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J. Biol. Chem., Vol. 284, Issue 1, 436-445, January 2, 2009

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Novel Role for Glutathione S-Transferase

REGULATOR OF PROTEIN S-GLUTATHIONYLATION FOLLOWING OXIDATIVE AND NITROSATIVE STRESS^*

Danyelle M. Townsend, Yefim Manevich, Lin He, Steven Hutchens, Christopher J. Pazoles^¶, and Kenneth D. Tew¹

From the Departments of Pharmaceutical and Biomedical Sciences and Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina 29425 and ^¶Novelos Inc., Newton, Massachusetts 02458

Glutathione S-transferase Pi (GST) is a marker protein in many cancers and high levels are linked to drug resistance, even when the selecting drug is not a substrate. S-Glutathionylation of proteins is critical to cellular stress response, but characteristics of the forward reaction are not known. Our results show that GST potentiates S-glutathionylation reactions following oxidative and nitrosative stress in vitro and in vivo. Mutational analysis indicated that the catalytic activity of GST is required. GST is itself redox-regulated. S-Glutathionylation on Cys⁴⁷ and Cys¹⁰¹ autoregulates GST, breaks ligand binding interactions with c-Jun NH₂-terminal kinase (JNK), and causes GST multimer formation, all critical to stress response. Catalysis of S-glutathionylation at low pK cysteines in proteins is a novel property for GST and may be a cause for its abundance in tumors and cells resistant to a range of mechanistically unrelated anticancer drugs.

Received for publication, July 22, 2008 , and in revised form, November 6, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants CA08660 and CA117259. This work was also supported by the South Carolina Centers of Excellence program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 96 Johnathan Lucas St., Charleston, SC 29425. E-mail: tewk{at}musc.edu.

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