Inhibition of the transcriptional function of p53 by EWS-Fli1 chimeric protein in Ewing Family Tumors
Inhibition of the transcriptional function of p53 by EWS-Fli1 chimeric protein in Ewing Family Tumors
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EWS-Fli1嵌合蛋白对尤文家族肿瘤中p53转录功能的抑制
DOI：
10.1016/j.canlet.2010.01.022
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发表时间：
2010-08-01
期刊：
影响因子：
9.7
通讯作者：
Iwamoto, Yukihide
中科院分区：
文献类型：
--
作者：
Li, Yan;Tanaka, Kazuhiro;Iwamoto, Yukihide
染色体易位t（11：22）（q24;q12）产生EWS-Fli 1融合基因，其有助于尤文家族肿瘤（EFT）的发展。虽然p53突变仅在5-20%的EFT中发现，但认为p53途径在EFT中被废除。EWS-Fli 1在肿瘤中p53通路中的作用仍然知之甚少。在这项研究中，使用免疫沉淀和共定位，我们表明，EWS-Fli 1在体内细胞核内与p53相互作用。EWS-Fli 1的导入显著降低了p21和mdm 2的启动子活性和mRNA水平，同时消除了p53依赖的生长抑制。与此相反，敲低EWS-Fli 1表达介导的小干扰RNA（siRNA）也增强了诱导p21和mdm 2的DNA损伤。此外，使用EWS-Fli 1融合蛋白的连续缺失构建体，我们确定EWS-Fli 1与p53的结合以及对p21和mdm 2启动子活性的抑制是由其N-末端结构域（氨基酸残基65-109）介导的。这些观察结果表明，EWS-Fli 1的N-末端区域可能与p53和损害其转录活性，随后抑制其下游基因的表达。这些结果可能为EWS-Fli 1通过抑制p53功能导致Errs的肿瘤发生提供新的见解。(C)2010爱思唯尔爱尔兰有限公司版权所有。
The chromosomal translocation t(11:22)(q24;q12) generates the EWS-Fli1 fusion gene, which contributes to the development of Ewing Family Tumors (EFTs). Although p53 mutations are found only in 5-20% of EFTs, the p53 pathway is thought to be abrogated in EFTs. The role of EWS-Fli1 in the p53 pathway in the tumor is still poorly understood. In this study, using immunoprecipitation and co-localization, we show that EWS-Fli1 interacts with p53 within the nucleus in vivo. The introduction of EWS-Fli1 resulted in significant reduction of promoter activities and mRNA levels of p21 and mdm2, meanwhile it canceled p53-dependent growth suppression. In contrast, knockdown of EWS-Fli1 expression mediated by small interfering RNAs (siRNA) also augmented the induction of p21 and mdm2 in response to DNA damage. Furthermore, using serial deletion constructs of the EWS-Fli1 fusion protein, we determined that EWS-Fli1 binding to p53 as well as inhibition of p21 and mdm2 promoter activities was mediated by its N-terminal domain (amino acid residues 65-109). These observations suggest that the N-terminal region of EWS-Fli1 might associate with p53 and impair its transcriptional activity, subsequently inhibiting the expression of its downstream genes. These results might provide new insight into the oncogenesis of Errs by EWS-Fli1 via the inhibition of p53 function. (C) 2010 Elsevier Ireland Ltd. All rights reserved.