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

Xiao Jun Wang, Zheng Sun, Weimin Chen, Yanjie Li, Nicole F. Villeneuve, Donna Zhang

Research output: Contribution to journalArticle

94 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)383-389
Number of pages7
JournalToxicology and Applied Pharmacology
Volume230
Issue number3
DOIs
StatePublished - Aug 1 2008

Fingerprint

Arsenic
Chemical activation
Ubiquitin-Protein Ligases
arsenite
monomethylarsonous acid
Cell signaling
Poisons
Ubiquitination
Ligases
Drinking Water
Carcinogens
Health
Degradation

Keywords

  • Arsenic
  • Cul3
  • E3 ubiquitin ligase
  • Keap1
  • Nrf2

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151 : enhanced Keap1-Cul3 interaction. / Wang, Xiao Jun; Sun, Zheng; Chen, Weimin; Li, Yanjie; Villeneuve, Nicole F.; Zhang, Donna.

In: Toxicology and Applied Pharmacology, Vol. 230, No. 3, 01.08.2008, p. 383-389.

Research output: Contribution to journalArticle

Wang, Xiao Jun ; Sun, Zheng ; Chen, Weimin ; Li, Yanjie ; Villeneuve, Nicole F. ; Zhang, Donna. / Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151 : enhanced Keap1-Cul3 interaction. In: Toxicology and Applied Pharmacology. 2008 ; Vol. 230, No. 3. pp. 383-389.
@article{85cbd6f91b744dceb73a3bfe6c4551fb,
title = "Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction",
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.",
keywords = "Arsenic, Cul3, E3 ubiquitin ligase, Keap1, Nrf2",
author = "Wang, {Xiao Jun} and Zheng Sun and Weimin Chen and Yanjie Li and Villeneuve, {Nicole F.} and Donna Zhang",
year = "2008",
month = "8",
day = "1",
doi = "10.1016/j.taap.2008.03.003",
language = "English (US)",
volume = "230",
pages = "383--389",
journal = "Toxicology and Applied Pharmacology",
issn = "0041-008X",
publisher = "Academic Press Inc.",
number = "3",

}

TY - JOUR

T1 - Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151

T2 - enhanced Keap1-Cul3 interaction

AU - Wang, Xiao Jun

AU - Sun, Zheng

AU - Chen, Weimin

AU - Li, Yanjie

AU - Villeneuve, Nicole F.

AU - Zhang, Donna

PY - 2008/8/1

Y1 - 2008/8/1

N2 - 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.

AB - 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.

KW - Arsenic

KW - Cul3

KW - E3 ubiquitin ligase

KW - Keap1

KW - Nrf2

UR - http://www.scopus.com/inward/record.url?scp=46749152185&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=46749152185&partnerID=8YFLogxK

U2 - 10.1016/j.taap.2008.03.003

DO - 10.1016/j.taap.2008.03.003

M3 - Article

C2 - 18417180

AN - SCOPUS:46749152185

VL - 230

SP - 383

EP - 389

JO - Toxicology and Applied Pharmacology

JF - Toxicology and Applied Pharmacology

SN - 0041-008X

IS - 3

ER -