title: The aryl hydrocarbon receptor and glucocorticoid receptor interact to activate human metallothionein 2A.
abstract: Although the aryl hydrocarbon receptor (AHR) and glucocorticoid receptor (GR) play essential roles in mammalian development, stress responses, and other physiological events, crosstalk between these receptors has been the subject of much debate. Metallothioneins are classic glucocorticoid-inducible genes that were reported to increase upon treatment with AHR agonists in rodent tissues and cultured human cells. In this study, the mechanism of human metallothionein 2A (MT2A) gene transcription activation by AHR was investigated. Cotreatment with 3-methylcholanthrene and dexamethasone, agonists of AHR and GR respectively, synergistically increased MT2A mRNA levels in HepG2 cells. MT2A induction was suppressed by RNA interference against AHR or GR. Coimmunoprecipitation experiments revealed a physical interaction between AHR and GR proteins. Moreover, chromatin immunoprecipitation assays indicated that AHR was recruited to the glucocorticoid response element in the MT2A promoter. Thus, we provide a novel mechanism whereby AHR modulates expression of human MT2A via the glucocorticoid response element and protein-protein interactions with GR.
authors.affiliation: Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan. Electronic address: satosho@rs.tus.ac.jp.
authors.forename: Shoko
authors.initials: S
authors.lastname: Sato
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shirakawa
authors.forename: Shuhei
authors.initials: S
authors.lastname: Tomita
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tohkin
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Michio
authors.initials: M
authors.lastname: Komai
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D047369:Chromatin Immunoprecipitation; D003907:Dexamethasone / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D047468:Immunoprecipitation; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D008748:Methylcholanthrene / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000187:drug effects; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: C491053:MT2A protein, human; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011965:Receptors, Glucocorticoid; D008748:Methylcholanthrene; D003907:Dexamethasone; D008668:Metallothionein
keywords: 3-MC; 3-Methylcholanthrene; 3-methylcholanthrene; AHR; Aryl hydrocarbon receptor; ChIP; Dex; Dexamethasone; GR; GRE; Glucocorticoid receptor; MT; MT2A; Metallothionein; Transcription; XRE; aryl hydrocarbon receptor; bHLH/PAS; basic helix–loop–helix/Per–Arnt–Sim; chromatin immunoprecipitation; dexamethasone; glucocorticoid receptor; glucocorticoid response element; metallothionein; metallothionein 2A; xenobiotic response element