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Daxx interacts with and modulates the activity of CREB

机译：Daxx与CREB相互作用并调节其活性

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摘要

The phosphorylation of cAMP response element-binding protein (CREB) induced by the cAMP-dependent protein kinase A (PKA) elicits the recruitment of CREB-binding protein (CBP) for activating cAMP responsive gene expression. Several reports indicate that proteins binding to CREB and/or CBP play important roles in modulating the CREB-dependent transactivation. Here, we show that Daxx interacts with CREB and modulates CREB-mediated transcription. Daxx was identified as a CREB-interacting protein by a yeast two-hybrid screen. Depletion of endogenous Daxx by specific shRNA or overexpression of Daxx resulted in decreased or increased levels of the cAMP/PKA-induced reporter activity and target gene expression, respectively. In vitro and in vivo binding studies revealed that Daxx C-terminal domain binds to CREB basic leucine zipper domain. The binding of Daxx to CREB correlates with its repressive effect on a CRE-mediated reporter activity induced by forskolin or PKA. Furthermore, the results of electrophoresis mobility shift assays and chromatin immunoprecipitation experiments showed that Daxx attenuated the DNA binding potential of the CREB. Our study provides a previously undescribed role of Daxx in repressing cAMP-responsive gene expression and also a mechanism underlying the repressive effect of Daxx on CREB transcriptional potential.
机译：由cAMP依赖性蛋白激酶A（PKA）诱导的cAMP反应元件结合蛋白（CREB）的磷酸化引发CREB结合蛋白（CBP）的募集，以激活cAMP反应基因表达。几篇报道表明，结合CREB和/或CBP的蛋白质在调节CREB依赖性反式激活中起重要作用。在这里，我们显示Daxx与CREB相互作用并调节CREB介导的转录。通过酵母双杂交筛选，Daxx被鉴定为与CREB相互作用的蛋白。特异性shRNA耗尽内源性Daxx或Daxx的过度表达分别导致cAMP / PKA诱导的报道分子活性和靶基因表达水平降低或升高。体外和体内结合研究表明，Daxx C末端结构域与CREB基本亮氨酸拉链结构域结合。 Daxx与CREB的结合与其对毛喉素或PKA诱导的CRE介导的报道分子活性的抑制作用有关。此外，电泳迁移率变动分析和染色质免疫沉淀实验的结果表明，Daxx减弱了CREB的DNA结合潜力。我们的研究提供了Daxx在抑制cAMP响应基因表达中未曾描述的作用，以及Daxx对CREB转录潜能的抑制作用的潜在机制。

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