The p300/CBP acetyltransferases function as transcriptional coactivators of β-catenin in vertebrates
The p300/CBP acetyltransferases function as transcriptional coactivators of β-catenin in vertebrates
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DOI：
10.1093/emboj/19.8.1839
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发表时间：
2000-04-17
期刊：
影响因子：
11.4
通讯作者：
Kemler, R
中科院分区：
文献类型：
--
作者：
Hecht, A;Vleminckx, K;Kemler, R
Wnt生长因子通过改变特定的基因表达模式来调控多种发育过程。在脊椎动物中，β -连环蛋白作为转录激活因子，它是克服Groucho/TLE蛋白对靶基因的抑制以及使启动子激活（作为Wnt信号传导的最终结果）所必需的。然而，β -连环蛋白转录激活的分子机制了解甚少。在此我们证明，密切相关的乙酰转移酶p300和CBP增强β -连环蛋白介导的siamois启动子（一种已知的Wnt靶标）的激活。β -连环蛋白和p300还协同刺激一种合成的报告基因构建体，而β -连环蛋白对细胞周期蛋白D1启动子的激活对p300刺激不敏感。非洲爪蟾胚胎中的轴形成以及β -连环蛋白靶基因siamois和Xnr - 3的激活对E1A癌蛋白敏感，E1A癌蛋白是一种已知的p300/CBP抑制剂。β -连环蛋白的C末端与p300的CH - 3结构域重叠区域直接相互作用。p300可能参与缓解染色质结构施加的启动子抑制，并参与招募基础转录机器到特定Wnt靶基因的启动子上。
Wnt growth factors regulate a variety of developmental processes by altering specific gene expression patterns. In vertebrates beta-catenin acts as transcriptional activator, which is needed to overcome target gene repression by Groucho/TLE proteins, and to permit promoter activation as the final consequence of Wnt signaling. However, the molecular mechanisms of transcriptional activation by beta-catenin are only poorly understood. Here we demonstrate that the closely related acetyltransferases p300 and CBP potentiate beta-catenin-mediated activation of the siamois promoter, a known Wnt target. beta-catenin and p300 also synergize to stimulate a synthetic reporter gene construct, whereas activation of the cyclin DI promoter by beta-catenin is refractory to p300 stimulation. Axis formation and activation of the beta-catenin target genes siamois and Xnr-3 in Xenopus embryos are sensitive to the E1A oncoprotein, a known inhibitor of p300/CBP, The C-terminus of beta-catenin interacts directly with a region overlapping the CH-3 domain of p300. p300 could participate in alleviating promoter repression imposed by chromatin structure and in recruiting the basal transcription machinery to promoters of particular Wnt target genes.