RGG-boxes of the EWS oncoprotein repress a range of transcriptional activation domains.
RGG-boxes of the EWS oncoprotein repress a range of transcriptional activation domains.
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DOI：
10.1093/nar/gki270
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发表时间：
2005
影响因子：
14.9
通讯作者：
Lee KA
中科院分区：
文献类型：
--
作者：
Alex D;Lee KA
尤文氏肉瘤癌蛋白（EWS）与哺乳动物转录和前mRNA剪接机制的几种组分相互作用，也存在于细胞质甚至细胞表面。然而，EWS的明显不同的细胞功能还没有很好地表征。EWS含有一个有效的N-末端转录激活结构域（EAD），其在致癌EWS融合蛋白（EFP）和C-末端RNA结合结构域（RBD）的背景下显示，该结构域招募前mRNA剪接因子，并可能偶联转录和剪接。与EFP相反，正常EWS的假定转录作用仍然是个谜。在这里，我们报告说，RBD内的多个RGG盒是必要的，足够的顺式阻遏EAD和RGG盒也可以抑制反式，在二聚体的合作伙伴。赖氨酸可以在功能上取代精氨酸，表明精氨酸侧链的基本性质是RGG盒介导的阻遏的关键决定因素。除了EAD之外，RGG盒还可以抑制广泛的激活结构域（包括VP 16、E1 a和CREB的激活结构域），但同时存在一个以上的激活结构域可以缓解抑制。因此，我们提出，RGG框内的原生EWS的一个关键功能是限制混杂激活EAD，同时仍然允许EWS进入功能性转录复合物，并参与其他交易涉及前mRNA。
The Ewings Sarcoma Oncoprotein (EWS) interacts with several components of the mammalian transcriptional and pre-mRNA splicing machinery and is also found in the cytoplasm and even on the cell surface. The apparently diverse cellular functions of EWS are, however, not well characterized. EWS harbours a potent N-terminal transcriptional activation domain (the EAD) that is revealed in the context of oncogenic EWS-fusion proteins (EFPs) and a C-terminal RNA-binding domain (RBD) that recruits pre-mRNA splicing factors and may couple transcription and splicing. In contrast to EFPs, the presumed transcriptional role of normal EWS remains enigmatic. Here, we report that multiple RGG-boxes within the RBD are necessary and sufficient for cis-repression of the EAD and that RGG-boxes can also repress in-trans, within dimeric partners. Lys can functionally substitute for Arg, indicating that the basic nature of the Arg side chain is the critical determinant of RGG-box-mediated repression. In addition to the EAD, RGG-boxes can repress a broad range of activation domains (including those of VP16, E1a and CREB), but repression can be alleviated by the simultaneous presence of more than one activation domain. We therefore propose that a key function of RGG boxes within native EWS is to restrict promiscuous activation by the EAD while still allowing EWS to enter functional transcription complexes and participate in other transactions involving pre-mRNAs.
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