A constitutive active MEK --> ERK pathway negatively regulates NF-kappa B-dependent gene expression by modulating TATA-binding protein phosphorylation.
A constitutive active MEK --> ERK pathway negatively regulates NF-kappa B-dependent gene expression by modulating TATA-binding protein phosphorylation.
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DOI：
10.1074/jbc.m003599200
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发表时间：
2000-06
期刊：
影响因子：
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通讯作者：
A. B. Carter;G. Hunninghake
中科院分区：
文献类型：
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作者：
A. B. Carter;G. Hunninghake
内毒素诱导的细胞因子基因表达部分受核因子-kappaB的调节。我们已经证明，ERK和p38丝裂原激活蛋白(MAP)激酶都是细胞因子基因转录所必需的，而p38 MAP激酶是NF-kappaB驱动的转录所必需的，因此我们假设MEK-->；ERK通路也调控着NF-kappaB驱动的转录。我们发现，一个结构性激活的MEK-->；ERK途径抑制了NF-kappaB的转录。此外，PD 98059和显性负的ERK2都促进了NF-kappaB的转录；然而，PD 98059和MEK1都不能在任何水平改变NF-kappaB的激活。结构性激活的MEK-->；ERK途径抑制TBP的磷酸化，这是与RERA相互作用和与TATA盒结合所必需的。由于我们已经证明p38 MAP激酶调节TBP的激活，我们评估了结构性激活的MEK-->；ERK通路对p38 MAP激酶活性的影响。我们发现，MEK-->；ERK通路通过抑制p38的MAPK活性，部分地负向调节了核因子-kappaB的转录。因此，ERK和p38在核因子-kappaB驱动的转录中具有不同的作用。
Endotoxin-induced cytokine gene expression is regulated, in part, by NF-kappaB. We have shown that both the ERK and p38 mitogen-activated protein (MAP) kinases are necessary for cytokine gene transcription and that the p38 MAP kinase is required for NF-kappaB-driven transcription, so we hypothesized that the MEK --> ERK pathway regulated NF-kappaB-driven transcription as well. We found that a constitutive active MEK --> ERK pathway inhibited NF-kappaB-driven transcription. In addition, both PD 98059 and a dominant negative ERK2 augmented NF-kappaB-driven transcription; however, neither PD 98059 nor MEK1 altered NF-kappaB activation at any level. The constitutive active MEK --> ERK pathway inhibited the phosphorylation of TBP, which is necessary for both interaction with RelA and binding to the TATA box. Due to the fact that we have shown that the p38 MAP kinase modulates TBP activation, we evaluated the effect of the constitutive active MEK --> ERK pathway on p38 MAP kinase activity. We found that the MEK --> ERK pathway negatively regulates NF-kappaB-driven transcription, in part, by inhibiting p38 MAP kinase activity. Thus, the ERK and p38 MAP kinases have differential effects on NF-kappaB-driven transcription.