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Pathway Description
Ahr Signal Transduction Pathway
Homo sapiens
Category:
Protein Pathway
Sub-Categories:
Gene Regulatory
Cellular Response
Created: 2018-06-13
Last Updated: 2019-08-16
The aryl hydrocarbon receptor, known as AHR, is a normally cytosolic transcription factor that can bind to foreign compounds such as flavonoids and indoles from foods, as well as synthetic ligands including polychlorobiphenyls (PCBs) and polychlorinated dibenzo-p-dioxins (PCDD). This includes 2,3,7,8-tetrachlorodibenzodioxin (TCDD), which is the ligand shown in this pathway.
AHR interacts with heat shock protein 90 (HSP90AA1), which acts as a chaperone for it. After this association, the ligand, in this case TCDD, can form a covalent bond with the complex in the cell's cytoplasm. This binding causes AHR and the rest of the complex to translocate into the nucleus of the cell. Once in the nucleus, the heat shock protein dissociates, leaving binding sites which the AHR nuclear translocator (ARNT) then binds to. Finally, the AHR/ARNT complex can interact, either directly or indirectly, with the DNA, in this case specifically a dioxin response element. With other ligands, the complex will bind to the equivalent DNA that corresponds to the genes that allow metabolism of the ligand.
References
Ahr Signal Transduction Pathway References
Li S, Pei X, Zhang W, Xie HQ, Zhao B: Functional analysis of the dioxin response elements (DREs) of the murine CYP1A1 gene promoter: beyond the core DRE sequence. Int J Mol Sci. 2014 Apr 16;15(4):6475-87. doi: 10.3390/ijms15046475.
Pubmed: 24743890
Ghotbaddini M, Powell JB: The AhR Ligand, TCDD, Regulates Androgen Receptor Activity Differently in Androgen-Sensitive versus Castration-Resistant Human Prostate Cancer Cells. Int J Environ Res Public Health. 2015 Jul 6;12(7):7506-18. doi: 10.3390/ijerph120707506.
Pubmed: 26154658
Sun YV, Boverhof DR, Burgoon LD, Fielden MR, Zacharewski TR: Comparative analysis of dioxin response elements in human, mouse and rat genomic sequences. Nucleic Acids Res. 2004 Aug 24;32(15):4512-23. doi: 10.1093/nar/gkh782. Print 2004.
Pubmed: 15328365
H_acrPathway. (n.d.). Retrieved from https://cgap.nci.nih.gov/Pathways/BioCarta/h_acrPathway
Denison MS, Rogers JM, Rushing SR, Jones CL, Tetangco SC, Heath-Pagliuso S: Analysis of the aryl hydrocarbon receptor (AhR) signal transduction pathway. Curr Protoc Toxicol. 2002 May;Chapter 4:Unit4.8. doi: 10.1002/0471140856.tx0408s11.
Pubmed: 20945300
Itoh S, Kamataki T: Human Ah receptor cDNA: analysis for highly conserved sequences. Nucleic Acids Res. 1993 Jul 25;21(15):3578. doi: 10.1093/nar/21.15.3578.
Pubmed: 8393992
Dolwick KM, Schmidt JV, Carver LA, Swanson HI, Bradfield CA: Cloning and expression of a human Ah receptor cDNA. Mol Pharmacol. 1993 Nov;44(5):911-7.
Pubmed: 8246913
Ema M, Matsushita N, Sogawa K, Ariyama T, Inazawa J, Nemoto T, Ota M, Oshimura M, Fujii-Kuriyama Y: Human arylhydrocarbon receptor: functional expression and chromosomal assignment to 7p21. J Biochem. 1994 Oct;116(4):845-51. doi: 10.1093/oxfordjournals.jbchem.a124605.
Pubmed: 7883760
Yamazaki M, Akaogi K, Miwa T, Imai T, Soeda E, Yokoyama K: Nucleotide sequence of a full-length cDNA for 90 kDa heat-shock protein from human peripheral blood lymphocytes. Nucleic Acids Res. 1989 Sep 12;17(17):7108. doi: 10.1093/nar/17.17.7108.
Pubmed: 2780322
Yamazaki M, Tashiro H, Yokoyama K, Soeda E: Molecular cloning of cDNA encoding a human heat-shock protein whose expression is induced by adenovirus type 12 E1A in HeLa cells. Agric Biol Chem. 1990 Dec;54(12):3163-70.
Pubmed: 1368637
Hickey E, Brandon SE, Smale G, Lloyd D, Weber LA: Sequence and regulation of a gene encoding a human 89-kilodalton heat shock protein. Mol Cell Biol. 1989 Jun;9(6):2615-26. doi: 10.1128/mcb.9.6.2615.
Pubmed: 2527334
Sakurai S, Shimizu T, Ohto U: The crystal structure of the AhRR-ARNT heterodimer reveals the structural basis of the repression of AhR-mediated transcription. J Biol Chem. 2017 Oct 27;292(43):17609-17616. doi: 10.1074/jbc.M117.812974. Epub 2017 Sep 13.
Pubmed: 28904176
Card PB, Erbel PJ, Gardner KH: Structural basis of ARNT PAS-B dimerization: use of a common beta-sheet interface for hetero- and homodimerization. J Mol Biol. 2005 Oct 28;353(3):664-77. doi: 10.1016/j.jmb.2005.08.043. Epub 2005 Sep 6.
Pubmed: 16181639
Evans MR, Card PB, Gardner KH: ARNT PAS-B has a fragile native state structure with an alternative beta-sheet register nearby in sequence space. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2617-22. doi: 10.1073/pnas.0808270106. Epub 2009 Feb 5.
Pubmed: 19196990
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