ToxSci Advance Access originally published online on July 28, 2004
Toxicological Sciences 2004 82(1):308-317; doi:10.1093/toxsci/kfh231
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Toxicological Sciences vol. 82 no. 1 © Society of Toxicology 2004; all rights reserved.
Compartmentation of Nrf-2 Redox Control: Regulation of Cytoplasmic Activation by Glutathione and DNA Binding by Thioredoxin-1
* Department of Medicine and Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, and Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205
Received June 30, 2004; accepted July 19, 2004
Nrf-2 is a redox-sensitive transcription factor that is activated by an oxidative signal in the cytoplasm but has a critical cysteine that must be reduced to bind to DNA in the nucleus. The glutathione (GSH) and thioredoxin (TRX) systems have overlapping functions in thiol/disulfide redox control in both the cytoplasm and the nucleus, and it is unclear whether these are redundant or have unique functions in control of Nrf-2-dependent signaling. To test whether GSH and Trx-1 have distinct functions in Nrf-2 signaling, we selectively modified GSH by metabolic manipulation and selectively modified Trx-1 expression by transient transfection. Cytoplasmic activation of Nrf-2 was measured by its nuclear translocation and nuclear activity of Nrf-2 was measured by expression of a luciferase reporter construct containing an ARE4 from glutamate cysteine ligase. Results showed that tert-butylhydroquinone (TBHQ), a transcriptional activator that functions through Nrf-2/ARE, promoted Nrf-2 nuclear translocation by a type I (thiylation) redox switch which was regulated by GSH not by Trx-1. In contrast, the ARE reporter was principally controlled by nuclear-targeted Trx-1 and not by GSH. The data show that the GSH and TRX systems have unique, compartmented functions in the control of transcriptional regulation by Nrf-2/ARE.
Key Words: thioredoxin; glutathione; redox; NE-F2 related factor; Nrf-2.
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