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Ah receptor interacts with Nrf2 to mediate induction of NQO1 by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin and benzo[a]pyrene
Author(s) -
Wang Liping,
He Xiaoqing,
Bi Yongyi,
Szklarz Grazyna,
Ma Qiang
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1014.3
Subject(s) - chromatin immunoprecipitation , aryl hydrocarbon receptor , keap1 , chemistry , response element , benzo(a)pyrene , promoter , signal transduction , transcription factor , receptor , microbiology and biotechnology , gene , gene expression , biochemistry , biology , carcinogen
Ah receptor mediates the induction of NQO1, GSTs, and UGTs by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) and benzo[a]pyrene (B[a]P); whereas, Nrf2 is critical for the induction of the genes by antioxidants such as tert‐butylhydroquinone (tBHQ). Induction of the genes by AhR agonists or antioxidants requires “dioxin response element” (DRE) or “antioxidant response element” (ARE) respectively. We have used induction of NQO1 as a prototype to elucidate the molecular steps governing the induction of the genes. We previously reported a cross‐interaction between AhR and Nrf2 signal transduction is required for induction of NQO1 by TCDD (Ma et al, Biochem J 377, 205–213, 2004). In this study, we analyzed the interaction between AhR and Nrf2 at the promoter of NQO1. Chromatin immunoprecipitation analyses revealed that treatment with TCDD recruits both AhR and Nrf2 to the promoter region where a DRE and an ARE locate; the finding is in agreement with the result from genetic studies in which induction by TCDD or B[a]P was shown to require both AhR and Nrf2. TCDD‐induced binding of AhR and Nrf2 to DNA is time‐dependent. Consistent with the activation of Nrf2, TCDD treatment inhibits Keap1‐dependent ubiquitination and proteasomal degradation of Nrf2 resulting in the stabilization and nuclear accumulation of Nrf2. Co‐immunoprecipitation experiments revealed that AhR directly interacts with Nrf2 in the presence of TCDD. Our findings demonstrate that AhR interacts with Nrf2 to induce NQO1 and provide a molecular model for studying the induction of NQO1, GSTs, and UGTs by AhR agonists.