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首页> 外文期刊>Molecular and Cellular Biology >The Cyclin E/Cdk2 Substrate and Cajal Body Component p220NPAT Activates Histone Transcription through a Novel LisH-Like Domain
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The Cyclin E/Cdk2 Substrate and Cajal Body Component p220NPAT Activates Histone Transcription through a Novel LisH-Like Domain

机译：细胞周期蛋白E / Cdk2底物和Cajal身体成分p220NPAT通过一个新的LisH-like域激活组蛋白转录。

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p220NPAT is a substrate of cyclin E/Cdk2 that localizes in nuclear organelles called Cajal bodies in a cell cycle-regulated manner. In normal diploid fibroblasts, p220 is concentrated in two Cajal bodies tethered to histone gene clusters at chromosome 6p21 during G1, S, and G2 phases and two additional Cajal bodies tethered to histone genes at 1q21 during S, and G2 phases. Overexpression of p220 in U2OS cells can promote the G1/S transition and can also promote transcription from histone H2B and H4 luciferase reporter constructs. How p220 expression induces these activities and whether the two activities are related are unknown. In this study, we developed a “lox-scanning” mutagenesis approach to identify functional domains in p220. We identified two distinct functional regions of p220. The C-terminal half of the protein contains multiple elements that are required for its ability to induce S phase in transfected cells. In contrast, sequences at the N terminus appear to be critical for activation of histone H4 and H2B reporter constructs. We identified an ～30-amino-acid motif at the N terminus of p220 that has the characteristics of a LisH motif. LisH motifs are found in a large number of proteins in the database but are of unknown function. Point mutations in conserved residues in the LisH motif of p220 block histone H4 transcriptional activity without affecting localization in Cajal bodies or phosphorylation on Cdk2 phosphorylation sites. These studies indicate that the ability of p220 to promote S phase is independent of its ability to promote histone H4 transcription and suggests that p220 may link cyclin E/Cdk2 to multiple independent downstream functions.
机译：p220 NPAT 是细胞周期蛋白E / Cdk2的底物，以细胞周期调控的方式位于称为Cajal体的核细胞器中。在正常的二倍体成纤维细胞中，p220在G 1，，S和G 2 阶段集中在两个与6p21染色体组蛋白基因簇相连的Cajal体中，另外两个Cajal体被束缚在S和G 2 阶段的1q21处表达组蛋白基因。 p220在U2OS细胞中的过表达可以促进G 1 / S过渡，还可以促进组蛋白H2B和H4荧光素酶报道基因构建体的转录。未知p220表达如何诱导这些活性以及这两种活性是否相关。在这项研究中，我们开发了一种“ lox -scanning”诱变方法来鉴定p220中的功能域。我们确定了p220的两个不同的功能区域。蛋白质的C末端一半包含多种元素，这是其在转染细胞中诱导S期的能力所必需的。相反，在N末端的序列似乎对于激活组蛋白H4和H2B报告基因构建体至关重要。我们在p220的N末端鉴定了一个约30个氨基酸的基序，该基序具有LisH基序的特征。在数据库中的大量蛋白质中发现了LisH基序，但功能未知。 p220 LisH基序中保守残基的点突变可阻断组蛋白H4的转录活性，而不会影响Cajal体内的定位或Cdk2磷酸化位点的磷酸化。这些研究表明，p220促进S期的能力与其促进组蛋白H4转录的能力无关，并暗示p220可能将细胞周期蛋白E / Cdk2连接到多个独立的下游功能。

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