity genes in [[THP-1 cell line|THP-1 cells]].<ref name="pmid26416282">{{cite journal | vauthors = Memari B, Bouttier M, Dimitrov V, Ouellette M, Behr MA, Fritz JH, White JH | title = Engagement of the Aryl Hydrocarbon Receptor in Mycobacterium tuberculosis-Infected Macrophages Has Pleiotropic Effects on Innate Immune Signaling | journal = Journal of Immunology | volume = 195 | issue = 9 | pages = 4479–91 | date = Nov 2015 | pmid = 26416282 | doi = 10.4049/jimmunol.1501141 }}</ref>
The Knockdown of AHR mostly downregulates the expression of innate immunity genes in [[THP-1 cell line|THP-1 cells]].<ref name="pmid26416282">{{cite journal | vauthors = Memari B, Bouttier M, Dimitrov V, Ouellette M, Behr MA, Fritz JH, White JH | title = Engagement of the Aryl Hydrocarbon Receptor in Mycobacterium tuberculosis-Infected Macrophages Has Pleiotropic Effects on Innate Immune Signaling | journal = Journal of Immunology | volume = 195 | issue = 9 | pages = 4479–91 | date = November 2015 | pmid = 26416282 | doi = 10.4049/jimmunol.1501141 }}</ref>


===Toxic response===
===Toxic response===
Extensions of the adaptive response are the toxic responses elicited by Ahr activation. Toxicity results from two different ways of Ahr signaling. The first is a side effect of the adaptive response in which the induction of metabolizing enzymes results in the production of toxic metabolites. For example, the polycyclic aromatic hydrocarbon [[benzo(a)pyrene|benzo[''a'']pyrene]] (BaP), a ligand for Ahr, induces its own metabolism and bioactivation to a toxic metabolite via the induction of [[CYP1A1]] and [[CYP1B1]] in several tissues.<ref name="pmid14691214">{{cite journal | vauthors = Harrigan JA, Vezina CM, McGarrigle BP, Ersing N, Box HC, Maccubbin AE, Olson JR | title = DNA adduct formation in precision-cut rat liver and lung slices exposed to benzo[a]pyrene | journal = Toxicol. Sci. | volume = 77 | issue = 2 | pages = 307–14 | date = February 2004 | pmid = 14691214 | doi = 10.1093/toxsci/kfh030 }}</ref> The second approach to toxicity is the result of aberrant changes in global gene transcription beyond those observed in the "Ahr gene battery." These global changes in gene expression lead to adverse changes in cellular processes and function.<ref name="pmid20624415">{{cite journal | vauthors = Lindén J, Lensu S, Tuomisto J, Pohjanvirta R | title = Dioxins, the aryl hydrocarbon receptor and the central regulation of energy balance | journal = Front Neuroendocrinol | volume = 31 | issue = 4 | pages = 452–78 | date = October 2010 | pmid = 20624415 | doi = 10.1016/j.yfrne.2010.07.002 }}</ref> [[DNA microarray|Microarray analysis]] has proved most beneficial in understanding and characterizing this response.<ref name="pmid16214954"/><ref name="pmid12377990">{{cite journal | vauthors = Martinez JM, Afshari CA, Bushel PR, Masuda A, Takahashi T, Walker NJ | title = Differential toxicogenomic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin in malignant and nonmalignant human airway epithelial cells | journal = Toxicol. Sci. | volume = 69 | issue = 2 | pages = 409–23 | year = 2002 | pmid = 12377990 | doi = 10.1093/toxsci/69.2.409 }}</ref><ref name="pmid15598615">{{cite journal | vauthors = Vezina CM, Walker NJ, Olson JR | title = Subchronic exposure to TCDD, PeCDF, PCB126, and PCB153: effect on hepatic gene expression | journal = Environ. Health Perspect. | volume = 112 | issue = 16 | pages = 1636–44 | year = 2004 | pmid = 15598615 | pmc = 1247661 | doi = 10.1289/ehp.7253 }}</ref><ref name="pmid16984957">{{cite journal | vauthors = Ovando BJ, Vezina CM, McGarrigle BP, Olson JR | title = Hepatic gene downregulation following acute and subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin | journal = Toxicol. Sci. | volume = 94 | issue = 2 | pages = 428–38 | year = 2006 | pmid = 16984957 | doi = 10.1093/toxsci/kfl111 }}</ref>
Extensions of the adaptive response are the toxic responses elicited by Ahr activation. Toxicity results from two different ways of Ahr signaling. The first is a side effect of the adaptive response in which the induction of metabolizing enzymes results in the production of toxic metabolites. For example, the polycyclic aromatic hydrocarbon [[benzo(a)pyrene|benzo[''a'']pyrene]] (BaP), a ligand for Ahr, induces its own metabolism and bioactivation to a toxic metabolite via the induction of [[CYP1A1]] and [[CYP1B1]] in several tissues.<ref name="pmid14691214">{{cite journal | vauthors = Harrigan JA, Vezina CM, McGarrigle BP, Ersing N, Box HC, Maccubbin AE, Olson JR | title = DNA adduct formation in precision-cut rat liver and lung slices exposed to benzo[a]pyrene | journal = Toxicological Sciences | volume = 77 | issue = 2 | pages = 307–14 | date = February 2004 | pmid = 14691214 | doi = 10.1093/toxsci/kfh030 }}</ref> The second approach to toxicity is the result of aberrant changes in global gene transcription beyond those observed in the "Ahr gene battery." These global changes in gene expression lead to adverse changes in cellular processes and function.<ref name="pmid20624415">{{cite journal | vauthors = Lindén J, Lensu S, Tuomisto J, Pohjanvirta R | title = Dioxins, the aryl hydrocarbon receptor and the central regulation of energy balance | journal = Frontiers in Neuroendocrinology | volume = 31 | issue = 4 | pages = 452–78 | date = October 2010 | pmid = 20624415 | doi = 10.1016/j.yfrne.2010.07.002 }}</ref> [[DNA microarray|Microarray analysis]] has proved most beneficial in understanding and characterizing this response.<ref name="pmid16214954"/><ref name="pmid12377990">{{cite journal | vauthors = Martinez JM, Afshari CA, Bushel PR, Masuda A, Takahashi T, Walker NJ | title = Differential toxicogenomic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin in malignant and nonmalignant human airway epithelial cells | journal = Toxicological Sciences | volume = 69 | issue = 2 | pages = 409–23 | date = October 2002 | pmid = 12377990 | doi = 10.1093/toxsci/69.2.409 }}</ref><ref name="pmid15598615">{{cite journal | vauthors = Vezina CM, Walker NJ, Olson JR | title = Subchronic exposure to TCDD, PeCDF, PCB126, and PCB153: effect on hepatic gene expression | journal = Environmental Health Perspectives | volume = 112 | issue = 16 | pages = 1636–44 | date = November 2004 | pmid = 15598615 | pmc = 1247661 | doi = 10.1289/ehp.7253 }}</ref><ref name="pmid16984957">{{cite journal | vauthors = Ovando BJ, Vezina CM, McGarrigle BP, Olson JR | title = Hepatic gene downregulation following acute and subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin | journal = Toxicological Sciences | volume = 94 | issue = 2 | pages = 428–38 | date = December 2006 | pmid = 16984957 | doi = 10.1093/toxsci/kfl111 }}</ref>


==Protein-protein interactions==
==Protein-protein interactions==
In addition to the protein interactions mentioned above, AhR has also been shown to [[Protein-protein interaction|interact]] with:
In addition to the protein interactions mentioned above, AhR has also been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
{{div col|colwidth=20em}}
* [[ARNTL]],<ref name = pmid9079689>{{cite journal | vauthors = Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA | title = Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway | journal = J. Biol. Chem. | volume = 272 | issue = 13 | pages = 8581–93 | year = 1997 | pmid = 9079689 | doi = 10.1074/jbc.272.13.8581 }}</ref>
*[[AH receptor-interacting protein|AIP]],<ref name = PMID25911105.>{{cite journal | vauthors = Zhou Q, Lavorgna A, Bowman M, Hiscott J, Harhaj EW | title = Aryl Hydrocarbon Receptor Interacting Protein Targets IRF7 to Suppress Antiviral Signaling and the Induction of Type I Interferon | journal = The Journal of Biological Chemistry | volume = 290 | issue = 23 | pages = 14729–39 | date = June 2015 | pmid = 25911105 | doi = 10.1074/jbc.M114.633065 | url = http://www.jbc.org/content/290/23/14729.short | pmc = 4505538 }}</ref>
* [[Cyclin T1|CCNT1]],<ref name = pmid12917420>{{cite journal | vauthors = Tian Y, Ke S, Chen M, Sheng T | title = Interactions between the aryl hydrocarbon receptor and P-TEFb. Sequential recruitment of transcription factors and differential phosphorylation of C-terminal domain of RNA polymerase II at cyp1a1 promoter | journal = J. Biol. Chem. | volume = 278 | issue = 45 | pages = 44041–8 | year = 2003 | pmid = 12917420 | doi = 10.1074/jbc.M306443200 }}</ref>
* [[ARNTL]],<ref name = pmid9079689>{{cite journal | vauthors = Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA | title = Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway | journal = The Journal of Biological Chemistry | volume = 272 | issue = 13 | pages = 8581–93 | date = March 1997 | pmid = 9079689 | doi = 10.1074/jbc.272.13.8581 }}</ref>
* [[Estrogen receptor alpha|ESR1]],<ref name = pmid12612060>{{cite journal | vauthors = Wormke M, Stoner M, Saville B, Walker K, Abdelrahim M, Burghardt R, Safe S | title = The aryl hydrocarbon receptor mediates degradation of estrogen receptor alpha through activation of proteasomes | journal = Mol. Cell. Biol. | volume = 23 | issue = 6 | pages = 1843–55 | year = 2003 | pmid = 12612060 | pmc = 149455 | doi = 10.1128/MCB.23.6.1843-1855.2003 }}</ref><ref name = pmid10620335>{{cite journal | vauthors = Klinge CM, Kaur K, Swanson HI | title = The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TFI and ERRalpha1 | journal = Arch. Biochem. Biophys. | volume = 373 | issue = 1 | pages = 163–74 | year = 2000 | pmid = 10620335 | doi = 10.1006/abbi.1999.1552 }}</ref>
* [[Cyclin T1|CCNT1]],<ref name = pmid12917420>{{cite journal | vauthors = Tian Y, Ke S, Chen M, Sheng T | title = Interactions between the aryl hydrocarbon receptor and P-TEFb. Sequential recruitment of transcription factors and differential phosphorylation of C-terminal domain of RNA polymerase II at cyp1a1 promoter | journal = The Journal of Biological Chemistry | volume = 278 | issue = 45 | pages = 44041–8 | date = November 2003 | pmid = 12917420 | doi = 10.1074/jbc.M306443200 }}</ref>
* [[Nuclear receptor coactivator 1|NCOA1]],<ref name = pmid12024042>{{cite journal | vauthors = Beischlag TV, Wang S, Rose DW, Torchia J, Reisz-Porszasz S, Muhammad K, Nelson WE, Probst MR, Rosenfeld MG, Hankinson O | title = Recruitment of the NCoA/SRC-1/p160 family of transcriptional coactivators by the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator complex | journal = Mol. Cell. Biol. | volume = 22 | issue = 12 | pages = 4319–33 | year = 2002 | pmid = 12024042 | pmc = 133867 | doi = 10.1128/MCB.22.12.4319-4333.2002 }}</ref>  
* [[Estrogen receptor alpha|ESR1]],<ref name = pmid12612060>{{cite journal | vauthors = Wormke M, Stoner M, Saville B, Walker K, Abdelrahim M, Burghardt R, Safe S | title = The aryl hydrocarbon receptor mediates degradation of estrogen receptor alpha through activation of proteasomes | journal = Molecular and Cellular Biology | volume = 23 | issue = 6 | pages = 1843–55 | date = March 2003 | pmid = 12612060 | pmc = 149455 | doi = 10.1128/MCB.23.6.1843-1855.2003 }}</ref><ref name = pmid10620335>{{cite journal | vauthors = Klinge CM, Kaur K, Swanson HI | title = The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TFI and ERRalpha1 | journal = Archives of Biochemistry and Biophysics | volume = 373 | issue = 1 | pages = 163–74 | date = January 2000 | pmid = 10620335 | doi = 10.1006/abbi.1999.1552 }}</ref>
* [[NEDD8]]<ref name = pmid12215427>{{cite journal | vauthors = Antenos M, Casper RF, Brown TJ | title = Interaction with Nedd8, a ubiquitin-like protein, enhances the transcriptional activity of the aryl hydrocarbon receptor | journal = J. Biol. Chem. | volume = 277 | issue = 46 | pages = 44028–34 | year = 2002 | pmid = 12215427 | doi = 10.1074/jbc.M202413200 }}</ref>  
* [[Nuclear receptor coactivator 1|NCOA1]],<ref name = pmid12024042>{{cite journal | vauthors = Beischlag TV, Wang S, Rose DW, Torchia J, Reisz-Porszasz S, Muhammad K, Nelson WE, Probst MR, Rosenfeld MG, Hankinson O | title = Recruitment of the NCoA/SRC-1/p160 family of transcriptional coactivators by the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator complex | journal = Molecular and Cellular Biology | volume = 22 | issue = 12 | pages = 4319–33 | date = June 2002 | pmid = 12024042 | pmc = 133867 | doi = 10.1128/MCB.22.12.4319-4333.2002 }}</ref>  
* [[NRIP1]],<ref name = pmid10428779>{{cite journal | vauthors = Kumar MB, Tarpey RW, Perdew GH | title = Differential recruitment of coactivator RIP140 by Ah and estrogen receptors. Absence of a role for LXXLL motifs | journal = J. Biol. Chem. | volume = 274 | issue = 32 | pages = 22155–64 | year = 1999 | pmid = 10428779 | doi = 10.1074/jbc.274.32.22155 }}</ref>  
* [[NEDD8]]<ref name = pmid12215427>{{cite journal | vauthors = Antenos M, Casper RF, Brown TJ | title = Interaction with Nedd8, a ubiquitin-like protein, enhances the transcriptional activity of the aryl hydrocarbon receptor | journal = The Journal of Biological Chemistry | volume = 277 | issue = 46 | pages = 44028–34 | date = November 2002 | pmid = 12215427 | doi = 10.1074/jbc.M202413200 }}</ref>  
* [[RELA]],<ref name = pmid11114727>{{cite journal | vauthors = Kim DW, Gazourian L, Quadri SA, Romieu-Mourez R, Sherr DH, Sonenshein GE | title = The RelA NF-kappaB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells | journal = Oncogene | volume = 19 | issue = 48 | pages = 5498–506 | year = 2000 | pmid = 11114727 | doi = 10.1038/sj.onc.1203945 }}</ref><ref name = pmid12181450>{{cite journal | vauthors = Ruby CE, Leid M, Kerkvliet NI | title = 2,3,7,8-Tetrachlorodibenzo-p-dioxin suppresses tumor necrosis factor-alpha and anti-CD40-induced activation of NF-kappaB/Rel in dendritic cells: p50 homodimer activation is not affected | journal = Mol. Pharmacol. | volume = 62 | issue = 3 | pages = 722–8 | year = 2002 | pmid = 12181450 | doi = 10.1124/mol.62.3.722 }}</ref>  
* [[NRIP1]],<ref name = pmid10428779>{{cite journal | vauthors = Kumar MB, Tarpey RW, Perdew GH | title = Differential recruitment of coactivator RIP140 by Ah and estrogen receptors. Absence of a role for LXXLL motifs | journal = The Journal of Biological Chemistry | volume = 274 | issue = 32 | pages = 22155–64 | date = August 1999 | pmid = 10428779 | doi = 10.1074/jbc.274.32.22155 }}</ref>  
* [[RELB]],<ref name="pmid17823304">{{cite journal | vauthors = Vogel CF, Sciullo E, Li W, Wong P, Lazennec G, Matsumura F | title = RelB, a new partner of aryl hydrocarbon receptor-mediated transcription | journal = Molecular Endocrinology (Baltimore, Md.) | volume = 21 | issue = 12 | pages = 2941–55 | year = 2007 | pmid = 17823304 | pmc = 2346533 | doi = 10.1210/me.2007-0211 | url = }}</ref> and
* [[RELA]],<ref name = pmid11114727>{{cite journal | vauthors = Kim DW, Gazourian L, Quadri SA, Romieu-Mourez R, Sherr DH, Sonenshein GE | title = The RelA NF-kappaB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells | journal = Oncogene | volume = 19 | issue = 48 | pages = 5498–506 | date = November 2000 | pmid = 11114727 | doi = 10.1038/sj.onc.1203945 }}</ref><ref name = pmid12181450>{{cite journal | vauthors = Ruby CE, Leid M, Kerkvliet NI | title = 2,3,7,8-Tetrachlorodibenzo-p-dioxin suppresses tumor necrosis factor-alpha and anti-CD40-induced activation of NF-kappaB/Rel in dendritic cells: p50 homodimer activation is not affected | journal = Molecular Pharmacology | volume = 62 | issue = 3 | pages = 722–8 | date = September 2002 | pmid = 12181450 | doi = 10.1124/mol.62.3.722 }}</ref>  
* [[Retinoblastoma protein|RP]].<ref name = pmid9712901>{{cite journal | vauthors = Ge NL, Elferink CJ | title = A direct interaction between the aryl hydrocarbon receptor and retinoblastoma protein. Linking dioxin signaling to the cell cycle | journal = J. Biol. Chem. | volume = 273 | issue = 35 | pages = 22708–13 | year = 1998 | pmid = 9712901 | doi = 10.1074/jbc.273.35.22708 }}</ref>  
* [[RELB]],<ref name="pmid17823304">{{cite journal | vauthors = Vogel CF, Sciullo E, Li W, Wong P, Lazennec G, Matsumura F | title = RelB, a new partner of aryl hydrocarbon receptor-mediated transcription | journal = Molecular Endocrinology | volume = 21 | issue = 12 | pages = 2941–55 | date = December 2007 | pmid = 17823304 | pmc = 2346533 | doi = 10.1210/me.2007-0211 }}</ref> and
* [[Retinoblastoma protein|RP]].<ref name = pmid9712901>{{cite journal | vauthors = Ge NL, Elferink CJ | title = A direct interaction between the aryl hydrocarbon receptor and retinoblastoma protein. Linking dioxin signaling to the cell cycle | journal = The Journal of Biological Chemistry | volume = 273 | issue = 35 | pages = 22708–13 | date = August 1998 | pmid = 9712901 | doi = 10.1074/jbc.273.35.22708 }}</ref>  
{{Div col end}}
{{Div col end}}


==References==
== References ==
{{Reflist|33em}}
{{Reflist|33em}}


==External links==
== External links ==
* {{MeshName|Aryl+hydrocarbon+receptor}}
* {{MeshName|Aryl+hydrocarbon+receptor}}
* {{UCSC gene info|AHR}}
* {{UCSC gene info|AHR}}

Revision as of 17:19, 7 November 2018

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The aryl hydrocarbon receptor (AhR or AHR or ahr or ahR) is a protein that in humans is encoded by the AHR gene. The aryl hydrocarbon receptor is a transcription factor that regulates gene expression. It was originally thought to function primarily as a sensor of xenobiotic chemicals and also as the regulator of enzymes such as cytochrome P450s that metabolize these chemicals. The most notable of these xenobiotic chemicals are aromatic (aryl) hydrocarbons from which the receptor derives its name.

More recently, it has been discovered that AhR is activated (or deactivated) by a number of endogenous indole derivatives such as kynurenine. In addition to regulating metabolism enzymes, the AhR has roles in regulating immunity, stem cell maintenance, and cellular differentiation.[1][2][3]

The aryl hydrocarbon receptor is a member of the family of basic helix-loop-helix transcription factors. AHR binds several exogenous ligands such as natural plant flavonoids, polyphenolics and indoles, as well as synthetic polycyclic aromatic hydrocarbons and dioxin-like compounds. AhR is a cytosolic transcription factor that is normally inactive, bound to several co-chaperones. Upon ligand binding to chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the chaperones dissociate resulting in AhR translocating into the nucleus and dimerizing with ARNT (AhR nuclear translocator), leading to changes in gene transcription.

Protein functional domains

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AhR Functional Domains

The AhR protein contains several domains critical for function and is classified as a member of the basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) family of transcription factors.[4][5] The bHLH motif is located in the N-terminal of the protein and is a common entity in a variety of transcription factors.[6] Members of the bHLH superfamily have two functionally distinctive and highly conserved domains. The first is the basic-region (b), which is involved in the binding of the transcription factor to DNA. The second is the helix-loop-helix (HLH) region, which facilitates protein-protein interactions. Also contained with the AhR are two PAS domains, PAS-A and PAS-B, which are stretches of 200-350 amino acids that exhibit a high sequence homology to the protein domains that were originally found in the Drosophila genes period (Per) and single-minded (Sim) and in AhR’s dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT).[7] The PAS domains support specific secondary interactions with other PAS domain containing proteins, as is the case with AhR and ARNT, so that dimeric and heteromeric protein complexes can form. The ligand binding site of AhR is contained within the PAS-B domain[8] and contains several conserved residues critical for ligand binding.[9] Finally, a glutamine-rich (Q-rich) domain is located in the C-terminal region of the protein and is involved in co-activator recruitment and transactivation.[10]

Ligands

AhR ligands have been generally classified into two categories, synthetic or naturally occurring. The first ligands to be discovered were synthetic and members of the halogenated aromatic hydrocarbons (polychlorinated dibenzodioxins, dibenzofurans and biphenyls) and polycyclic aromatic hydrocarbons (3-methylcholanthrene, benzo[a]pyrene, benzanthracenes and benzoflavones).[11][12]

Research has focused on naturally occurring compounds with the hope of identifying an endogenous ligand. Naturally occurring compounds that have been identified as ligands of Ahr include derivatives of tryptophan such as indigo dye and indirubin,[13] tetrapyrroles such as bilirubin,[14] the arachidonic acid metabolites lipoxin A4 and prostaglandin G,[15] modified low-density lipoprotein[16] and several dietary carotenoids.[12] One assumption made in the search for an endogenous ligand is that the ligand will be a receptor agonist. However, work by Savouret et al. has shown this may not be the case since their findings demonstrate that 7-ketocholesterol competitively inhibits Ahr signal transduction.[17]

Carbidopa is a selective aryl hydrocarbon receptor modulator (SAhRM).[18]

ICZ[expand acronym] is one of the strongest non-halogenated agonists for AHR in vitro reported.[citation needed]

Signaling pathway

AhR Signaling Pathway - Denison MS, Nagy SR (2003). "Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals". Annu. Rev. Pharmacol. Toxicol. 43: 309-34. *Reprinted, with permission, from the Annual Review of Pharmacology and Toxicology, Volume 43 (c)2003 by Annual Reviews.[12]

Cytosolic complex

Non-ligand bound Ahr is retained in the cytoplasm as an inactive protein complex consisting of a dimer of Hsp90,[19][20] prostaglandin E synthase 3 (PTGES3, p23)[21][22][23][24] and a single molecule of the immunophilin-like AH receptor-interacting protein, also known as hepatitis B virus X-associated protein 2 (XAP2),[25] AhR interacting protein (AIP),[26][27] and AhR-activated 9 (ARA9).[28] The dimer of Hsp90, along with PTGES3 (p23), has a multifunctional role in the protection of the receptor from proteolysis, constraining the receptor in a conformation receptive to ligand binding and preventing the premature binding of ARNT.[8][22][24][29][30][31] AIP interacts with carboxyl-terminal of Hsp90 and binds to the AhR nuclear localization sequence (NLS) preventing the inappropriate trafficking of the receptor into the nucleus.[32][33][34]

Receptor activation

Upon ligand binding to AhR, AIP is released resulting in exposure of the NLS, which is located in the bHLH region,[35] leading to import into the nucleus.[36] It is presumed that once in the nucleus, Hsp90 dissociates exposing the two PAS domains allowing the binding of ARNT.[31][37][38][39] The activated AhR/ARNT heterodimer complex is then capable of either directly and indirectly interacting with DNA by binding to recognition sequences located in the 5’- regulatory region of dioxin-responsive genes.[31][38][40]

DNA binding (xenobiotic response element – XRE)

The classical recognition motif of the AhR/ARNT complex, referred to as either the AhR-, dioxin- or xenobiotic- responsive element (AHRE, DRE or XRE), contains the core sequence 5'-GCGTG-3'[41] within the consensus sequence 5'-T/GNGCGTGA/CG/CA-3'[42][43] in the promoter region of AhR responsive genes. The AhR/ARNT heterodimer directly binds the AHRE/DRE/XRE core sequence in an asymmetric manner such that ARNT binds to 5'-GTG-3' and AhR binding 5'-TC/TGC-3'.[44][45][46] Recent research suggests that a second type of element termed AHRE-II, 5'-CATG(N6)C[T/A]TG-3', is capable of indirectly acting with the AhR/ARNT complex.[47][48] Regardless of the response element, the end result is a variety of differential changes in gene expression.

Functional role in physiology and toxicology

Role in development

In terms of evolution, the oldest physiological role of Ahr is in development. Ahr is presumed to have evolved from invertebrates where it served a ligand-independent role in normal development processes.[49] The Ahr homolog in Drosophila, spineless (ss) is necessary for development of the distal segments of the antenna and leg.[50][51] Ss dimerizes with tango (tgo), which is the homolog to the mammalian Arnt, to initiate gene transcription. Evolution of the receptor in vertebrates resulted in the ability to bind ligand and might have helped humans evolve to tolerate smoke of fires. In developing vertebrates, Ahr seemingly plays a role in cellular proliferation and differentiation.[52] Despite lacking a clear endogenous ligand, AHR appears to play a role in the differentiation of many developmental pathways, including hematopoiesis,[53] lymphoid systems,[54][55] T-cells,[56] neurons,[57] and hepatocytes.[58] AhR has also been found to have an important function in hematopoietic stem cells: AhR antagonism promotes their self-renewal and ex-vivo expansion[59] and is involved in megakaryocyte differentiation.[60]

Adaptive and innate response

The adaptive response is manifested as the induction of xenobiotic metabolizing enzymes. Evidence of this response was first observed from the induction of cytochrome P450, family 1, subfamily A, polypeptide 1 (Cyp1a1) resultant from TCDD exposure, which was determined to be directly related to activation of the Ahr signaling pathway.[61][62][63] The search for other metabolizing genes induced by Ahr ligands, due to the presence of DREs, has led to the identification of an "Ahr gene battery" of Phase I and Phase II metabolizing enzymes consisting of CYP1A1, CYP1A2, CYP1B1, NQO1, ALDH3A1, UGT1A2 and GSTA1.[64] Presumably, vertebrates have this function to be able to detect a wide range of chemicals, indicated by the wide range of substrates Ahr is able to bind and facilitate their biotransformation and elimination. The AhR may also signal the presence of toxic chemicals in food and cause aversion of such foods.[65]

AhR activation seems to be also important for immunological responses and inhibiting inflammation [55] through upregulation of interleukin 22 [66] and downregulation of Th17 response.[67] The Knockdown of AHR mostly downregulates the expression of innate immunity genes in THP-1 cells.[68]

Toxic response

Extensions of the adaptive response are the toxic responses elicited by Ahr activation. Toxicity results from two different ways of Ahr signaling. The first is a side effect of the adaptive response in which the induction of metabolizing enzymes results in the production of toxic metabolites. For example, the polycyclic aromatic hydrocarbon benzo[a]pyrene (BaP), a ligand for Ahr, induces its own metabolism and bioactivation to a toxic metabolite via the induction of CYP1A1 and CYP1B1 in several tissues.[69] The second approach to toxicity is the result of aberrant changes in global gene transcription beyond those observed in the "Ahr gene battery." These global changes in gene expression lead to adverse changes in cellular processes and function.[70] Microarray analysis has proved most beneficial in understanding and characterizing this response.[52][71][72][73]

Protein-protein interactions

In addition to the protein interactions mentioned above, AhR has also been shown to interact with:

References

  1. ↑ Esser C (2016). The Aryl Hydrocarbon Receptor in Immunity: Tools and Potential. Methods in Molecular Biology. 1371. pp. 239–57. doi:10.1007/978-1-4939-3139-2_16. ISBN 978-1-4939-3138-5. PMID 26530806.
  2. ↑ Kawajiri K, Fujii-Kuriyama Y (May 2017). "The aryl hydrocarbon receptor: a multifunctional chemical sensor for host defense and homeostatic maintenance". Experimental Animals. 66 (2): 75–89. doi:10.1538/expanim.16-0092. PMC 5411294. PMID 27980293.
  3. ↑ Gutiérrez-Vázquez C, Quintana FJ (January 2018). "Regulation of the Immune Response by the Aryl Hydrocarbon Receptor". Immunity. 48 (1): 19–33. doi:10.1016/j.immuni.2017.12.012. PMC 5777317. PMID 29343438.
  4. ↑ Burbach KM, Poland A, Bradfield CA (September 1992). "Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor". Proceedings of the National Academy of Sciences of the United States of America. 89 (17): 8185–9. doi:10.1073/pnas.89.17.8185. PMC 49882. PMID 1325649.
  5. ↑ Fukunaga BN, Probst MR, Reisz-Porszasz S, Hankinson O (December 1995). "Identification of functional domains of the aryl hydrocarbon receptor". The Journal of Biological Chemistry. 270 (49): 29270–8. doi:10.1074/jbc.270.49.29270. PMID 7493958.
  6. ↑ Jones S (2004). "An overview of the basic helix-loop-helix proteins". Genome Biology. 5 (6): 226. doi:10.1186/gb-2004-5-6-226. PMC 463060. PMID 15186484.
  7. ↑ Ema M, Sogawa K, Watanabe N, Chujoh Y, Matsushita N, Gotoh O, Funae Y, Fujii-Kuriyama Y (April 1992). "cDNA cloning and structure of mouse putative Ah receptor". Biochemical and Biophysical Research Communications. 184 (1): 246–53. doi:10.1016/0006-291X(92)91185-S. PMID 1314586.
  8. ↑ 8.0 8.1 Coumailleau P, Poellinger L, Gustafsson JA, Whitelaw ML (October 1995). "Definition of a minimal domain of the dioxin receptor that is associated with Hsp90 and maintains wild type ligand binding affinity and specificity". The Journal of Biological Chemistry. 270 (42): 25291–300. doi:10.1074/jbc.270.42.25291. PMID 7559670.
  9. ↑ Goryo K, Suzuki A, Del Carpio CA, Siizaki K, Kuriyama E, Mikami Y, Kinoshita K, Yasumoto K, Rannug A, Miyamoto A, Fujii-Kuriyama Y, Sogawa K (March 2007). "Identification of amino acid residues in the Ah receptor involved in ligand binding". Biochemical and Biophysical Research Communications. 354 (2): 396–402. doi:10.1016/j.bbrc.2006.12.227. PMID 17227672.
  10. ↑ Kumar MB, Ramadoss P, Reen RK, Vanden Heuvel JP, Perdew GH (November 2001). "The Q-rich subdomain of the human Ah receptor transactivation domain is required for dioxin-mediated transcriptional activity". The Journal of Biological Chemistry. 276 (45): 42302–10. doi:10.1074/jbc.M104798200. PMID 11551916.
  11. ↑ Denison MS, Pandini A, Nagy SR, Baldwin EP, Bonati L (September 2002). "Ligand binding and activation of the Ah receptor". Chemico-Biological Interactions (Submitted manuscript). 141 (1–2): 3–24. doi:10.1016/S0009-2797(02)00063-7. PMID 12213382.
  12. ↑ 12.0 12.1 12.2 Denison MS, Nagy SR (2003). "Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals". Annual Review of Pharmacology and Toxicology. 43: 309–34. doi:10.1146/annurev.pharmtox.43.100901.135828. PMID 12540743.
  13. ↑ Adachi J, Mori Y, Matsui S, Takigami H, Fujino J, Kitagawa H, Miller CA, Kato T, Saeki K, Matsuda T (August 2001). "Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine". The Journal of Biological Chemistry. 276 (34): 31475–8. doi:10.1074/jbc.C100238200. PMID 11425848.
  14. ↑ Sinal CJ, Bend JR (October 1997). "Aryl hydrocarbon receptor-dependent induction of cyp1a1 by bilirubin in mouse hepatoma hepa 1c1c7 cells". Molecular Pharmacology. 52 (4): 590–9. PMID 9380021.
  15. ↑ Seidel SD, Winters GM, Rogers WJ, Ziccardi MH, Li V, Keser B, Denison MS (2001). "Activation of the Ah receptor signaling pathway by prostaglandins". Journal of Biochemical and Molecular Toxicology. 15 (4): 187–96. doi:10.1002/jbt.16. PMID 11673847.
  16. ↑ McMillan BJ, Bradfield CA (January 2007). "The aryl hydrocarbon receptor is activated by modified low-density lipoprotein". Proceedings of the National Academy of Sciences of the United States of America. 104 (4): 1412–7. doi:10.1073/pnas.0607296104. PMC 1783125. PMID 17227852.
  17. ↑ Savouret JF, Antenos M, Quesne M, Xu J, Milgrom E, Casper RF (February 2001). "7-ketocholesterol is an endogenous modulator for the arylhydrocarbon receptor". The Journal of Biological Chemistry. 276 (5): 3054–9. doi:10.1074/jbc.M005988200. PMID 11042205.
  18. ↑ Safe, Stephen (2017). "Carbidopa: A selective Ah receptor modulator (SAhRM)". Biochemical Journal. 474 (22): 3763–3765. doi:10.1042/BCJ20170728. PMID 29109131.
  19. ↑ Denis M, Cuthill S, Wikström AC, Poellinger L, Gustafsson JA (September 1988). "Association of the dioxin receptor with the Mr 90,000 heat shock protein: a structural kinship with the glucocorticoid receptor". Biochemical and Biophysical Research Communications. 155 (2): 801–7. doi:10.1016/S0006-291X(88)80566-7. PMID 2844180.
  20. ↑ Perdew GH (September 1988). "Association of the Ah receptor with the 90-kDa heat shock protein". The Journal of Biological Chemistry. 263 (27): 13802–5. PMID 2843537.
  21. ↑ Cox MB, Miller CA (March 2004). "Cooperation of heat shock protein 90 and p23 in aryl hydrocarbon receptor signaling". Cell Stress & Chaperones. 9 (1): 4–20. doi:10.1379/460.1. PMC 1065305. PMID 15270073.
  22. ↑ 22.0 22.1 Kazlauskas A, Poellinger L, Pongratz I (May 1999). "Evidence that the co-chaperone p23 regulates ligand responsiveness of the dioxin (Aryl hydrocarbon) receptor". The Journal of Biological Chemistry. 274 (19): 13519–24. doi:10.1074/jbc.274.19.13519. PMID 10224120.
  23. ↑ Kazlauskas A, Sundström S, Poellinger L, Pongratz I (April 2001). "The hsp90 chaperone complex regulates intracellular localization of the dioxin receptor". Molecular and Cellular Biology. 21 (7): 2594–607. doi:10.1128/MCB.21.7.2594-2607.2001. PMC 86890. PMID 11259606.
  24. ↑ 24.0 24.1 Shetty PV, Bhagwat BY, Chan WK (March 2003). "P23 enhances the formation of the aryl hydrocarbon receptor-DNA complex". Biochemical Pharmacology. 65 (6): 941–8. doi:10.1016/S0006-2952(02)01650-7. PMID 12623125.
  25. ↑ Meyer BK, Pray-Grant MG, Vanden Heuvel JP, Perdew GH (February 1998). "Hepatitis B virus X-associated protein 2 is a subunit of the unliganded aryl hydrocarbon receptor core complex and exhibits transcriptional enhancer activity". Molecular and Cellular Biology. 18 (2): 978–88. PMC 108810. PMID 9447995.
  26. ↑ Ma Q, Whitlock JP (April 1997). "A novel cytoplasmic protein that interacts with the Ah receptor, contains tetratricopeptide repeat motifs, and augments the transcriptional response to 2,3,7,8-tetrachlorodibenzo-p-dioxin". The Journal of Biological Chemistry. 272 (14): 8878–84. doi:10.1074/jbc.272.14.8878. PMID 9083006.
  27. ↑ Zhou Q, Lavorgna A, Bowman M, Hiscott J, Harhaj EW (June 2015). "Aryl Hydrocarbon Receptor Interacting Protein Targets IRF7 to Suppress Antiviral Signaling and the Induction of Type I Interferon". The Journal of Biological Chemistry. 290 (23): 14729–39. doi:10.1074/jbc.M114.633065. PMC 4505538. PMID 25911105.
  28. ↑ Carver LA, Bradfield CA (April 1997). "Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo". The Journal of Biological Chemistry. 272 (17): 11452–6. doi:10.1074/jbc.272.17.11452. PMID 9111057.
  29. ↑ Carver LA, Jackiw V, Bradfield CA (December 1994). "The 90-kDa heat shock protein is essential for Ah receptor signaling in a yeast expression system". The Journal of Biological Chemistry. 269 (48): 30109–12. PMID 7982913.
  30. ↑ Pongratz I, Mason GG, Poellinger L (July 1992). "Dual roles of the 90-kDa heat shock protein hsp90 in modulating functional activities of the dioxin receptor. Evidence that the dioxin receptor functionally belongs to a subclass of nuclear receptors which require hsp90 both for ligand binding activity and repression of intrinsic DNA binding activity". The Journal of Biological Chemistry. 267 (19): 13728–34. PMID 1320028.
  31. ↑ 31.0 31.1 31.2 Whitelaw M, Pongratz I, Wilhelmsson A, Gustafsson JA, Poellinger L (April 1993). "Ligand-dependent recruitment of the Arnt coregulator determines DNA recognition by the dioxin receptor". Molecular and Cellular Biology. 13 (4): 2504–14. PMC 359572. PMID 8384309.
  32. ↑ Carver LA, LaPres JJ, Jain S, Dunham EE, Bradfield CA (December 1998). "Characterization of the Ah receptor-associated protein, ARA9". The Journal of Biological Chemistry. 273 (50): 33580–7. doi:10.1074/jbc.273.50.33580. PMID 9837941.
  33. ↑ Petrulis JR, Hord NG, Perdew GH (December 2000). "Subcellular localization of the aryl hydrocarbon receptor is modulated by the immunophilin homolog hepatitis B virus X-associated protein 2". The Journal of Biological Chemistry. 275 (48): 37448–53. doi:10.1074/jbc.M006873200. PMID 10986286.
  34. ↑ Petrulis JR, Kusnadi A, Ramadoss P, Hollingshead B, Perdew GH (January 2003). "The hsp90 Co-chaperone XAP2 alters importin beta recognition of the bipartite nuclear localization signal of the Ah receptor and represses transcriptional activity". The Journal of Biological Chemistry. 278 (4): 2677–85. doi:10.1074/jbc.M209331200. PMID 12431985.
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