The p38 mitogen-activated protein kinase is required for NF-κB-dependent gene expression -: The role of TATA-binding protein (TBP)
The p38 mitogen-activated protein kinase is required for NF-κB-dependent gene expression -: The role of TATA-binding protein (TBP)
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DOI：
10.1074/jbc.274.43.30858
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发表时间：
1999-10-22
影响因子：
4.8
通讯作者：
Hunninghake, GW
中科院分区：
文献类型：
--
作者：
Carter, AB;Knudtson, KL;Hunninghake, GW
单核细胞和巨噬细胞中内毒素诱导的细胞因子基因转录部分受 NF-kappa B 调节。我们之前已经表明，p38 丝裂原激活蛋白 (MAP) 激酶是内毒素诱导的细胞因子基因转录所必需的。由于大多数细胞因子启动子序列具有活性 NF-κ B 位点，我们假设 p38 MAP 激酶对于 NF-κ B 依赖性基因表达是必需的。我们发现，使用 SB 203580 或显性失活 p38 MAP 激酶表达载体，NF-κ B 依赖性基因表达降低至接近对照水平。 p38 MAP 激酶的抑制不会在任何水平上改变 NF-κ B 的激活，但它显着降低了 TATA 结合蛋白 (TBP) 与 TATA 盒的 DNA 结合。显性失活 p38 MAP 激酶表达载体干扰了天然 TFIID (TBP) 与共转染的 p65 融合蛋白的直接相互作用。同样，这种显性失活质粒也干扰共转染的 TBP 融合蛋白与天然 p65 亚基的直接相互作用。 p38 激酶还在体外磷酸化 TFIID (TBP)，而 SB 203580 在体内抑制 TFIID (TBP) 磷酸化。因此，p38 MAP 激酶部分通过调节 TFIID (TBP) 的激活来调节 NF-κ B 依赖性基因转录。
Endotoxin-induced cytokine gene transcription in monocytes and macrophages is regulated in part by NF-kappa B. We have previously shown that the p38 mitogen-activated protein (MAP) kinase is necessary for endotoxin-induced cytokine gene transcription. Due to the fact that most cytokine promoter sequences have active NF-kappa B sites, we hypothesized that the p38 MAP kinase was necessary for NF-kappa B-dependent gene expression. We found that NF-kappa B-dependent gene expression was reduced to near control levels with either SB 203580 or a dominant-negative p38 MAP kinase expression vector. Inhibition of the p38 MAP kinase did not alter NF-kappa B activation at any level, but it significantly reduced the DNA binding of TATA-binding protein (TBP) to the TATA box, The dominant-negative p38 MAP kinase expression vector interfered with the direct interaction of native TFIID (TBP) with a co-transfected p65 fusion protein. Likewise, this dominant-negative plasmid also interfered with the direct interaction of a co-transfected TBP fusion protein with the native p65 subunit. The p38 kinase also phosphorylated TFIID (TBP) in vitro, and SB 203580 inhibited phosphorylation of TFIID (TBP) in vivo. Thus, the p38 MAP kinase regulates NF-kappa B-dependent gene transcription, in part, by modulating activation of TFIID (TBP).