Independent regulation of JNK/p38 mitogen-activated protein kinases by metabolic oxidative stress in the liver
Independent regulation of JNK/p38 mitogen-activated protein kinases by metabolic oxidative stress in the liver
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DOI：
10.1073/pnas.93.23.12908
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发表时间：
1996-11-12
影响因子：
11.1
通讯作者：
Paulson, KE
中科院分区：
文献类型：
--
作者：
Mendelson, KG;Contois, LR;Paulson, KE
应激激活蛋白激酶 JNK 和 p38 介导基因表达增加，并被环境应激和促炎细胞因子激活。使用肝脏中通过细胞内代谢产生氧化应激的体内模型，观察到应激激活的 AP-1 靶基因 a- 上快速形成蛋白质-DNA 复合物，对诱导的结合复合物的分析表明存在 c-fos、c-fun 和 ATF-2，而且还存在另外两个 jun 家族成员 JunB 和 JunD。 JNK 的激活先于 AP-1 DNA 结合的增加，此外，JunB 被证明是 JNK 的底物，并且磷酸化需要 N 端激活结构域。出乎意料的是，p38 活性被发现在肝脏中具有组成型活性，并通过氧化应激后的选择性去磷酸化而下调。 p38 去磷酸化的一种潜在机制是应激诱导的磷酸酶 MKP-1 的快速激活，该酶对作为底物的磷酸化 p38 具有高亲和力。这些数据表明，肝脏代谢氧化应激后存在独立调节 JNK 和 p38 丝裂原激活蛋白激酶信号转导途径的机制。
The stress-activated protein kinases JNK and p38 mediate increased gene expression and are activated by environmental stresses and proinflammatory cytokines. Using an in vivo model in which oxidative stress is generated in the liver by intracellular metabolism, rapid protein-DNA complex formation on stress-activated AP-1 target genes a-as observed, Analysis of the induced binding complexes indicates that c-fos, c-fun, and ATF-2 were present, but also two additional jun family members, JunB and JunD. Activation of JNK precedes increased AP-1 DNA binding, Furthermore, JunB was shown to be a substrate far JNK and phosphorylation requires the N-terminal activation domain. Unexpectedly, p38 activity was found to be constitutively active in the liver and was down-regulated through selective dephosphorylation following oxidative stress. One potential mechanism for p38 dephosphorylation is the rapid stress-induced activation of the phosphatase MKP-1, which has high affinity for phosphorylated p38 as a substrate. These data demonstrate that there are mechanisms for independent regulation of the JNK and p38 mitogen-activated protein kinase signal transduction pathways after metabolic oxidative stress in the liver.