Aryl hydrocarbon receptor pathway (WP2586)

The Aryl Hydrocarbon receptor (AhR) is ligand activated transcription factor that regulates wide spectrum of gene expression. The main mediator of AhR is 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) or polycyclic aromatic hydrocarbons which are widespread environmental pollutant causing a variety of severe health effects, e.g. immunosuppression, carcinogenesis and hepatotoxicity. AhR is a member of basic helix-loop-helix-Per-Arnt-Sim (bHLH-PAS) superfamily of transcription factors. In the absence of ligand, the AhR can be found in the cytosol, bound to a dimer of the heat shock protein of 90 kDa (Hsp90) and the immunophilin-like protein, AIP (also known as XAP2 and ARA9). Upon ligand binding, the AHR translocates to the nucleus and binds with ARNT. The AHR/ARNT heterodimer binds to xenobiotic response elements and regulates a diverse set of genes. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP2586 CPTAC Assay Portal]
last edited

Authors

Prakamya1986, AlexanderPico, Mkutmon, MaintBot, Zari, Egonw, MirellaKalafati, DeSl, Khanspers, and Eweitz

Cited In

Organism

Homo sapiens

Communities

Annotations

Pathway Ontology: regulatory pathway

Participants

Label Type Compact Identifier
KLF6 GeneProduct ncbigene:1316
VEGFA GeneProduct ncbigene:7422
CCL1 GeneProduct ncbigene:6346
NQO1 Protein ncbigene:1728
CDKN1B GeneProduct ncbigene:1027
HSP90AA1 Protein ncbigene:3320
ESR1 Protein ncbigene:2099
Unknown None
DRE region Complex None
XRE Unknown None
ARNT GeneProduct ncbigene:405
AIP GeneProduct ensembl:ENSG00000110711
TCDD Metabolite chebi:28119
Calcium channel Unknown None
CYP1A1 GeneProduct ncbigene:1543
EGFR GeneProduct ncbigene:1956
EP300 Protein ncbigene:2033
PAH Metabolite chebi:33848
pRb Protein uniprot:P06400
Proliferation and tumorigenesis Pathway None
EBNA-3 Protein ncbigene:17494212
ZAC1 Protein ncbigene:5325
RET Protein ncbigene:5979
NFE2L2 Rna ncbigene:4780
AIP GeneProduct ensembl:ENSG00000110711
AHR GeneProduct ncbigene:196
P23 GeneProduct ensembl:ENSG00000110711
AHR GeneProduct ncbigene:196
AHR GeneProduct ncbigene:196
HSP90AA1 GeneProduct ncbigene:3320
HSP90AA1 GeneProduct ncbigene:3320
MYC Protein ncbigene:4609
TATA Complex None
EGFR pathway Pathway wikipathways:WP1910
TNF GeneProduct ncbigene:7124
CDC37 GeneProduct ncbigene:11140
SRC Protein ncbigene:6714
RAF1 GeneProduct ensembl:ENSG00000132155
MAP2K1 GeneProduct ensembl:ENSG00000169032
MAPK1 Protein ncbigene:5594
PTGS2 GeneProduct ncbigene:5743
PSRC1 GeneProduct ncbigene:84722
RELA GeneProduct ncbigene:5970
NFKB1 GeneProduct ncbigene:4790
RELA GeneProduct ncbigene:5970
NFKB1 GeneProduct ncbigene:4790
EP300 Protein ncbigene:2033
PSRC1 GeneProduct ncbigene:84722
Angiogenesis Pathway wikipathways:WP1539
NCOA7 Protein ncbigene:135112
NRIP1 Protein ncbigene:8204
CYP1A1 Protein ncbigene:1543
CD36 GeneProduct ncbigene:948
LPL Protein ncbigene:4023
NFE2L2 GeneProduct ncbigene:4780
FGF21 Protein ncbigene:26291
HPGDS Protein ncbigene:27306
GCLC Protein ncbigene:2729
Oxidative stress Pathway wikipathways:WP408
NRIP1 Protein ncbigene:8204
NF1 Protein ncbigene:4763
NCOA7 Protein ncbigene:135112
NCOR2 Protein ncbigene:9612
CYP1A2 GeneProduct ncbigene:1544
CYP1B1 GeneProduct ncbigene:1545
Estrogen metabolism Pathway wikipathways:WP697
CDKN1A GeneProduct ncbigene:1026
CDK2 GeneProduct ncbigene:1017
RB1 GeneProduct ncbigene:5925
E2F1 GeneProduct ncbigene:1869
Cell cycle inhibition Pathway None
Detoxification and metabolism of xenobiotics Pathway None
Cell survival Pathway None
AHRR GeneProduct ncbigene:57491
EP300 Protein ncbigene:2033
FAS / FAS-L (Apoptosis) Pathway wikipathways:WP254
NRAS GeneProduct ensembl:ENSG00000213281
HRAS GeneProduct ensembl:ENSG00000174775
KRAS GeneProduct ensembl:ENSG00000133703
TCDD Metabolite chebi:28119
PAH Metabolite chebi:33848
Cell survival Pathway None
Modulation of estrogen receptor signaling Pathway wikipathways:WP712
HSP90AA1 GeneProduct ncbigene:3320

References

  1. Poland A, Glover E, Kende AS. Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase. J Biol Chem. 1976 Aug 25;251(16):4936–46. PubMed Europe PMC Scholia
  2. Nebert DW, Petersen DD, Puga A. Human AH locus polymorphism and cancer: inducibility of CYP1A1 and other genes by combustion products and dioxin. Pharmacogenetics. 1991 Nov;1(2):68–78. PubMed Europe PMC Scholia
  3. Perdew GH. Association of the Ah receptor with the 90-kDa heat shock protein. J Biol Chem. 1988 Sep 25;263(27):13802–5. PubMed Europe PMC Scholia
  4. Madhukar BV, Ebner K, Matsumura F, Bombick DW, Brewster DW, Kawamoto T. 2,3,7,8-Tetrachlorodibenzo-p-dioxin causes an increase in protein kinases associated with epidermal growth factor receptor in the hepatic plasma membrane. J Biochem Toxicol. 1988;3:261–77. PubMed Europe PMC Scholia
  5. Madhukar BV, Brewster DW, Matsumura F. Effects of in vivo-administered 2,3,7,8-tetrachlorodibenzo-p-dioxin on receptor binding of epidermal growth factor in the hepatic plasma membrane of rat, guinea pig, mouse, and hamster. Proc Natl Acad Sci U S A. 1984 Dec;81(23):7407–11. PubMed Europe PMC Scholia
  6. Muntané-Relat J, Ourlin JC, Domergue J, Maurel P. Differential effects of cytokines on the inducible expression of CYP1A1, CYP1A2, and CYP3A4 in human hepatocytes in primary culture. Hepatology. 1995 Oct;22(4 Pt 1):1143–53. PubMed Europe PMC Scholia
  7. Quattrochi LC, Vu T, Tukey RH. The human CYP1A2 gene and induction by 3-methylcholanthrene. A region of DNA that supports AH-receptor binding and promoter-specific induction. J Biol Chem. 1994 Mar 4;269(9):6949–54. PubMed Europe PMC Scholia
  8. Probst MR, Reisz-Porszasz S, Agbunag RV, Ong MS, Hankinson O. Role of the aryl hydrocarbon receptor nuclear translocator protein in aryl hydrocarbon (dioxin) receptor action. Mol Pharmacol. 1993 Sep;44(3):511–8. PubMed Europe PMC Scholia
  9. Tang YM, Wo YY, Stewart J, Hawkins AL, Griffin CA, Sutter TR, et al. Isolation and characterization of the human cytochrome P450 CYP1B1 gene. J Biol Chem. 1996 Nov 8;271(45):28324–30. PubMed Europe PMC Scholia
  10. Enan E, Matsumura F. Identification of c-Src as the integral component of the cytosolic Ah receptor complex, transducing the signal of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through the protein phosphorylation pathway. Biochem Pharmacol. 1996 Nov 22;52(10):1599–612. PubMed Europe PMC Scholia
  11. Blankenship A, Matsumura F. 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced activation of a protein tyrosine kinase, pp60src, in murine hepatic cytosol using a cell-free system. Mol Pharmacol. 1997 Oct;52(4):667–75. PubMed Europe PMC Scholia
  12. Kwon TK, Nordin AA. Identification of cdk2 binding sites on the p27Kip1 cyclin-dependent kinase inhibitor. Oncogene. 1998 Feb 12;16(6):755–62. PubMed Europe PMC Scholia
  13. Riese DJ 2nd, Stern DF. Specificity within the EGF family/ErbB receptor family signaling network. Bioessays. 1998 Jan;20(1):41–8. PubMed Europe PMC Scholia
  14. Takahata S, Sogawa K, Kobayashi A, Ema M, Mimura J, Ozaki N, et al. Transcriptionally active heterodimer formation of an Arnt-like PAS protein, Arnt3, with HIF-1a, HLF, and clock. Biochem Biophys Res Commun. 1998 Jul 30;248(3):789–94. PubMed Europe PMC Scholia
  15. Ge NL, Elferink CJ. A direct interaction between the aryl hydrocarbon receptor and retinoblastoma protein. Linking dioxin signaling to the cell cycle. J Biol Chem. 1998 Aug 28;273(35):22708–13. PubMed Europe PMC Scholia
  16. Coats S, Whyte P, Fero ML, Lacy S, Chung G, Randel E, et al. A new pathway for mitogen-dependent cdk2 regulation uncovered in p27(Kip1)-deficient cells. Curr Biol. 1999 Feb 25;9(4):163–73. PubMed Europe PMC Scholia
  17. Biscardi JS, Maa MC, Tice DA, Cox ME, Leu TH, Parsons SJ. c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function. J Biol Chem. 1999 Mar 19;274(12):8335–43. PubMed Europe PMC Scholia
  18. Kazlauskas A, Poellinger L, Pongratz I. Evidence that the co-chaperone p23 regulates ligand responsiveness of the dioxin (Aryl hydrocarbon) receptor. J Biol Chem. 1999 May 7;274(19):13519–24. PubMed Europe PMC Scholia
  19. Nguyen TA, Hoivik D, Lee JE, Safe S. Interactions of nuclear receptor coactivator/corepressor proteins with the aryl hydrocarbon receptor complex. Arch Biochem Biophys. 1999 Jul 15;367(2):250–7. PubMed Europe PMC Scholia
  20. Kolluri SK, Weiss C, Koff A, Göttlicher M. p27(Kip1) induction and inhibition of proliferation by the intracellular Ah receptor in developing thymus and hepatoma cells. Genes Dev. 1999 Jul 1;13(13):1742–53. PubMed Europe PMC Scholia
  21. Klinge CM, Kaur K, Swanson HI. The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TFI and ERRalpha1. Arch Biochem Biophys. 2000 Jan 1;373(1):163–74. PubMed Europe PMC Scholia
  22. Kashuba E, Kashuba V, Pokrovskaja K, Klein G, Szekely L. Epstein-Barr virus encoded nuclear protein EBNA-3 binds XAP-2, a protein associated with Hepatitis B virus X antigen. Oncogene. 2000 Mar 30;19(14):1801–6. PubMed Europe PMC Scholia
  23. Bell DR, Poland A. Binding of aryl hydrocarbon receptor (AhR) to AhR-interacting protein. The role of hsp90. J Biol Chem. 2000 Nov 17;275(46):36407–14. PubMed Europe PMC Scholia
  24. Trombino AF, Near RI, Matulka RA, Yang S, Hafer LJ, Toselli PA, et al. Expression of the aryl hydrocarbon receptor/transcription factor (AhR) and AhR-regulated CYP1 gene transcripts in a rat model of mammary tumorigenesis. Breast Cancer Res Treat. 2000 Sep;63(2):117–31. PubMed Europe PMC Scholia
  25. Kim DW, Gazourian L, Quadri SA, Romieu-Mourez R, Sherr DH, Sonenshein GE. The RelA NF-kappaB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells. Oncogene. 2000 Nov 16;19(48):5498–506. PubMed Europe PMC Scholia
  26. Elferink CJ, Ge NL, Levine A. Maximal aryl hydrocarbon receptor activity depends on an interaction with the retinoblastoma protein. Mol Pharmacol. 2001 Apr;59(4):664–73. PubMed Europe PMC Scholia
  27. Ke S, Rabson AB, Germino JF, Gallo MA, Tian Y. Mechanism of suppression of cytochrome P-450 1A1 expression by tumor necrosis factor-alpha and lipopolysaccharide. J Biol Chem. 2001 Oct 26;276(43):39638–44. PubMed Europe PMC Scholia
  28. Shimada T, Oda Y, Gillam EM, Guengerich FP, Inoue K. Metabolic activation of polycyclic aromatic hydrocarbons and other procarcinogens by cytochromes P450 1A1 and P450 1B1 allelic variants and other human cytochromes P450 in Salmonella typhimurium NM2009. Drug Metab Dispos. 2001 Sep;29(9):1176–82. PubMed Europe PMC Scholia
  29. Billiard SM, Hahn ME, Franks DG, Peterson RE, Bols NC, Hodson PV. Binding of polycyclic aromatic hydrocarbons (PAHs) to teleost aryl hydrocarbon receptors (AHRs). Comp Biochem Physiol B Biochem Mol Biol. 2002 Sep;133(1):55–68. PubMed Europe PMC Scholia
  30. Landi MT, Bertazzi PA, Baccarelli A, Consonni D, Masten S, Lucier G, et al. TCDD-mediated alterations in the AhR-dependent pathway in Seveso, Italy, 20 years after the accident. Carcinogenesis. 2003 Apr;24(4):673–80. PubMed Europe PMC Scholia
  31. Gottifredi V, McKinney K, Poyurovsky MV, Prives C. Decreased p21 levels are required for efficient restart of DNA synthesis after S phase block. J Biol Chem. 2004 Feb 13;279(7):5802–10. PubMed Europe PMC Scholia
  32. Hollingshead BD, Petrulis JR, Perdew GH. The aryl hydrocarbon (Ah) receptor transcriptional regulator hepatitis B virus X-associated protein 2 antagonizes p23 binding to Ah receptor-Hsp90 complexes and is dispensable for receptor function. J Biol Chem. 2004 Oct 29;279(44):45652–61. PubMed Europe PMC Scholia
  33. Miao W, Hu L, Scrivens PJ, Batist G. Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes. J Biol Chem. 2005 May 27;280(21):20340–8. PubMed Europe PMC Scholia
  34. Beischlag TV, Perdew GH. ER alpha-AHR-ARNT protein-protein interactions mediate estradiol-dependent transrepression of dioxin-inducible gene transcription. J Biol Chem. 2005 Jun 3;280(22):21607–11. PubMed Europe PMC Scholia
  35. N’Diaye M, Le Ferrec E, Lagadic-Gossmann D, Corre S, Gilot D, Lecureur V, et al. Aryl hydrocarbon receptor- and calcium-dependent induction of the chemokine CCL1 by the environmental contaminant benzo[a]pyrene. J Biol Chem. 2006 Jul 21;281(29):19906–15. PubMed Europe PMC Scholia
  36. Singh NP, Nagarkatti M, Nagarkatti PS. Role of dioxin response element and nuclear factor-kappaB motifs in 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated regulation of Fas and Fas ligand expression. Mol Pharmacol. 2007 Jan;71(1):145–57. PubMed Europe PMC Scholia
  37. Shin S, Wakabayashi N, Misra V, Biswal S, Lee GH, Agoston ES, et al. NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis. Mol Cell Biol. 2007 Oct;27(20):7188–97. PubMed Europe PMC Scholia
  38. Cheon H, Woo Y-S, Lee JY, Kim HS, Kim HJ, Cho S, et al. Signaling pathway for 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced TNF-alpha production in differentiated THP-1 human macrophages. Exp Mol Med. 2007 Aug 31;39(4):524–34. PubMed Europe PMC Scholia
  39. Monteiro P, Gilot D, Le Ferrec E, Rauch C, Lagadic-Gossmann D, Fardel O. Dioxin-mediated up-regulation of aryl hydrocarbon receptor target genes is dependent on the calcium/calmodulin/CaMKIalpha pathway. Mol Pharmacol. 2008 Mar;73(3):769–77. PubMed Europe PMC Scholia
  40. Umannová L, Machala M, Topinka J, Nováková Z, Milcová A, Kozubík A, et al. Tumor necrosis factor-alpha potentiates genotoxic effects of benzo[a]pyrene in rat liver epithelial cells through upregulation of cytochrome P450 1B1 expression. Mutat Res. 2008 Apr 2;640(1–2):162–9. PubMed Europe PMC Scholia
  41. Kimura A, Naka T, Nohara K, Fujii-Kuriyama Y, Kishimoto T. Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells. Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9721–6. PubMed Europe PMC Scholia
  42. Minami K, Nakajima M, Fujiki Y, Katoh M, Gonzalez FJ, Yokoi T. Regulation of insulin-like growth factor binding protein-1 and lipoprotein lipase by the aryl hydrocarbon receptor. J Toxicol Sci. 2008 Oct;33(4):405–13. PubMed Europe PMC Scholia
  43. Kekatpure VD, Dannenberg AJ, Subbaramaiah K. HDAC6 modulates Hsp90 chaperone activity and regulates activation of aryl hydrocarbon receptor signaling. J Biol Chem. 2009 Mar 20;284(12):7436–45. PubMed Europe PMC Scholia
  44. Chang K-Y, Shen M-R, Lee M-Y, Wang W-L, Su W-C, Chang W-C, et al. Epidermal growth factor-activated aryl hydrocarbon receptor nuclear translocator/HIF-1{beta} signal pathway up-regulates cyclooxygenase-2 gene expression associated with squamous cell carcinoma. J Biol Chem. 2009 Apr 10;284(15):9908–16. PubMed Europe PMC Scholia
  45. Sutter CH, Yin H, Li Y, Mammen JS, Bodreddigari S, Stevens G, et al. EGF receptor signaling blocks aryl hydrocarbon receptor-mediated transcription and cell differentiation in human epidermal keratinocytes. Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4266–71. PubMed Europe PMC Scholia
  46. Vargiolu M, Fusco D, Kurelac I, Dirnberger D, Baumeister R, Morra I, et al. The tyrosine kinase receptor RET interacts in vivo with aryl hydrocarbon receptor-interacting protein to alter survivin availability. J Clin Endocrinol Metab. 2009 Jul;94(7):2571–8. PubMed Europe PMC Scholia
  47. Yeager RL, Reisman SA, Aleksunes LM, Klaassen CD. Introducing the “TCDD-inducible AhR-Nrf2 gene battery.” Toxicol Sci. 2009 Oct;111(2):238–46. PubMed Europe PMC Scholia
  48. Ahmed S, Valen E, Sandelin A, Matthews J. Dioxin increases the interaction between aryl hydrocarbon receptor and estrogen receptor alpha at human promoters. Toxicol Sci. 2009 Oct;111(2):254–66. PubMed Europe PMC Scholia
  49. Roman AC, Carvajal-Gonzalez JM, Rico-Leo EM, Fernandez-Salguero PM. Dioxin receptor deficiency impairs angiogenesis by a mechanism involving VEGF-A depletion in the endothelium and transforming growth factor-beta overexpression in the stroma. J Biol Chem. 2009 Sep 11;284(37):25135–48. PubMed Europe PMC Scholia
  50. Xu S, Weerachayaphorn J, Cai S-Y, Soroka CJ, Boyer JL. Aryl hydrocarbon receptor and NF-E2-related factor 2 are key regulators of human MRP4 expression. Am J Physiol Gastrointest Liver Physiol. 2010 Jul;299(1):G126-35. PubMed Europe PMC Scholia
  51. Soshilov A, Denison MS. Ligand displaces heat shock protein 90 from overlapping binding sites within the aryl hydrocarbon receptor ligand-binding domain. J Biol Chem. 2011 Oct 7;286(40):35275–82. PubMed Europe PMC Scholia
  52. Chahal HS, Trivellin G, Leontiou CA, Alband N, Fowkes RC, Tahir A, et al. Somatostatin analogs modulate AIP in somatotroph adenomas: the role of the ZAC1 pathway. J Clin Endocrinol Metab. 2012 Aug;97(8):E1411-20. PubMed Europe PMC Scholia
  53. Lo R, Matthews J. High-resolution genome-wide mapping of AHR and ARNT binding sites by ChIP-Seq. Toxicol Sci. 2012 Dec;130(2):349–61. PubMed Europe PMC Scholia
  54. Wilson SR, Joshi AD, Elferink CJ. The tumor suppressor Kruppel-like factor 6 is a novel aryl hydrocarbon receptor DNA binding partner. J Pharmacol Exp Ther. 2013 Jun;345(3):419–29. PubMed Europe PMC Scholia