Increased constitutive c-Jun N-terminal kinase signaling in mice lacking glutathione S-transferase Pi.
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.
Elsby
Robert
R
Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, United Kingdom.
Kitteringham
Neil R
NR
Goldring
Christopher E
CE
Lovatt
Cerys A
CA
Chamberlain
Mark
M
Henderson
Colin J
CJ
Wolf
C Roland
CR
Park
B Kevin
BK
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D014453:Glucuronosyltransferase / Q000235:genetics; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000172:deficiency* / Q000235:genetics; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics; D051547:Heme Oxygenase-1; D007527:Isoenzymes / Q000172:deficiency* / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases; D008099:Liver / Q000201:enzymology; D008168:Lung / Q000201:enzymology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000235:genetics
D004268:DNA-Binding Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D013482:Superoxide Dismutase; D014453:Glucuronosyltransferase; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C496557:Gstp1 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases