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.

The Biochemical journal ·Vol. 377 ·No. Pt 1 ·2004-01-01 ·Pages 205-13

Ma Q, Kinneer K, Bi Y, Chan JY, Kan YW

Abstract

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 bZip (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 Arnt, 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.

MeSH Terms

Animals Antioxidants/pharmacology Cell Line, Tumor Cells, Cultured Cycloheximide/pharmacology Cysteine Endopeptidases/metabolism DNA-Binding Proteins/chemistry,metabolism,physiology Enzyme Induction Hydroquinones/pharmacology Leucine Zippers Ligands Mice Multienzyme Complexes/metabolism NAD(P)H Dehydrogenase (Quinone)/biosynthesis,genetics,metabolism NF-E2-Related Factor 2 Polychlorinated Dibenzodioxins/pharmacology Proteasome Endopeptidase Complex Protein Synthesis Inhibitors/pharmacology Receptors, Aryl Hydrocarbon/metabolism Signal Transduction Trans-Activators/chemistry,metabolism,physiology Transcription, Genetic Ubiquitins/metabolism

Chemicals

Antioxidants DNA-Binding Proteins Hydroquinones Ligands Multienzyme Complexes NF-E2-Related Factor 2 Nfe2l2 protein, mouse Polychlorinated Dibenzodioxins Protein Synthesis Inhibitors Receptors, Aryl Hydrocarbon Trans-Activators Ubiquitins Cycloheximide 2-tert-butylhydroquinone NAD(P)H Dehydrogenase (Quinone) Cysteine Endopeptidases Proteasome Endopeptidase Complex

Authors & Affiliations

5 authors, click to expand affiliations / ORCID

Ma Qiang

Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV 26505, USA. [email protected]

Kinneer Krista

Bi Yongyi

Chan Jefferson Y

Kan Yuet Wai

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Article Info

Journal

The Biochemical journal

Abbr.

Biochem J

ISSN

1470-8728

DOI

10.1042/BJ20031123

[email protected]

Published

2004-01-01

Pages

205-13

Language

English

Region

England

NLM ID

2984726R

PMCID

PMC1223846

Subset

External Links

PubMed source DOI: 10.1042/BJ20031123 PMC Full Text View journal details

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