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Cited by 404

The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.

Identification of Sensor Cysteines in Human Keap1 Modified by the Cancer Chemopreventive Agent Sulforaphane

Hong, Fei, Freeman, Michael L., Liebler, Daniel C.·2005·Chemical Research in Toxicology
DOI 10.1021/tx0502138
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Abstract

The chemopreventive agent sulforaphane is an isothiocyanate derived from cruciferous vegetables. Sulforaphane exerts cancer chemopreventive effects by inducing antioxidant/electrophile response element (ARE)-regulated phase 2 enzyme and antioxidant genes through activation of the transcription factor nuclear factor-E2-related factor 2 (Nrf2), which is regulated by the thiol-rich sensor protein Kelch-like ECH-associated protein 1 (Keap1). Sulforaphane is an electrophile that can react with protein thiols to form thionoacyl adducts. We hypothesized that, like other electrophilic Nrf2 activators, sulforaphane activates this system through specific modifications of the Keap1 protein. However, thionoacyl adducts are labile to hydrolysis and transacylation reactions, which complicate the identification of the sulforaphane adduct sites on Keap1. In this study, we characterized the stability of sulforaphane thionoacyl adducts and developed a liquid chromatography-tandem mass spectrometry method to map labile sulforaphane adduct sites formed on Keap1 in vitro. Sulforaphane displays a distinctly different pattern of Keap1 modification than previously studied ARE inducers that modify Keap1 by alkylation. Sulforaphane modified Keap1 most readily in the Kelch domain, rather than in the central linker domain, which is targeted by previously characterized ARE inducers. Also, in contrast to previously studied ARE inducers and as reported recently [Zhang, et al. (2005) J. Biol. Chem. 280, 30091-30099], sulforaphane treatment in vivo does not lead to the accumulation of ubiquitinated Keap1. Our observations suggest a novel mechanism for Nrf2 stabilization by sulforaphane-Keap1 thionoacyl adduct formation.

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Metadata

Authors
Hong, F., Freeman, M. L., & Liebler, D. C.
Venue
Chemical Research in Toxicology
Publisher
American Chemical Society (ACS)
Published
2005-11-08
Volume
18
Issue
12
Pages
1917-1926
ISSN
  • 0893-228X (ISSN-L)
  • 1520-5010
DOI
10.1021/tx0502138
OpenAlex
W2021270662
Cited by
404
References
3
FWCI
6.91
Type
journal article
Language
en
Open access
closed

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