Increased constitutive c-Jun N-terminal kinase signaling in mice lacking glutathione S-transferase Pi

被引:125
作者
Elsby, R
Kitteringham, NR
Goldring, CE
Lovatt, CA
Chamberlain, M
Henderson, CJ
Wolf, CR
Park, BK
机构
[1] Univ Liverpool, Dept Pharmacol & Therapeut, Liverpool L69 3GE, Merseyside, England
[2] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Ctr, Canc Res UK Mol Pharmacol Unit, Dundee DD1 9SY, Scotland
关键词
D O I
10.1074/jbc.M301211200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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收藏
页码:22243 / 22249
页数:7
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