Induction of murine NAD(P)H:quinone oxidoreductase by 2,3,7,8-tetrachlorodibenzo-p-dioxin requires the CNC (cap 'n' collar) basic leucine zipper transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2):: cross-interaction between AhR (aryl hydrocarbon receptor) and Nrf2 signal transduction

被引:163
作者
Ma, Q
Kinneer, K
Bi, YY
Chan, JY
Kan, YW
机构
[1] Ctr Dis Control & Prevent, Receptor Biol Lab, Toxicol & Mol Biol Branch, Hlth Effect Lab Div,Natl Inst Occupat Safety & Hl, Morgantown, WV 26505 USA
[2] Univ Calif Irvine, Dept Pathol, Coll Med, Irvine, CA 92697 USA
[3] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA
[4] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA
关键词
NQO1 [NAD(P)H : quinone oxidoreductase 1; Nrf2 (nuclear factor erythroid 2-related factor 2); AhR (aryl hydrocarbon receptor); ARE (antioxidant response element); DRE (dioxin response element); TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin);
D O I
10.1042/BJ20031123
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
TCDD (2,3,7,8-tetrachlorodibenzo-p-dixoin) induces phase II drug-metabolizing enzyme NQO1 [NAD(P)H:quinone oxidoreductase; EC 1.6.99.2; DT-diaphorase] in a wide range of mammalian tissues and cells. Here, we analysed the molecular pathway mediating NQO1 induction by TCDD in mouse hepatoma cells. Inhibition of protein synthesis with CHX (cycloheximide) completely blocks induction of NQO1 by TCDD as well as the basal expression and induction by phenolic antioxidant tBHQ (2-t-butylbenzene-1,4-diol), implicating a labile factor in NQO1 mRNA expression. The inhibition is both time- and concentration-dependent, requires inhibition of protein synthesis, and occurs at a transcriptional level. Inhibition of NQO1 transcription by CHX correlates with a rapid reduction of the CNC blip (cap 'n' collar basic leucine zipper) transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) through the 26 S proteasome pathway. Moreover, blocking Nrf2 degradation with proteasome inhibitor MG132 increases the amount of Nrf2 and superinduces NQO1 in the presence of TCDD or tBHQ. Finally, genetic experiments using AhR (aryl hydrocarbon receptor)-, Arnt (aryl hydrocarbon receptor nuclear translocator)- or Nrf2-deficient cells reveal that, while induction of NQO1 by TCDD depends on the presence of AhR and Arm, the basal and inducible expression of NQO1 by either TCDD or tBHQ requires functional Nrf2. The findings demonstrate a novel role of Nrf2 in the induction of NQO1 by TCDD and provide new insights into the mechanism by which Nrf2 regulates the induction of phase II enzymes by both phenolic antioxidants and AhR ligands.
引用
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页码:205 / 213
页数:9
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