Aryl hydrocarbon receptor

"AHR" redirects here. For other uses, see Ahr (disambiguation).

For the similarly named protein encoded by the AIP gene, see AH receptor-interacting protein.

AHR
Identifiers
Aliases	AHR , bHLHe76, aryl hydrocarbon receptor, Aryl hydrocarbon receptor, RP85
External IDs	OMIM: 600253; MGI: 105043; HomoloGene: 1224; GeneCards: AHR; OMA:AHR - orthologs
Gene location (Human) Chr. Chromosome 7 (human) [1] Band 7p21.1 Start 16,916,359 bp [1] End 17,346,152 bp [1]
Gene location (Mouse) Chr. Chromosome 12 (mouse) [2] Band 12 A3|12 15.78 cM Start 35,547,973 bp [2] End 35,585,037 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in visceral pleura parietal pleura superficial temporal artery Achilles tendon lower lobe of lung gallbladder vulva tibial nerve mucosa of urinary bladder lactiferous duct Top expressed in left lung lobe urothelium mucosa of urinary bladder carotid body sciatic nerve right lung conjunctival fornix retinal pigment epithelium right lung lobe utricle More reference expression data BioGPS n/a
Gene ontology Molecular function DNA binding Hsp90 protein binding protein dimerization activity transcription factor binding nuclear receptor activity E-box binding protein binding protein heterodimerization activity DNA-binding transcription factor activity TFIID-class transcription factor complex binding transcription coactivator binding TBP-class protein binding DNA-binding transcription factor activity, RNA polymerase II-specific protein homodimerization activity sequence-specific double-stranded DNA binding Cellular component cytoplasm transcription regulator complex cytosolic aryl hydrocarbon receptor complex nuclear aryl hydrocarbon receptor complex nucleus aryl hydrocarbon receptor complex cytosol nucleoplasm protein-containing complex Biological process regulation of transcription, DNA-templated rhythmic process regulation of transcription by RNA polymerase II transcription by RNA polymerase II circadian regulation of gene expression transcription, DNA-templated positive regulation of transcription, DNA-templated regulation of B cell proliferation blood vessel development regulation of gene expression xenobiotic metabolic process cell cycle negative regulation of transcription, DNA-templated response to toxic substance positive regulation of transcription by RNA polymerase II apoptotic process intracellular receptor signaling pathway response to drug cAMP-mediated signaling cellular response to cAMP cellular response to forskolin cellular response to 2,3,7,8-tetrachlorodibenzodioxine Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 196 11622 Ensembl ENSG00000106546 ENSMUSG00000019256 UniProt P35869 P30561 RefSeq (mRNA) NM_001621 NM_013464 NM_001314027 RefSeq (protein) NP_001612 NP_001300956 NP_038492 Location (UCSC) Chr 7: 16.92 – 17.35 Mb Chr 12: 35.55 – 35.59 Mb PubMed search [3] [4]
Wikidata
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The aryl hydrocarbon receptor (also known as AhR, AHR, ahr, ahR, AH receptor, or as the dioxin receptor) 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 immune cells, stem cell maintenance, and cellular differentiation. ^{[5] [6] [7]}

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, polyphenols 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

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. ^{[8] [9]} The bHLH motif is located in the N-terminal of the protein and is a common entity in a variety of transcription factors. ^[10] 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). ^[11] 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 ^[12] and contains several conserved residues critical for ligand binding. ^[13] 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. ^[14]

Ligands

AhR ligands have been generally classified into two categories, synthetic or naturally occurring. The first ligands to be discovered were synthetic aromatic hydrocarbons such as the polychlorinated dibenzodioxins, dibenzofurans, biphenyls and the non-chlorinated naphthoflavones alongside the naturally occurring polycyclic aromatic hydrocarbons (3-methylcholanthrene, benzo[a]pyrene and benzanthracene). ^{[15] [16]} A range of synthetic ligands have been designed as potential breast cancer treatments. ^[17]

Research has focused on other 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, ^[18] tetrapyrroles such as bilirubin, ^[19] the arachidonic acid metabolites lipoxin A4 and prostaglandin G, ^[20] modified low-density lipoprotein ^[21] and several dietary carotenoids. ^[16] 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. ^[22]

Carbidopa is a selective aryl hydrocarbon receptor modulator (SAhRM). ^[23] Other SAhRMs include microbial-derived 1,4-dihydroxy-2-naphthoic acid ^[24] and plant-derived 3,3'-diindolylmethane. ^[25]

Indolocarbazole ^{[ clarification needed ]} (ICZ) is one of the strongest non-halogenated agonists for AhR in vitro reported. ^[26]

Ligand-independent AhR activity can be seen in mammalian AhR. The mammalian AhR needs no exogenous ligand-dependent activation to be functional, and this appears to be the case for its role in the regulation of the expression of some transforming growth factor-beta (TGF-b) isoforms. This is not to say that ligand-dependent AhR activation is not needed for the AhR to function in those cases, but that, if a ligand is needed, it is provided endogenously by the cells or tissues in question and its identity is unknown. ^[27]

Signaling pathway

AhR Signaling Pathway

Complex of the aryl hydrocarbon receptor (AhR, blue), AhR-interacting protein (XAP2, yellow) and heat shock protein 90-beta (Hsp90, red). AhR and Hsp90 are bound to indirubin and ADP, respectively.

Cytosolic complex

Non-ligand bound AhR is retained in the cytoplasm as an inactive protein complex consisting of a dimer of Hsp90, ^{[28] [29]} prostaglandin E synthase 3 (PTGES3, p23) ^{[30] [31] [32] [33]} and a single molecule of the immunophilin-like AH receptor-interacting protein, also known as hepatitis B virus X-associated protein 2 (XAP2), ^[34] AhR interacting protein (AIP), ^{[35] [36]} and AhR-activated 9 (ARA9). ^[37] 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. ^{[12] [31] [33] [38] [39] [40]} 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. ^{[41] [42] [43]}

Transforming growth factor-beta (TGF-β) signaling pathway

TGF-β cytokines are members of a signaling protein family that includes activin, Nodal subfamily, bone morphogenetic proteins, growth and differentiation factors, and Müllerian inhibitor subfamily. TGF-β signaling plays an important role in cell physiology and development by inhibiting cell proliferation, promoting apoptosis, inducing differentiation, and determining developmental fate in vertebrates and invertebrates. ^[44] TGF-β activators include proteases such as plasmin, cathepsins, and calpains. Thrombospondin 1, a glycoprotein that inhibits angiogenesis, and matrix metalloproteinase 2 (MMP-2). The extracellular matrix itself appears to play an important regulatory role in TGF-β signaling. ^{[45] [46]}

Receptor activation

Upon ligand binding to AhR, AIP is released resulting in exposure of the NLS, which is located in the bHLH region, ^[47] leading to import into the nucleus. ^[48] It is presumed that once in the nucleus, Hsp90 dissociates exposing the two PAS domains allowing the binding of ARNT. ^{[40] [49] [50] [51]} The activated AhR/ARNT heterodimer complex is then capable of either directly or indirectly interacting with DNA by binding to recognition sequences located in the 5’- regulatory region of dioxin-responsive genes. ^{[40] [50] [52]}

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' ^[53] within the consensus sequence 5'-T/GNGCGTGA/CG/CA-3' ^{[54] [55]} 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'. ^{[56] [57] [58]} 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. ^{[59] [60]} Regardless of the response element, the 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. ^[61] The AhR homolog in Drosophila, spineless (ss) is necessary for development of the distal segments of the antenna and leg. ^{[62] [63]} 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 ligands and might have helped humans evolve to tolerate smoky fires. In developing vertebrates, AhR seemingly plays a role in cellular proliferation and differentiation. ^[64] Despite lacking a clear endogenous ligand, AhR appears to play a role in the differentiation of many developmental pathways, including hematopoiesis, ^[65] lymphoid systems, ^{[66] [67]} T-cells, ^[68] neurons, ^[69] and hepatocytes. ^[70] AhR has also been found to have an important function in hematopoietic stem cells: AhR antagonism promotes their self-renewal and ex-vivo expansion ^[71] and is involved in megakaryocyte differentiation. ^[72] In adulthood, signaling is associated with the stress response and mutations in AhR are associated with major depressive disorder. ^[73]

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. ^{[74] [75] [76]} 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. ^[77] 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. ^[78]

AhR activation seems to be also important for immunological responses and inhibiting inflammation ^[67] through upregulation of interleukin 22 ^[79] and downregulation of Th17 response. ^[80] The Knockdown of AHR mostly downregulates the expression of innate immunity genes in THP-1 cells. ^[81]

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. ^[82] 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. ^[83] Microarray analysis has proved most beneficial in understanding and characterizing this response. ^{[64] [84] [85] [86]}

Xenobiotic metabolizing enzymes help with the metabolic process by transforming and the excretion of chemicals. The most potent inducer of CYP1A1 is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In addition, TCDD induces a broad spectrum of biochemical and toxic effects, such as teratogenesis, immunosuppression and tumor promotion. Most, if not all, of the effects caused by TCDD and other PAHs are known to be mediated by AhR which has a high binding affinity to TCDD. ^[44]

Protein-protein interactions

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

• AIP ^[36]
• ARNTL ^[87]
• CCNT1 ^[88]
• ESR1 ^{[89] [90]}
• NCOA1 ^[91]
• NEDD8 ^[92]
• NRIP1 ^[93]
• RELA ^{[94] [95]}
• RELB ^[96]
• RP ^[97]

References

1. GRCh38: Ensembl release 89: ENSG00000106546 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000019256 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Esser C (2016). "The Aryl Hydrocarbon Receptor in Immunity: Tools and Potential". Suppression and Regulation of Immune Responses. Methods in Molecular Biology. Vol. 1371. pp. 239–57. doi:10.1007/978-1-4939-3139-2_16. ISBN   978-1-4939-3138-5. PMID   26530806.
6. 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.
7. 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.
8. 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): 8185–8189. Bibcode:1992PNAS...89.8185B. doi: 10.1073/pnas.89.17.8185 . PMC   49882 . PMID   1325649.
9. 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): 29270–29278. doi: 10.1074/jbc.270.49.29270 . PMID   7493958.
10. 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.
11. Ema M, Sogawa K, Watanabe N, Chujoh Y, Matsushita N, Gotoh O, et al. (April 1992). "cDNA cloning and structure of mouse putative Ah receptor". Biochemical and Biophysical Research Communications. 184 (1): 246–253. doi:10.1016/0006-291X(92)91185-S. PMID   1314586.
12. 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): 25291–25300. doi: 10.1074/jbc.270.42.25291 . PMID   7559670.
13. Goryo K, Suzuki A, Del Carpio CA, Siizaki K, Kuriyama E, Mikami Y, et al. (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.
14. 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): 42302–42310. doi: 10.1074/jbc.M104798200 . PMID   11551916.
15. 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. Bibcode:2002CBI...141....3D. doi:10.1016/S0009-2797(02)00063-7. PMID   12213382. S2CID   29379967.
16. 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: 309–334. doi:10.1146/annurev.pharmtox.43.100901.135828. PMID   12540743.
17. Baker JR, Sakoff JA, McCluskey A (May 2020). "The aryl hydrocarbon receptor (AhR) as a breast cancer drug target". Medicinal Research Reviews. 40 (3): 972–1001. doi: 10.1002/med.21645 . PMID   31721255.
18. Adachi J, Mori Y, Matsui S, Takigami H, Fujino J, Kitagawa H, et al. (August 2001). "Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine". The Journal of Biological Chemistry. 276 (34): 31475–31478. doi: 10.1074/jbc.C100238200 . PMID   11425848.
19. 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): 590–599. doi:10.1124/mol.52.4.590. PMID   9380021.
20. Seidel SD, Winters GM, Rogers WJ, Ziccardi MH, Li V, Keser B, et al. (2001). "Activation of the Ah receptor signaling pathway by prostaglandins". Journal of Biochemical and Molecular Toxicology. 15 (4): 187–196. doi:10.1002/jbt.16. PMID   11673847. S2CID   21953408.
21. 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): 1412–1417. Bibcode:2007PNAS..104.1412M. doi: 10.1073/pnas.0607296104 . PMC   1783125 . PMID   17227852.
22. 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): 3054–3059. doi: 10.1074/jbc.M005988200 . PMID   11042205.
23. Safe S (November 2017). "Carbidopa: a selective Ah receptor modulator (SAhRM)". The Biochemical Journal. 474 (22): 3763–3765. doi:10.1042/BCJ20170728. PMID   29109131.
24. Cheng Y, Jin UH, Davidson LA, Chapkin RS, Jayaraman A, Tamamis P, et al. (February 2017). "Editor's Highlight: Microbial-Derived 1,4-Dihydroxy-2-naphthoic Acid and Related Compounds as Aryl Hydrocarbon Receptor Agonists/Antagonists: Structure-Activity Relationships and Receptor Modeling". Toxicological Sciences. 155 (2): 458–473. doi:10.1093/toxsci/kfw230. PMC   5291215 . PMID   27837168.
25. Yin XF, Chen J, Mao W, Wang YH, Chen MH (May 2012). "A selective aryl hydrocarbon receptor modulator 3,3'-Diindolylmethane inhibits gastric cancer cell growth". Journal of Experimental & Clinical Cancer Research. 31 (1): 46. doi: 10.1186/1756-9966-31-46 . PMC   3403951 . PMID   22592002.
26. Wincent E, Shirani H, Bergman J, Rannug U, Janosik T (February 2009). "Synthesis and biological evaluation of fused thio- and selenopyrans as new indolocarbazole analogues with aryl hydrocarbon receptor affinity". Bioorganic & Medicinal Chemistry. 17 (4): 1648–1653. doi:10.1016/j.bmc.2008.12.072. PMID   19186062.
27. Denison MS, Pandini A, Nagy SR, Baldwin EP, Bonati L (September 2002). "Ligand binding and activation of the Ah receptor". Chemico-Biological Interactions. 141 (1–2): 3–24. Bibcode:2002CBI...141....3D. doi:10.1016/S0009-2797(02)00063-7. PMID   12213382. S2CID   29379967.
28. 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): 801–807. doi:10.1016/S0006-291X(88)80566-7. PMID   2844180.
29. Perdew GH (September 1988). "Association of the Ah receptor with the 90-kDa heat shock protein". The Journal of Biological Chemistry. 263 (27): 13802–13805. doi: 10.1016/S0021-9258(18)68314-0 . PMID   2843537.
30. 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.
31. 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): 13519–13524. doi: 10.1074/jbc.274.19.13519 . PMID   10224120.
32. 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): 2594–2607. doi:10.1128/MCB.21.7.2594-2607.2001. PMC   86890 . PMID   11259606.
33. Shetty PV, Bhagwat BY, Chan WK (March 2003). "P23 enhances the formation of the aryl hydrocarbon receptor-DNA complex". Biochemical Pharmacology. 65 (6): 941–948. doi:10.1016/S0006-2952(02)01650-7. PMID   12623125.
34. 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): 978–988. doi:10.1128/MCB.18.2.978. PMC   108810 . PMID   9447995.
35. 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): 8878–8884. doi: 10.1074/jbc.272.14.8878 . PMID   9083006.
36. 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): 14729–14739. doi: 10.1074/jbc.M114.633065 . PMC   4505538 . PMID   25911105.
37. 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): 11452–11456. doi: 10.1074/jbc.272.17.11452 . PMID   9111057.
38. 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): 30109–30112. doi: 10.1016/S0021-9258(18)43782-9 . PMID   7982913.
39. 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): 13728–13734. doi: 10.1016/S0021-9258(18)42274-0 . PMID   1320028.
40. 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): 2504–2514. doi:10.1128/MCB.13.4.2504. PMC   359572 . PMID   8384309.
41. 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): 33580–33587. doi: 10.1074/jbc.273.50.33580 . PMID   9837941.
42. 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): 37448–37453. doi: 10.1074/jbc.M006873200 . PMID   10986286.
43. 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): 2677–2685. doi: 10.1074/jbc.M209331200 . PMID   12431985.
44. Mimura J, Fujii-Kuriyama Y (February 2003). "Functional role of AhR in the expression of toxic effects by TCDD". Biochimica et Biophysica Acta (BBA) - General Subjects. Cellular Biology of Cytochrome P450 Regulation. 1619 (3): 263–268. doi:10.1016/S0304-4165(02)00485-3. PMID   12573486.
45. Puga A, Tomlinson CR, Xia Y (January 2005). "Ah receptor signals cross-talk with multiple developmental pathways". Biochemical Pharmacology. 69 (2): 199–207. doi:10.1016/j.bcp.2004.06.043. PMID   15627472.
46. Puga A, Ma C, Marlowe JL (February 2009). "The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways". Biochemical Pharmacology. 77 (4): 713–722. doi:10.1016/j.bcp.2008.08.031. PMC   2657192 . PMID   18817753.
47. Ikuta T, Eguchi H, Tachibana T, Yoneda Y, Kawajiri K (January 1998). "Nuclear localization and export signals of the human aryl hydrocarbon receptor". The Journal of Biological Chemistry. 273 (5): 2895–2904. doi: 10.1074/jbc.273.5.2895 . PMID   9446600.
48. Pollenz RS, Barbour ER (August 2000). "Analysis of the complex relationship between nuclear export and aryl hydrocarbon receptor-mediated gene regulation". Molecular and Cellular Biology. 20 (16): 6095–6104. doi:10.1128/MCB.20.16.6095-6104.2000. PMC   86085 . PMID   10913191.
49. Hoffman EC, Reyes H, Chu FF, Sander F, Conley LH, Brooks BA, et al. (May 1991). "Cloning of a factor required for activity of the Ah (dioxin) receptor". Science. 252 (5008): 954–958. Bibcode:1991Sci...252..954H. doi:10.1126/science.1852076. PMID   1852076.
50. Probst MR, Reisz-Porszasz S, Agbunag RV, Ong MS, Hankinson O (September 1993). "Role of the aryl hydrocarbon receptor nuclear translocator protein in aryl hydrocarbon (dioxin) receptor action". Molecular Pharmacology. 44 (3): 511–518. PMID   8396713.
51. Reyes H, Reisz-Porszasz S, Hankinson O (May 1992). "Identification of the Ah receptor nuclear translocator protein (Arnt) as a component of the DNA binding form of the Ah receptor". Science. 256 (5060): 1193–1195. Bibcode:1992Sci...256.1193R. doi:10.1126/science.256.5060.1193. PMID   1317062. S2CID   34075046.
52. Dolwick KM, Swanson HI, Bradfield CA (September 1993). "In vitro analysis of Ah receptor domains involved in ligand-activated DNA recognition". Proceedings of the National Academy of Sciences of the United States of America. 90 (18): 8566–8570. Bibcode:1993PNAS...90.8566D. doi: 10.1073/pnas.90.18.8566 . PMC   47398 . PMID   8397410.
53. Shen ES, Whitlock JP (April 1992). "Protein-DNA interactions at a dioxin-responsive enhancer. Mutational analysis of the DNA-binding site for the liganded Ah receptor". The Journal of Biological Chemistry. 267 (10): 6815–6819. doi: 10.1016/S0021-9258(19)50499-9 . PMID   1313023.
54. Lusska A, Shen E, Whitlock JP (March 1993). "Protein-DNA interactions at a dioxin-responsive enhancer. Analysis of six bona fide DNA-binding sites for the liganded Ah receptor". The Journal of Biological Chemistry. 268 (9): 6575–6580. doi: 10.1016/S0021-9258(18)53289-0 . PMID   8384216.
55. Yao EF, Denison MS (June 1992). "DNA sequence determinants for binding of transformed Ah receptor to a dioxin-responsive enhancer". Biochemistry. 31 (21): 5060–5067. doi:10.1021/bi00136a019. PMID   1318077.
56. Wharton KA, Franks RG, Kasai Y, Crews ST (December 1994). "Control of CNS midline transcription by asymmetric E-box-like elements: similarity to xenobiotic responsive regulation". Development. 120 (12): 3563–3569. doi: 10.1242/dev.120.12.3563 . PMID   7821222.
57. Bacsi SG, Reisz-Porszasz S, Hankinson O (March 1995). "Orientation of the heterodimeric aryl hydrocarbon (dioxin) receptor complex on its asymmetric DNA recognition sequence". Molecular Pharmacology. 47 (3): 432–438. PMID   7700240.
58. Swanson HI, Chan WK, Bradfield CA (November 1995). "DNA binding specificities and pairing rules of the Ah receptor, ARNT, and SIM proteins". The Journal of Biological Chemistry. 270 (44): 26292–26302. doi: 10.1074/jbc.270.44.26292 . PMID   7592839.
59. Boutros PC, Moffat ID, Franc MA, Tijet N, Tuomisto J, Pohjanvirta R, et al. (August 2004). "Dioxin-responsive AHRE-II gene battery: identification by phylogenetic footprinting". Biochemical and Biophysical Research Communications. 321 (3): 707–715. doi:10.1016/j.bbrc.2004.06.177. PMID   15358164.
60. Sogawa K, Numayama-Tsuruta K, Takahashi T, Matsushita N, Miura C, Nikawa J, et al. (June 2004). "A novel induction mechanism of the rat CYP1A2 gene mediated by Ah receptor-Arnt heterodimer". Biochemical and Biophysical Research Communications. 318 (3): 746–755. doi:10.1016/j.bbrc.2004.04.090. PMID   15144902.
61. Hahn ME, Karchner SI, Evans BR, Franks DG, Merson RR, Lapseritis JM (September 2006). "Unexpected diversity of aryl hydrocarbon receptors in non-mammalian vertebrates: insights from comparative genomics". Journal of Experimental Zoology Part A: Comparative Experimental Biology. 305 (9): 693–706. Bibcode:2006JEZA..305..693H. doi:10.1002/jez.a.323. PMID   16902966.
62. Duncan DM, Burgess EA, Duncan I (May 1998). "Control of distal antennal identity and tarsal development in Drosophila by spineless-aristapedia, a homolog of the mammalian dioxin receptor". Genes & Development. 12 (9): 1290–1303. doi:10.1101/gad.12.9.1290. PMC   316766 . PMID   9573046.
63. Emmons RB, Duncan D, Estes PA, Kiefel P, Mosher JT, Sonnenfeld M, et al. (September 1999). "The spineless-aristapedia and tango bHLH-PAS proteins interact to control antennal and tarsal development in Drosophila". Development. 126 (17): 3937–3945. doi:10.1242/dev.126.17.3937. PMID   10433921.
64. Tijet N, Boutros PC, Moffat ID, Okey AB, Tuomisto J, Pohjanvirta R (January 2006). "Aryl hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries". Molecular Pharmacology. 69 (1): 140–153. doi:10.1124/mol.105.018705. PMID   16214954. S2CID   1913812.
65. Gasiewicz TA, Singh KP, Casado FL (March 2010). "The aryl hydrocarbon receptor has an important role in the regulation of hematopoiesis: implications for benzene-induced hematopoietic toxicity". Chemico-Biological Interactions. 184 (1–2): 246–251. Bibcode:2010CBI...184..246G. doi:10.1016/j.cbi.2009.10.019. PMC   2846208 . PMID   19896476.
66. Kiss EA, Vonarbourg C, Kopfmann S, Hobeika E, Finke D, Esser C, et al. (December 2011). "Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles". Science. 334 (6062): 1561–1565. Bibcode:2011Sci...334.1561K. doi:10.1126/science.1214914. PMID   22033518. S2CID   206537957.
67. Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR, Grigorieva EF, et al. (October 2011). "Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation". Cell. 147 (3): 629–640. doi: 10.1016/j.cell.2011.09.025 . PMID   21999944. S2CID   16090460.
68. Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, et al. (May 2008). "Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor". Nature. 453 (7191): 65–71. doi:10.1038/nature06880. PMID   18362915. S2CID   4384276.
69. Akahoshi E, Yoshimura S, Ishihara-Sugano M (September 2006). "Over-expression of AhR (aryl hydrocarbon receptor) induces neural differentiation of Neuro2a cells: neurotoxicology study". Environmental Health. 5 (1): 24. Bibcode:2006EnvHe...5...24A. doi: 10.1186/1476-069X-5-24 . PMC   1570454 . PMID   16956419.
70. Walisser JA, Glover E, Pande K, Liss AL, Bradfield CA (December 2005). "Aryl hydrocarbon receptor-dependent liver development and hepatotoxicity are mediated by different cell types". Proceedings of the National Academy of Sciences of the United States of America. 102 (49): 17858–17863. Bibcode:2005PNAS..10217858W. doi: 10.1073/pnas.0504757102 . PMC   1308889 . PMID   16301529.
71. Boitano AE, Wang J, Romeo R, Bouchez LC, Parker AE, Sutton SE, et al. (September 2010). "Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells". Science. 329 (5997): 1345–1348. Bibcode:2010Sci...329.1345B. doi:10.1126/science.1191536. PMC   3033342 . PMID   20688981.
72. Lindsey S, Papoutsakis ET (February 2011). "The aryl hydrocarbon receptor (AHR) transcription factor regulates megakaryocytic polyploidization". British Journal of Haematology. 152 (4): 469–484. doi:10.1111/j.1365-2141.2010.08548.x. PMC   3408620 . PMID   21226706.
73. Merchak A, Gaultier A (December 2020). "Microbial metabolites and immune regulation: New targets for major depressive disorder". Brain, Behavior, & Immunity - Health. 9: 100169. doi:10.1016/j.bbih.2020.100169. PMC   8474524 . PMID   34589904.
74. Israel DI, Whitlock JP (September 1983). "Induction of mRNA specific for cytochrome P1-450 in wild type and variant mouse hepatoma cells". The Journal of Biological Chemistry. 258 (17): 10390–10394. doi: 10.1016/S0021-9258(17)44469-3 . PMID   6885786.
75. Israel DI, Whitlock JP (May 1984). "Regulation of cytochrome P1-450 gene transcription by 2,3,7, 8-tetrachlorodibenzo-p-dioxin in wild type and variant mouse hepatoma cells". The Journal of Biological Chemistry. 259 (9): 5400–5402. doi: 10.1016/S0021-9258(18)91022-7 . PMID   6715350.
76. Ko HP, Okino ST, Ma Q, Whitlock JP (January 1996). "Dioxin-induced CYP1A1 transcription in vivo: the aromatic hydrocarbon receptor mediates transactivation, enhancer-promoter communication, and changes in chromatin structure". Molecular and Cellular Biology. 16 (1): 430–436. doi:10.1128/MCB.16.1.430. PMC   231019 . PMID   8524325.
77. Nebert DW, Roe AL, Dieter MZ, Solis WA, Yang Y, Dalton TP (January 2000). "Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis". Biochemical Pharmacology. 59 (1): 65–85. doi:10.1016/S0006-2952(99)00310-X. PMID   10605936.
78. Lensu S, Tuomisto JT, Tuomisto J, Viluksela M, Niittynen M, Pohjanvirta R (June 2011). "Immediate and highly sensitive aversion response to a novel food item linked to AH receptor stimulation". Toxicology Letters. 203 (3): 252–257. doi:10.1016/j.toxlet.2011.03.025. PMID   21458548.
79. Monteleone I, Rizzo A, Sarra M, Sica G, Sileri P, Biancone L, et al. (July 2011). "Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract". Gastroenterology. 141 (1): 237–48, 248.e1. doi: 10.1053/j.gastro.2011.04.007 . PMID   21600206.
80. Wei P, Hu GH, Kang HY, Yao HB, Kou W, Liu H, et al. (May 2014). "An aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress the Th17 response in allergic rhinitis patients". Laboratory Investigation; A Journal of Technical Methods and Pathology. 94 (5): 528–535. doi: 10.1038/labinvest.2014.8 . PMID   24514067.
81. Memari B, Bouttier M, Dimitrov V, Ouellette M, Behr MA, Fritz JH, et al. (November 2015). "Engagement of the Aryl Hydrocarbon Receptor in Mycobacterium tuberculosis-Infected Macrophages Has Pleiotropic Effects on Innate Immune Signaling". Journal of Immunology. 195 (9): 4479–4491. doi: 10.4049/jimmunol.1501141 . PMID   26416282.
82. Harrigan JA, Vezina CM, McGarrigle BP, Ersing N, Box HC, Maccubbin AE, et al. (February 2004). "DNA adduct formation in precision-cut rat liver and lung slices exposed to benzo[a]pyrene". Toxicological Sciences. 77 (2): 307–314. doi: 10.1093/toxsci/kfh030 . PMID   14691214.
83. Lindén J, Lensu S, Tuomisto J, Pohjanvirta R (October 2010). "Dioxins, the aryl hydrocarbon receptor and the central regulation of energy balance". Frontiers in Neuroendocrinology. 31 (4): 452–478. doi:10.1016/j.yfrne.2010.07.002. PMID   20624415. S2CID   34036181.
84. Martinez JM, Afshari CA, Bushel PR, Masuda A, Takahashi T, Walker NJ (October 2002). "Differential toxicogenomic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin in malignant and nonmalignant human airway epithelial cells". Toxicological Sciences. 69 (2): 409–423. doi: 10.1093/toxsci/69.2.409 . PMID   12377990.
85. Vezina CM, Walker NJ, Olson JR (November 2004). "Subchronic exposure to TCDD, PeCDF, PCB126, and PCB153: effect on hepatic gene expression". Environmental Health Perspectives. 112 (16): 1636–1644. doi:10.1289/ehp.7253. PMC   1247661 . PMID   15598615.
86. Ovando BJ, Vezina CM, McGarrigle BP, Olson JR (December 2006). "Hepatic gene downregulation following acute and subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin". Toxicological Sciences. 94 (2): 428–438. doi: 10.1093/toxsci/kfl111 . PMID   16984957.
87. Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, et al. (March 1997). "Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway". The Journal of Biological Chemistry. 272 (13): 8581–8593. doi: 10.1074/jbc.272.13.8581 . PMID   9079689.
88. Tian Y, Ke S, Chen M, Sheng T (November 2003). "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". The Journal of Biological Chemistry. 278 (45): 44041–44048. doi: 10.1074/jbc.M306443200 . PMID   12917420.
89. Wormke M, Stoner M, Saville B, Walker K, Abdelrahim M, Burghardt R, et al. (March 2003). "The aryl hydrocarbon receptor mediates degradation of estrogen receptor alpha through activation of proteasomes". Molecular and Cellular Biology. 23 (6): 1843–1855. doi:10.1128/MCB.23.6.1843-1855.2003. PMC   149455 . PMID   12612060.
90. Klinge CM, Kaur K, Swanson HI (January 2000). "The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TFI and ERRalpha1". Archives of Biochemistry and Biophysics. 373 (1): 163–174. doi:10.1006/abbi.1999.1552. PMID   10620335.
91. Beischlag TV, Wang S, Rose DW, Torchia J, Reisz-Porszasz S, Muhammad K, et al. (June 2002). "Recruitment of the NCoA/SRC-1/p160 family of transcriptional coactivators by the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator complex". Molecular and Cellular Biology. 22 (12): 4319–4333. doi:10.1128/MCB.22.12.4319-4333.2002. PMC   133867 . PMID   12024042.
92. Antenos M, Casper RF, Brown TJ (November 2002). "Interaction with Nedd8, a ubiquitin-like protein, enhances the transcriptional activity of the aryl hydrocarbon receptor". The Journal of Biological Chemistry. 277 (46): 44028–44034. doi: 10.1074/jbc.M202413200 . PMID   12215427.
93. Kumar MB, Tarpey RW, Perdew GH (August 1999). "Differential recruitment of coactivator RIP140 by Ah and estrogen receptors. Absence of a role for LXXLL motifs". The Journal of Biological Chemistry. 274 (32): 22155–22164. doi: 10.1074/jbc.274.32.22155 . PMID   10428779.
94. Kim DW, Gazourian L, Quadri SA, Romieu-Mourez R, Sherr DH, Sonenshein GE (November 2000). "The RelA NF-kappaB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells". Oncogene. 19 (48): 5498–5506. doi: 10.1038/sj.onc.1203945 . PMID   11114727.
95. Ruby CE, Leid M, Kerkvliet NI (September 2002). "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". Molecular Pharmacology. 62 (3): 722–728. doi:10.1124/mol.62.3.722. PMID   12181450. S2CID   2376236.
96. Vogel CF, Sciullo E, Li W, Wong P, Lazennec G, Matsumura F (December 2007). "RelB, a new partner of aryl hydrocarbon receptor-mediated transcription". Molecular Endocrinology. 21 (12): 2941–2955. doi:10.1210/me.2007-0211. PMC   2346533 . PMID   17823304.
97. Ge NL, Elferink CJ (August 1998). "A direct interaction between the aryl hydrocarbon receptor and retinoblastoma protein. Linking dioxin signaling to the cell cycle". The Journal of Biological Chemistry. 273 (35): 22708–22713. doi: 10.1074/jbc.273.35.22708 . PMID   9712901.

External links

• Aryl+hydrocarbon+receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human AHR genome location and AHR gene details page in the UCSC Genome Browser .
• Human ARNT genome location and ARNT gene details page in the UCSC Genome Browser .