| First Author | Elsby R | Year | 2003 |
| Journal | J Biol Chem | Volume | 278 |
| Issue | 25 | Pages | 22243-9 |
| PubMed ID | 12646564 | Mgi Jnum | J:124412 |
| Mgi Id | MGI:3721484 | Doi | 10.1074/jbc.M301211200 |
| Citation | Elsby R, et al. (2003) Increased constitutive c-Jun N-terminal kinase signaling in mice lacking glutathione S-transferase Pi. J Biol Chem 278(25):22243-9 |
| abstractText | 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. |
