Activation of the MAP kinase cascade by histone deacetylase inhibitors is required for the stimulation of choline acetyltransferase gene promoter
Activation of the MAP kinase cascade by histone deacetylase inhibitors is required for the stimulation of choline acetyltransferase gene promoter
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DOI：
10.1016/s0169-328x(98)00036-9
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发表时间：
1998-05-01
期刊：
影响因子：
--
通讯作者：
Weber, MJ
中科院分区：
文献类型：
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作者：
Espinos, E;Weber, MJ
我们先前描述了在转染的CHP 126神经上皮瘤细胞中，人胆碱乙酰转移酶（ChAT）基因的主要启动子（M）被三种组蛋白去乙酰化酶抑制剂丁酸盐、曲马多司他丁和trapoxin激活。我们现在表明，trapoxin和丁酸触发了ERK 1/2激酶的快速和短暂的磷酸化，这是由PD 98059，MAP激酶激酶MEK 1的高度特异性抑制剂抑制。Trapoxin或丁酸盐对ChAT启动子活性的刺激不需要持续的蛋白质合成，并且被PD 98059抑制。在瞬时转染实验中，H-ras或ERK 2蛋白显性失活突变体的温育表达抑制了Trapoxin对ChAT启动子的激活。相反，组成型活性突变体的H-ras或MEK 1蛋白的过表达有很少或没有影响ChAT启动子活性，但强烈协同trapoxin。因此，这些数据表明，MEK/ERK激酶级联的激活在组蛋白脱乙酰酶抑制剂对ChAT启动子的调节中起着必要的，但不是充分的作用。(C)1998年Elsevier Science B.V.
We previously described that the major promoter (M) of human choline acetyltransferase (ChAT) gene is activated by three inhibitors of histone deacetylase, butyrate, trichostatin and trapoxin, in transfected CHP126 neuroepithelioma cells. We now show that trapoxin and butyrate triggered a rapid and transient phosphorylation of ERK1/2 kinases, that was suppressed by PD98059, a highly specific inhibitor of MAP kinase kinase MEK1. The stimulation of ChAT promoter activity by trapoxin or butyrate did not require ongoing protein synthesis, and was suppressed by PD98059. The ovenexpression of dominant negative mutants of H-ras or ERK2 proteins depressed ChAT promoter activation by trapoxin in transient transfection assays. Conversely, the overexpression of constitutively active mutants of H-ras or MEK1 proteins had little or no effect on ChAT promoter activity, but strongly synergized with trapoxin. These data thus suggest that the activation of the MEK/ERK kinase cascade plays a necessary, but not sufficient, role in the regulation of ChAT promoter by inhibitors of histone deacetylase. (C) 1998 Elsevier Science B.V.