The aryl hydrocarbon receptor and glucocorticoid receptor interact to activate human metallothionein 2A

• Published in: Toxicology and applied pharmacology Vol. 273; no. 1; pp. 90 - 99
• Main Authors: Sato, Shoko, Shirakawa, Hitoshi, Tomita, Shuhei, Tohkin, Masahiro, Gonzalez, Frank J., Komai, Michio
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 15.11.2013; Elsevier
• Subjects: 3-METHYLCHOLANTHRENE; 60 APPLIED LIFE SCIENCES; AMINO ACIDS; ANIMAL TISSUES; Animals; Aryl hydrocarbon receptor; Biological and medical sciences; Cercopithecus aethiops; CHROMATIN; Chromatin Immunoprecipitation; COS Cells; DEXAMETHASONE; Dexamethasone - pharmacology; GENES; Glucocorticoid receptor; Hep G2 Cells; Humans; Immunoprecipitation; Medical sciences; MESSENGER-RNA; METALLOTHIONEIN; Metallothionein - genetics; Metallothionein - metabolism; Methylcholanthrene - pharmacology; Promoter Regions, Genetic; Protein Interaction Domains and Motifs - drug effects; RECEPTORS; Receptors, Aryl Hydrocarbon - agonists; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; Receptors, Glucocorticoid - agonists; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Response Elements - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; RODENTS; Signal Transduction; Toxicology; Transcription; Transcriptional Activation; Dexamethasone; bHLH/PAS; Transcription; 3-Methylcholanthrene; 3-MC; MT; XRE; AHR; GR; ChIP; Aryl hydrocarbon receptor; MT2A; Dex; Glucocorticoid receptor; GRE; Metallothionein; Human; Corticosteroid; Hydrocarbon; Steroid hormone; Antiinflammatory agent; Ah receptor; 3―Methylcholanthrene; Hormonal receptor; metallothionein 2A; glucocorticoid response element; chromatin immunoprecipitation; xenobiotic response element; basic helix–loop–helix/Per–Arnt–Sim
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2013.08.017

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. •Aryl hydrocarbon receptor forms a complex with glucocorticoid receptor in cells.•Human metallothionein gene is regulated by the AHR and GR interaction.•AHR–GR complex binds to glucocorticoid response element in metallothionein gene.•We demonstrated a novel transcriptional mechanism via AHR and GR interaction.