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

Shoko Sato, Hitoshi Shirakawa, Shuhei Tomita, Masahiro Tohkin, Frank J. Gonzalez, Michio Komai

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)90-99
Number of pages10
JournalToxicology and Applied Pharmacology
Volume273
Issue number1
DOIs
Publication statusPublished - 2013 Nov 15

Keywords

  • 3-Methylcholanthrene
  • Aryl hydrocarbon receptor
  • Dexamethasone
  • Glucocorticoid receptor
  • Metallothionein
  • Transcription

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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