Wysk M, Yang D D, Lu H T, Flavell R A, Davis R J
Howard Hughes Medical Institute and Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3763-8. doi: 10.1073/pnas.96.7.3763.
The p38 mitogen-activated protein kinase is activated by treatment of cells with cytokines and by exposure to environmental stress. The effects of these stimuli on p38 MAP kinase are mediated by the MAP kinase kinases (MKKs) MKK3, MKK4, and MKK6. We have examined the function of the p38 MAP kinase signaling pathway by investigating the effect of targeted disruption of the Mkk3 gene. Here we report that Mkk3 gene disruption caused a selective defect in the response of fibroblasts to the proinflammatory cytokine tumor necrosis factor, including reduced p38 MAP kinase activation and cytokine expression. These data demonstrate that the MKK3 protein kinase is a critical component of a tumor necrosis factor-stimulated signaling pathway that causes increased expression of inflammatory cytokines.
p38丝裂原活化蛋白激酶可通过细胞因子处理细胞以及暴露于环境应激而被激活。这些刺激对p38丝裂原活化蛋白激酶的作用由丝裂原活化蛋白激酶激酶（MKKs）MKK3、MKK4和MKK6介导。我们通过研究Mkk3基因靶向破坏的影响，来检测p38丝裂原活化蛋白激酶信号通路的功能。在此我们报告，Mkk3基因破坏导致成纤维细胞对促炎细胞因子肿瘤坏死因子的反应出现选择性缺陷，包括p38丝裂原活化蛋白激酶激活减少和细胞因子表达降低。这些数据表明，MKK3蛋白激酶是肿瘤坏死因子刺激的信号通路的关键组成部分，该信号通路可导致炎性细胞因子表达增加。
