Role of protein-protein interactions in the antiapoptotic function of EWS-Fli-1
Role of protein-protein interactions in the antiapoptotic function of EWS-Fli-1
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DOI：
10.1038/sj.onc.1207927
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发表时间：
2004-09-16
期刊：
影响因子：
8
通讯作者：
Reddy, ESP
中科院分区：
文献类型：
--
作者：
Ramakrishnan, R;Fujimura, Y;Reddy, ESP
在大多数尤文氏家族肿瘤中，染色体易位t（11; 22）导致RNA结合蛋白EWS与DNA结合ETS转录因子Fli-1的异常融合。EWS-Fli-1改变了转录活性，通过这种转录活性调节其下游靶基因被认为是该肿瘤的原因。我们以前已经表明，EWS-Fli-1和Fli-1对几种凋亡诱导剂具有抗凋亡活性。在这里，我们表明，EWS-Fli-1和Fli-1的转录活性不是必不可少的抗凋亡活性。我们还证明了EWS-Fli-1和Fli-1通过其氨基末端区域与CBP相互作用，并抑制RXR的CBP依赖性转录活性。这种活性似乎不依赖于EWS-Fli-1的DNA结合活性。将CBP的显性阴性形式引入尤文肉瘤细胞中使这些细胞对遗传毒性或视黄酸诱导的细胞凋亡敏感。这些结果表明EWS-Fli-1/Fli-1靶向转录辅因子和调节凋亡途径的能力可能是其抗凋亡和致瘤活性的原因。
In the majority of Ewing's family tumors, chromosomal translocation t(11; 22) leads to aberrant fusion of RNA-binding protein EWS with DNA-binding ETS transcriptional factor Fli-1. EWS-Fli-1 has altered the transcriptional activity and modulating its downstream target genes through this transcriptional activity is thought to be responsible for this tumor. We have previously shown that both EWS-Fli-1 and Fli-1 have antiapoptotic activity against several apoptotic inducers. Here, we show that the transcriptional activity of EWS-Fli-1 and Fli-1 is not essential for its antiapoptotic activity. We also demonstrate that EWS-Fli-1 and Fli-1 interact with CBP through its amino-terminal region and inhibit the CBP-dependent transcriptional activity of RXR. This activity appears to be independent of DNA-binding activity of EWS-Fli-1. Introduction of the dominant-negative form of CBP into Ewing's sarcoma cells sensitizes these cells against genotoxic or retinoic-acid induced apoptosis. These results suggest that the ability of EWS-Fli-1/Fli-1 to target transcriptional cofactor(s) and modulate apoptotic pathways may be responsible for its antiapoptotic and tumorigenic activities.