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ToxSci Advance Access published online on July 28, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh231
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received June 30, 2004
Accepted July 19, 2004

Systems Toxicology

Compartmentation of Nrf-2 Redox Control: Regulation of Cytoplasmic Activation by Glutathione and DNA Binding by Thioredoxin-1

Jason M. Hansen 1, Walter H. Watson 2, Dean P. Jones 1*

1 Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322, USA
2 Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21205, USA

* To whom correspondence should be addressed. E-mail: dpjones{at}emory.edu.


  Abstract

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.

Keywords: Thioredoxin; Glutathione; Redox; NE-F2 related factor; Nrf-2.
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