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首页> 外文期刊>Molecular and Cellular Biology >Cooperation between Phosphorylation and Acetylation Processes in Transcriptional Control
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Cooperation between Phosphorylation and Acetylation Processes in Transcriptional Control

机译：转录控制中的磷酸化和乙酰化过程之间的合作

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We previously reported that the activation of the M promoter of the human choline acetyltransferase (ChAT) gene by butyrate and trapoxin in transfected CHP126 cells is blocked by PD98059, a specific mitogen-activated protein kinase kinase (MEK) inhibitor (E. Espinos and M. J. Weber, Mol. Brain Res. 56:118–124, 1998). We now report that the transcriptional effects of histone deacetylase inhibitors are mediated by an H7-sensitive serine/threonine protein kinase. Activation of the ChAT promoter by butyrate and trapoxin was blocked by 50 μM H7 in both transient- and stable-transfection assays. Overexpression of p300, a coactivator protein endowed with histone acetyltransferase activity, stimulated the ChAT promoter and had a synergistic effect on butyrate treatment. These effects were blocked by H7 and by overexpressed adenovirus E1A 12S protein. Moreover, both H7 and PD98059 suppressed the activation of the Rous sarcoma virus (RSV) and simian virus 40 promoters by butyrate in transfection experiments. Similarly, the induction of the cellular histone H10 gene by butyrate in CHP126 cells was blocked by H7 and by PD98059. Previous data (L. Cuisset, L. Tichonicky, P. Jaffray, and M. Delpech, J. Biol. Chem. 272:24148–24153, 1997) showed that the induction of the H10 gene by butyrate is blocked by okadaic acid, an inhibitor of protein phosphatases. We now show that the activation of the ChAT and RSV promoters by butyrate in transfected CHP126 cells is also blocked by 200 nM okadaic acid. Western blotting and in vivo metabolic labeling experiments showed that butyrate has a biphasic effect on histone H3 phosphorylation, i.e., depression for up to 16 h followed by stimulation. The data thus strongly suggest that the transcriptional effects of histone deacetylase inhibitors are mediated through the activation of MEK1 and of an H7-sensitive protein kinase in addition to protein phosphatases.
机译：我们之前曾报道过，PD98059是一种特定的促分裂原活化蛋白激酶激酶（MEK）抑制剂（E. Espinos和MJ），通过丁酸和曲霉毒素在转染的CHP126细胞中激活人胆碱乙酰基转移酶（ChAT）基因的M启动子。 Weber，Mol。Brain Res。56：118–124，1998）。现在我们报道，组蛋白脱乙酰基酶抑制剂的转录作用是由H7敏感的丝氨酸/苏氨酸蛋白激酶介导的。在瞬时转染和稳定转染测定中，丁酸和曲霉毒素对ChAT启动子的激活均被50μMH7阻断。带有组蛋白乙酰转移酶活性的共激活蛋白p300的过表达刺激了ChAT启动子，并在丁酸盐处理中具有协同作用。这些作用被H7和过表达的腺病毒E1A 12S蛋白阻断。此外，在转染实验中，H7和PD98059均通过丁酸盐抑制了劳斯肉瘤病毒（RSV）和猿猴病毒40启动子的激活。同样，丁酸在CHP126细胞中诱导细胞组蛋白H1 0 基因被H7和PD98059阻断。先前的数据（L. Cuisset，L。Tichonicky，P。Jaffray和M. Delpech，J。Biol。Chem。272：24148-24153，1997）表明，H1 0 基因的诱导丁酸酯被蛋白酸磷酸酶抑制剂冈田酸阻断。我们现在显示，在转染的CHP126细胞中由丁酸酯激活ChAT和RSV启动子也被200 nM冈田酸所阻断。蛋白质印迹和体内代谢标记实验表明，丁酸对组蛋白H3磷酸化具有双相作用，即抑制长达16小时，然后刺激。因此，数据有力地表明，除蛋白磷酸酶外，组蛋白脱乙酰基酶抑制剂的转录作用还通过MEK1和H7敏感蛋白激酶的激活来介导。

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