A small-molecule inducer of the antioxidant response element

Wooyoung Hur; Zheng Sun; Tao Jiang; Daniel E. Mason; Eric C. Peters; Donna D. Zhang; Hendrik Luesch; Peter G. Schultz; Nathanael S. Gray

doi:10.1016/j.chembiol.2010.03.013

A small-molecule inducer of the antioxidant response element

Wooyoung Hur, Zheng Sun, Tao Jiang, Daniel E. Mason, Eric C. Peters, Donna D. Zhang, Hendrik Luesch, Peter G. Schultz, Nathanael S. Gray

Research output: Contribution to journal › Article › peer-review

72 Scopus citations

Abstract

Eukaryotic cells counteract oxidative and other environmental stress through the activation of Nrf2, the transcription factor that controls the expression of a host of protective enzymes by binding to the antioxidant response element (ARE). The electrophilic molecules that are able to activate Nrf2 and its downstream target genes have demonstrated therapeutic potential in carcinogen-induced tumor models. Using a high-throughput cellular screen, we discovered a class of ARE activator, which we named AI-1, that activates Nrf2 by covalently modifying Keap1, the negative regulator of Nrf2. Biochemical studies indicated that modification of Cys151 of Keap1 by AI-1 disrupted the ability of Keap1 to serve as an adaptor for Cul3-Keap1 ubiquitin ligase complex, thereby causing stabilization and transcriptional activation of Nrf2. AI-1 and its biotinylated derivative are useful pharmacological probes for investigating the molecular details of the cellular antioxidant response.

Original language	English (US)
Pages (from-to)	537-547
Number of pages	11
Journal	Chemistry and Biology
Volume	17
Issue number	5
DOIs	https://doi.org/10.1016/j.chembiol.2010.03.013
State	Published - 2010

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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10.1016/j.chembiol.2010.03.013

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title = "A small-molecule inducer of the antioxidant response element",

abstract = "Eukaryotic cells counteract oxidative and other environmental stress through the activation of Nrf2, the transcription factor that controls the expression of a host of protective enzymes by binding to the antioxidant response element (ARE). The electrophilic molecules that are able to activate Nrf2 and its downstream target genes have demonstrated therapeutic potential in carcinogen-induced tumor models. Using a high-throughput cellular screen, we discovered a class of ARE activator, which we named AI-1, that activates Nrf2 by covalently modifying Keap1, the negative regulator of Nrf2. Biochemical studies indicated that modification of Cys151 of Keap1 by AI-1 disrupted the ability of Keap1 to serve as an adaptor for Cul3-Keap1 ubiquitin ligase complex, thereby causing stabilization and transcriptional activation of Nrf2. AI-1 and its biotinylated derivative are useful pharmacological probes for investigating the molecular details of the cellular antioxidant response.",

author = "Wooyoung Hur and Zheng Sun and Tao Jiang and Mason, {Daniel E.} and Peters, {Eric C.} and Zhang, {Donna D.} and Hendrik Luesch and Schultz, {Peter G.} and Gray, {Nathanael S.}",

note = "Funding Information: This work was supported by the Ellison Medical Foundation (P.G.S.), the American Heart Association (H.L.), and the Evelyn F. and William L. McKnight Brain Institute of the University of Florida (H.L.). We thank Jonathan Kern for assistance with the screens. The authors declare no competing financial interests. ",

year = "2010",

doi = "10.1016/j.chembiol.2010.03.013",

language = "English (US)",

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pages = "537--547",

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AU - Hur, Wooyoung

AU - Sun, Zheng

AU - Jiang, Tao

AU - Mason, Daniel E.

AU - Peters, Eric C.

AU - Zhang, Donna D.

AU - Luesch, Hendrik

AU - Schultz, Peter G.

AU - Gray, Nathanael S.

N1 - Funding Information: This work was supported by the Ellison Medical Foundation (P.G.S.), the American Heart Association (H.L.), and the Evelyn F. and William L. McKnight Brain Institute of the University of Florida (H.L.). We thank Jonathan Kern for assistance with the screens. The authors declare no competing financial interests.

PY - 2010

Y1 - 2010

N2 - Eukaryotic cells counteract oxidative and other environmental stress through the activation of Nrf2, the transcription factor that controls the expression of a host of protective enzymes by binding to the antioxidant response element (ARE). The electrophilic molecules that are able to activate Nrf2 and its downstream target genes have demonstrated therapeutic potential in carcinogen-induced tumor models. Using a high-throughput cellular screen, we discovered a class of ARE activator, which we named AI-1, that activates Nrf2 by covalently modifying Keap1, the negative regulator of Nrf2. Biochemical studies indicated that modification of Cys151 of Keap1 by AI-1 disrupted the ability of Keap1 to serve as an adaptor for Cul3-Keap1 ubiquitin ligase complex, thereby causing stabilization and transcriptional activation of Nrf2. AI-1 and its biotinylated derivative are useful pharmacological probes for investigating the molecular details of the cellular antioxidant response.

AB - Eukaryotic cells counteract oxidative and other environmental stress through the activation of Nrf2, the transcription factor that controls the expression of a host of protective enzymes by binding to the antioxidant response element (ARE). The electrophilic molecules that are able to activate Nrf2 and its downstream target genes have demonstrated therapeutic potential in carcinogen-induced tumor models. Using a high-throughput cellular screen, we discovered a class of ARE activator, which we named AI-1, that activates Nrf2 by covalently modifying Keap1, the negative regulator of Nrf2. Biochemical studies indicated that modification of Cys151 of Keap1 by AI-1 disrupted the ability of Keap1 to serve as an adaptor for Cul3-Keap1 ubiquitin ligase complex, thereby causing stabilization and transcriptional activation of Nrf2. AI-1 and its biotinylated derivative are useful pharmacological probes for investigating the molecular details of the cellular antioxidant response.

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A small-molecule inducer of the antioxidant response element

Abstract

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