Mendelson K G, Contois L R, Tevosian S G, Davis R J, Paulson K E
Department of Biochemistry, Tufts University School of Medicine, Boston, MA 02111, USA.
Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):12908-13. doi: 10.1073/pnas.93.23.12908.
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 was observed. Analysis of the induced binding complexes indicates that c-fos, c-jun, 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 for 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.
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。利用一种体内模型，通过细胞内代谢在肝脏中产生氧化应激，观察到应激激活的AP-1靶基因上快速形成蛋白质-DNA复合物。对诱导的结合复合物的分析表明，存在c-fos、c-jun和ATF-2，但也有另外两个Jun家族成员JunB和JunD。JNK的激活先于AP-1 DNA结合增加。此外，JunB被证明是JNK的底物，磷酸化需要N端激活域。出乎意料的是，发现p38活性在肝脏中组成性激活，并在氧化应激后通过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快速诱导磷酸酶MKP-1激活，MKP-1对磷酸化的p38作为底物具有高亲和力。这些数据表明，肝脏中代谢性氧化应激后，存在独立调节JNK和p38丝裂原活化蛋白激酶信号转导途径的机制。
