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PMID: 18417180 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction.

Toxicology and applied pharmacology ·Vol. 230 ·No. 3 ·2008-08-01 ·Pages 383-9

Wang XJ, Sun Z, Chen W, Li Y, Villeneuve NF, Zhang DD

Abstract

Drinking water contaminated with arsenic, a human carcinogen, is a worldwide health issue. An understanding of cellular signaling events in response to arsenic exposure and rational designing of strategies to reduce arsenic damages by modulating signaling events are important to fight against arsenic-induced diseases. Previously, we reported that activation of the Nrf2-mediated cellular defense pathway confers protection against toxic effects induced by sodium arsenite [As(III)] or monomethylarsonous acid [MMA(III)]. Paradoxically, arsenic has been reported to induce the Nrf2-dependent signaling pathway. Here, we report the unique mechanism of Nrf2 induction by arsenic. Similar to tert-butylhydroquinone (tBHQ) or sulforaphane (SF), arsenic induced the Nrf2-dependent response through enhancing Nrf2 protein levels by inhibiting Nrf2 ubiquitination and degradation. However, the detailed action of arsenic in Nrf2 induction is different from that of tBHQ or SF. Arsenic markedly enhanced the interaction between Keap1 and Cul3, subunits of the E3 ubiquitin ligase for Nrf2, which led to impaired dynamic assembly/disassembly of the E3 ubiquitin ligase and thus decreased its ligase activity. Furthermore, induction of Nrf2 by arsenic is independent of the previously identified C151 residue in Keap1 that is required for Nrf2 activation by tBHQ or SF. Distinct mechanisms of Nrf2 activation by seemingly harmful and beneficial reagents provide a molecular basis to design Nrf2-activating agents for therapeutic intervention.

MeSH Terms
Arsenites/pharmacology Cell Line, Tumor Cullin Proteins/physiology Cysteine Female Humans Intracellular Signaling Peptides and Proteins/chemistry,physiology Kelch-Like ECH-Associated Protein 1 NF-E2-Related Factor 2/metabolism Organometallic Compounds/pharmacology Ubiquitin-Protein Ligases/physiology
Chemicals
Arsenites CUL3 protein, human Cullin Proteins Intracellular Signaling Peptides and Proteins KEAP1 protein, human Kelch-Like ECH-Associated Protein 1 NF-E2-Related Factor 2 NFE2L2 protein, human Organometallic Compounds monomethylarsonous acid Ubiquitin-Protein Ligases Cysteine arsenite
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Wang Xiao-Jun
Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, USA.
Sun Zheng
Chen Weimin
Li Yanjie
Villeneuve Nicole F
Zhang Donna D
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Article Info
Journal
Toxicology and applied pharmacology
Abbr.
Toxicol Appl Pharmacol
ISSN
0041-008X
DOI
10.1016/j.taap.2008.03.003
Published
2008-08-01
Epub
2008-00-12
Pages
383-9
Language
English
Region
United States
NLM ID
0416575
PMCID
PMC2610481
Subset
IM
Grants
NIEHS NIH HHS · R01 ES015010-02 · United States
NIEHS NIH HHS · ES 06694 · United States
NIEHS NIH HHS · ES 015010-01 · United States
NIEHS NIH HHS · R01 ES015010-01 · United States
NIEHS NIH HHS · R01 ES015010 · United States
External Links
PubMed source DOI: 10.1016/j.taap.2008.03.003 PMC Full Text View journal details
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