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, B. Kevin Park

    Research output: Contribution to journalArticle

    120 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)22243-22249
    Number of pages7
    JournalJournal of Biological Chemistry
    Volume278
    Issue number25
    DOIs
    Publication statusPublished - 20 Jun 2003

    Cite this