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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >A Novel Mechanism Involving Coordinated Regulation of Nuclear Levels and Acetylation of NF-YA and Bcl6 Activates RGS4 Transcription
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A Novel Mechanism Involving Coordinated Regulation of Nuclear Levels and Acetylation of NF-YA and Bcl6 Activates RGS4 Transcription

机译：涉及核水平的协调调节和NF-YA和Bcl6乙酰化的新机制激活RGS4转录。

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Neuronally enriched RGS4 plays a critical role attenuating G protein signaling in brain, although the mechanisms regulating RGS4 expression are unknown. Here we describe a novel mechanism for transcriptional activation of RGS4 in neuron-like PC6 cells, where RGS4 is markedly induced during confluence-induced growth arrest. Transcriptional activation of RGS4 in confluent PC6 cells was accompanied by impaired Gi/o-dependent MAPK activation. In the human RGS4 gene promoter, we identified three phylogenetically conserved cis-elements: an inverted CCAAT box element (ICE), a cAMP response element, and a B-cell lymphoma 6 (Bcl6)-binding site. The ICE and the cAMP response element mediate activation, and the Bcl6 site mediates repression of RGS4 transcription. Activation of RGS4 transcription in confluent PC6 cells is accompanied by increases in NF-YA and C/EBPβ and decreases in Bcl6 levels in the nucleus. Increases in NF-YA and C/EBPβ lead to their increased binding to the RGS4 promoter in vivo, and dominant negative forms of these proteins repressed RGS4 promoter activity. Acetylation of NF-YA and Bcl6 were increased in postconfluent cells. Trichostatin A stimulation of RGS4 promoter activity, accompanied by increased binding of NF-YA and decreased binding of Bcl6 to the promoter, was abolished by mutation of the ICE and enhanced by mutation of the Bcl6 site. These findings demonstrate a dynamic and coordinated regulation of nuclear levels and acetylation status of trans-acting factors critical in determining the off/on state of the RGS4 promoter.
机译：尽管调节RGS4表达的机制尚不清楚，但富含神经元的RGS4在减弱脑中G蛋白信号传导中起着关键作用。在这里，我们描述了神经元样PC6细胞中RGS4转录激活的新机制，其中在融合诱导的生长停滞期间明显诱导了RGS4。融合PC6细胞中RGS4的转录激活伴随着Gi / o依赖性MAPK激活受损。在人类RGS4基因启动子中，我们确定了三个系统发育上保守的顺式元件：一个倒置的CCAAT盒元件（ICE），一个cAMP反应元件和一个B细胞淋巴瘤6（Bcl6）结合位点。 ICE和cAMP反应元件介导激活，而Bcl6位点介导RGS4转录的阻遏。在融合的PC6细胞中，RGS4转录的激活伴随着核内NF-YA和C /EBPβ的增加以及Bcl6水平的降低。 NF-YA和C /EBPβ的增加导致它们在体内与RGS4启动子的结合增加，而这些蛋白质的显性负型抑制了RGS4启动子的活性。融合后细胞中NF-YA和Bcl6的乙酰化增加。曲古他汀的ICE突变消除了RGS4启动子活性的刺激，伴随着NF-YA结合的增加和Bcl6与启动子的结合的减少，而Bcl6位点的突变则消除了刺激。这些发现证明了动态和协调的核作用水平和反式作用因子的乙酰化状态对决定RGS4启动子的关闭/开启状态至关重要。

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