A small-molecule inducer of the antioxidant response element.
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.
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Wooyoung
W
Hur
Zheng
Z
Sun
Tao
T
Jiang
Daniel E
DE
Mason
Eric C
EC
Peters
Donna D
DD
Zhang
Hendrik
H
Luesch
Peter G
PG
Schultz
Nathanael S
NS
Gray
D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology; D002273:Carcinogens / Q000633:toxicity; D002460:Cell Line; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009369:Neoplasms / Q000139:chemically induced / Q000188:drug therapy; D011485:Protein Binding; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology; D020218:Response Elements; D013329:Structure-Activity Relationship; D054875:Ubiquitination
D000975:Antioxidants; D002273:Carcinogens; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D015363:Quinolones