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Homotypic and heterotypic interactions of EWS, FLI1 and their oncogenic fusion protein

机译：EWS，FLI1及其致癌融合蛋白的同型和异型相互作用

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In Ewing's sarcoma family tumors, the ets transcription factor gene FLI1 is rearranged with one EWS allele resulting in coexpression of germline EWS and chimeric EWS-FLI1 proteins. Here, we investigated the potential of germline EWS, FLI1 and EWS-FLI1 to oligomerize. In two functional in vivo tests, fluorescence resonance energy transfer (FRET) and the mammalian two-hybrid (MTH) assay, self-association of EWS and EWS-FLI1, but not of FLI1 was detected. In addition, interaction of EWS-FLI1 with EWS and FLI1 was observed. GST pull-down assays and immunoprecipitation experiments largely confirmed these results. The EWS N-terminal domain present in both EWS and EWS-FLI1 was found to contribute to homotypic and heterotypic interactions of these proteins. However, in the context of germline EWS, the presence of the whole or part of the C-terminal RNA-binding domain greatly supported the self-association potential of the protein. Involvement of an RNA component in EWS oligomerization was confirmed by sensitivity of the corresponding GST pull-down assay to RNaseA treatment. In contrast, EWS-FLI1 was able to self-associate and also bind to FLI1 via its C-terminal domain, which comprises the FLI1 DNA-binding motif. Accordingly, the EWS-FLI1 interaction was not disrupted by RNaseA treatment. Despite its potential to oligomerize, EWS-FLI1 bound to a tandem ets-binding site of the TGF type II receptor promoter as a monomer. Therefore, the functional consequences of homo- and hetero-oligomerization of EWS and EWS-FLI1 proteins remain to be elucidated.
机译：在尤因氏肉瘤家族肿瘤中，ets转录因子基因FLI1与一个EWS等位基因重排，导致种系EWS和嵌合EWS-FLI1蛋白共表达。在这里，我们调查了种系EWS，FLI1和EWS-FLI1寡聚化的潜力。在两项功能性体内测试中，检测到了荧光共振能量转移（FRET）和哺乳动物双杂交（MTH）分析，检测到EWS和EWS-FLI1的自缔合，但未检测到FLI1的自缔合。另外，观察到EWS-FLI1与EWS和FLI1的相互作用。 GST下拉试验和免疫沉淀实验在很大程度上证实了这些结果。发现在EWS和EWS-FLI1中都存在的EWS N末端结构域有助于这些蛋白质的同型和异型相互作用。然而，在种系EWS的背景下，全部或部分C端RNA结合结构域的存在极大地支持了蛋白质的自缔合潜力。通过相应的GST下拉测定法对RNaseA处理的敏感性，证实了RNA成分参与EWS寡聚化。相反，EWS-FLI1能够自我关联，并通过其C端结构域与FLI1结合，该C端结构域包含FLI1 DNA结合基序。因此，RNaseA处理不会破坏EWS-FLI1的相互作用。尽管具有潜在的低聚性，EWS-FLI1还是以单体形式结合到TGF II型受体启动子的串联ets结合位点。因此，EWS和EWS-FLI1蛋白的均聚和异源寡聚化的功能后果仍有待阐明。

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