EWS/FLI1 oncogene activates caspase 3 transcription and triggers apoptosis in vivo.
EWS/FLI1 oncogene activates caspase 3 transcription and triggers apoptosis in vivo.
复制标题
DOI：
10.1158/0008-5472.can-09-1993
复制
发表时间：
2010-02-01
期刊：
影响因子：
11.2
通讯作者：
Lee SB
中科院分区：
文献类型：
--
作者：
Sohn EJ;Li H;Reidy K;Beers LF;Christensen BL;Lee SB
EWS/FLI 1是尤文肉瘤中发现的染色体易位t（q24; q12）产生的融合基因产物。EWS/FLI 1编码一种具有体外致癌特性的异常转录因子。有趣的是，EWS/FLI 1在未转化的原代细胞中的表达导致凋亡，但确切的机制仍不清楚。在来自条件EWS/FLI 1基因敲入胚胎的原代小鼠胚胎成纤维细胞（MEFs）中，EWS/FLI 1的表达导致细胞凋亡，伴随内源性Caspase 3（Casp 3）mRNA的增加。EWS/FLI 1直接结合并激活CASP 3启动子，而siRNA介导的EWS/FLI 1敲低导致尤文肉瘤细胞系中CASP 3转录物显著减少。EWS/FLI 1的异位表达导致CASP 3蛋白在异源细胞系中的表达增加。重要的是，EWS/FLI 1在小鼠中的表达触发了肾脏细胞凋亡的早期发作和急性致死。这些发现表明，EWS/FLI 1诱导细胞凋亡，至少部分地，通过激活CASP 3，并证明EWS/FLI 1在细胞凋亡和肿瘤发生中的细胞环境依赖性作用。
EWS/FLI1 is a fusion gene product generated by a chromosomal translocation t(q24; q12) found in Ewing sarcoma. EWS/FLI1 encodes an aberrant transcription factor with oncogenic properties in vitro. Paradoxically, expression of EWS/FLI1 in non-transformed primary cells results in apoptosis, but the exact mechanism remains unclear. In primary mouse embryonic fibroblasts (MEFs) derived from conditional EWS/FLI1 knock-in embryos, expression of EWS/FLI1 resulted in apoptosis with concomitant increase in the endogenous Caspase 3 (Casp3) mRNA. EWS/FLI1 directly bound and activated the CASP3 promoter, while siRNA-mediated knockdown of EWS/FLI1 led to a marked decrease in CASP3 transcripts in Ewing sarcoma cell lines. Ectopic expression of EWS/FLI1 resulted in an increased expression of CASP3 protein in heterologous cell lines. Importantly, expression of EWS/FLI1 in the mouse triggered an early onset of apoptosis in kidneys and acute lethality. These findings suggest that EWS/FLI1 induces apoptosis, at least partially, through the activation of CASP3 and demonstrate the cell-context dependent roles of EWS/FLI1 in apoptosis and tumorigenesis.