Somatic chromosomal translocation between Ewsr1 and Fli1 loci leads to dilated cardiomyopathy in a mouse model.
Somatic chromosomal translocation between Ewsr1 and Fli1 loci leads to dilated cardiomyopathy in a mouse model.
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DOI：
10.1038/srep07826
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发表时间：
2015-01-16
影响因子：
4.6
通讯作者：
Nakamura T
中科院分区：
文献类型：
--
作者：
Tanaka M;Yamaguchi S;Yamazaki Y;Kinoshita H;Kuwahara K;Nakao K;Jay PY;Noda T;Nakamura T
利用Cre/loxP介导的重组技术产生了一种小鼠模型，该模型重现了人尤文肉瘤特异性染色体易位。Ewsr 1-loxP和Fli 1-loxP小鼠之间的交叉和无处不在的Cre重组酶的表达诱导了成年小鼠和胚胎全身器官中Ewsr 1和Fli 1位点之间的特异性易位。结果Ewsr 1-Fli 1融合转录本表达，表明功能性Ews-Fli 1蛋白可能在体内合成。然而，到2岁时，Ewsr 1-loxP/Fli 1-loxP/CAG-Cre（EFCC）小鼠均未发生任何恶性肿瘤，包括尤文样小圆细胞肉瘤。出乎意料的是，所有的EFCC小鼠都患有扩张型心肌病，并死于慢性心力衰竭。Ewsr 1和Fli 1之间的基因重组被证实在心肌组织和心肌细胞的凋亡细胞死亡，观察到在EFCC小鼠在显着更高的频率。Ews-Fli 1在培养的心肌细胞中的表达可诱导细胞凋亡。总的来说，这些结果表明，异位表达的Ews-Fli 1癌基因刺激凋亡信号，并提出了一个重要的关系致癌信号和细胞环境中的尤文肉瘤的起源细胞。
A mouse model that recapitulates the human Ewing's sarcoma-specific chromosomal translocation was generated utilizing the Cre/loxP-mediated recombination technique. A cross between Ewsr1-loxP and Fli1-loxP mice and expression of ubiquitous Cre recombinase induced a specific translocation between Ewsr1 and Fli1 loci in systemic organs of both adult mice and embryos. As a result Ewsr1-Fli1 fusion transcripts were expressed, suggesting a functional Ews-Fli1 protein might be synthesized in vivo. However, by two years of age, none of the Ewsr1-loxP/Fli1-loxP/CAG-Cre (EFCC) mice developed any malignancies, including Ewing-like small round cell sarcoma. Unexpectedly, all the EFCC mice suffered from dilated cardiomyopathy and died of chronic cardiac failure. Genetic recombination between Ewsr1 and Fli1 was confirmed in the myocardial tissue and apoptotic cell death of cardiac myocytes was observed at significantly higher frequency in EFCC mice. Moreover, expression of Ews-Fli1 in the cultured cardiac myocytes induced apoptosis. Collectively, these results indicated that ectopic expression of the Ews-Fli1 oncogene stimulated apoptotic signals, and suggested an important relationship between oncogenic signals and cellular context in the cell-of-origin of Ewing's sarcoma.