Increased constitutive c-Jun N-terminal kinase signaling in mice lacking glutathione S-transferase Pi
Increased constitutive c-Jun N-terminal kinase signaling in mice lacking glutathione S-transferase Pi
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DOI：
10.1074/jbc.m301211200
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发表时间：
2003-06-20
影响因子：
4.8
通讯作者：
Park, BK
中科院分区：
文献类型：
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作者：
Elsby, R;Kitteringham, NR;Park, BK
谷胱甘肽s -转移酶（GSTP）通过催化亲电试剂与还原性谷胱甘肽的结合来解毒。该蛋白在细胞防御中的第二个功能最近被提出与其与c-Jun n末端激酶（JNK）相互作用的能力有关。本研究旨在确定GstP1/P2（(-/-)）小鼠在GSTP缺失的情况下，这种相互作用是否会导致组成性JNK活性增加，以及这种现象是否会导致与细胞防御相关的基因上调。我们发现，与GstP1/P2（(+/+)）小鼠相比，GstP1/P2（-/-）小鼠的肝脏和肺部组成性JNK活性显著增加。与野生型相比，在无肝中观察到组成型JNK活性的最大增加，并伴随着激活蛋白-1 DNA结合活性（8倍）和抗氧化蛋白血红素加氧酶-1 mRNA水平的显著增加。此外，与GstP1/P2（(+/+)）小鼠相比，GstP1/P2（(-/-)）小鼠肝脏中的udp -葡萄糖醛酸糖基转移酶1A6 mRNA水平显著升高，这与体外和体内组成活性增加2倍相关。GstP1/ P2（(-/-)）和GstP1/ P2（(+/+)）小鼠的其他udp -葡萄糖醛基转移酶异构体、锰超氧化物歧化酶、微体环氧化物水解酶或GSTA1基因表达无差异。此外，对乙酰氨基酚对血红素加氧酶-1 mRNA的诱导没有表型差异。本研究不仅证明了GSTP在体内作为JNK的直接抑制剂的作用，而且还证明了GSTP在调节JNK信号通路下游特定分子靶点的组成性表达中的作用。
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.