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 journalArticle

55 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 languageEnglish (US)
Pages (from-to)537-547
Number of pages11
JournalChemistry and Biology
Volume17
Issue number5
DOIs
StatePublished - Jul 7 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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