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J. Biol. Chem., Vol. 278, Issue 25, 22243-22249, June 20, 2003

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Increased Constitutive c-Jun N-terminal Kinase Signaling in Mice Lacking Glutathione S-Transferase Pi^*

Robert Elsby , Neil R. Kitteringham , Christopher E. Goldring , Cerys A. Lovatt , Mark Chamberlain , Colin J. Henderson , C. Roland Wolf  and B. Kevin Park  ¶

From the Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, United Kingdom, and the Cancer Research UK Molecular Pharmacology Unit, Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom

Glutathione S-transferase Pi (GSTP) detoxifies electrophiles by catalyzing their conjugation with reduced glutathione. A second function of this protein in cell defense has recently been proposed that is related to its ability to interact with c-Jun N-terminal kinase (JNK). The present study aimed to determine whether this interaction results in increased constitutive JNK activity in the absence of GSTP in GstP1/P2^(–/–) mice and whether such a phenomenon leads to the up-regulation of genes that are relevant to cell defense. We found a significant increase in constitutive JNK activity in the liver and lung of GstP1/P2^–/– compared with GstP1/P2^(+/+) mice. The greatest increase in constitutive JNK activity was observed in null liver and was accompanied by a significant increase in activator protein-1 DNA binding activity (8-fold) and in the mRNA levels for the antioxidant protein heme oxygenase-1 compared with wild type. Furthermore UDP-glucuronosyltransferase 1A6 mRNA levels were significantly higher in the livers of GstP1/P2^(–/–) compared with GstP1/P2^(+/+) mice, which correlated to a 2-fold increase in constitutive activity both in vitro and in vivo. There was no difference in the gene expression of other UDP-glucuronosyltransferase isoforms, manganese superoxide dismutase, microsomal epoxide hydrolase, or GSTA1 between GstP1/P2^(–/–) and GstP1/P2^(+/+) mice. Additionally there was no phenotypic difference in the induction of heme oxygenase-1 mRNA after acetaminophen administration. This study not only demonstrates the role of GSTP as a direct inhibitor of JNK in vivo but also its role in regulating the constitutive expression of specific downstream molecular targets of the JNK signaling pathway.

Received for publication, February 4, 2003 , and in revised form, March 13, 2003.

^* This work was supported by The Wellcome Trust. 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.

^¶ To whom correspondence should be addressed: Dept. of Pharmacology and Therapeutics, University of Liverpool, The Sherrington Bldgs., Ashton St., Liverpool L69 3GE, UK. Tel.: 44-151-794-5559; Fax: 44-151-794-5540; E-mail: bkpark{at}liverpool.ac.uk.

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