MEK kinase is involved in tumor necrosis factor alpha-induced NF-kappa B activation and degradation of I kappa B-alpha
MEK kinase is involved in tumor necrosis factor alpha-induced NF-kappa B activation and degradation of I kappa B-alpha
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DOI：
10.1074/jbc.271.22.13234
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发表时间：
1996-05-31
影响因子：
4.8
通讯作者：
Ohno, S
中科院分区：
文献类型：
--
作者：
Hirano, M;Osada, S;Ohno, S
转录因子NF-kappa B的信号依赖性激活主要受I kappa B-α蛋白降解的调节。然而，导致降解的信号通路尚不清楚。在这里，我们报道了丝裂原激活的蛋白激酶/细胞外信号调节的蛋白激酶(MEK)，一种应激激活的蛋白激酶/Jun激酶-1(SAPKs/JNK1)，参与了这些信号转导途径。MEK激酶在NIH3T3成纤维细胞中的瞬时过表达激活了kappa B-CAT报告基因的表达，并与肿瘤坏死因子α的刺激具有协同作用。相反，过表达激酶阴性的MEK激酶抑制了肿瘤坏死因子α诱导的报告基因的表达。MEK激酶的过表达抑制了共转染的I kappa B-α对Kappa B-CAT或人类免疫缺陷病毒长末端重复序列荧光素酶报告基因表达的抑制作用，并导致过度表达的I kappa B-α同时消失。抑制I kappa B-α降解的钙蛋白酶抑制物-I可阻止聚合酶的过度表达导致外源性I kappa B-α的消失。这些结果提示，MEK是参与肿瘤坏死因子-α诱导的核因子-kappaB活化的信号介质，而聚合酶对核因子-kappaB的激活是通过i-kappaB-α的降解来调节的。
Signal-dependent activation of the transcription factor NF-kappa B is dominantly regulated by degradation of I kappa B-alpha protein. However, the signaling pathways that lead to the degradation are not clear. Here we report that mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) kinase, an activator of stress-activated protein kinases/jun kinase-1 (SAPKs/JNK1), is involved in such signaling pathways. The transient overexpression of MEK kinase in NIH3T3 fibroblasts activates kappa B-CAT reporter expression in a synergistic: manner with TNF alpha stimulation. In contrast, overexpression of kinase-negative MEK kinase suppresses TNF alpha-induced reporter expression. The overexpression of MEK kinase suppresses the inhibitory activity of co-transfected I kappa B-alpha on the kappa B-CAT or human immunodeficiency virus-long terminal repeat-luciferase reporter expression and causes the simultaneous disappearance of the overexpressed I kappa B-alpha. The disappearance of exogenous I kappa B-alpha by the overexpression of MER kinase is prevented by calpain inhibitor-I, an inhibitor of I kappa B-alpha degradation. These results suggest that MEK kinase is a signal mediator involved in TNF alpha-induced NF-kappa B activation and that the activation of NF-kappa B by MER kinase is regulated through the degradation of I kappa B-alpha.