Ewing sarcoma fusion protein EWSR1/FLI1 interacts with EWSR1 leading to mitotic defects in zebrafish embryos and human cell lines.
Ewing sarcoma fusion protein EWSR1/FLI1 interacts with EWSR1 leading to mitotic defects in zebrafish embryos and human cell lines.
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DOI：
10.1158/0008-5472.can-08-3229
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发表时间：
2009-05-15
期刊：
影响因子：
11.2
通讯作者：
Hickstein DD
中科院分区：
文献类型：
--
作者：
Embree LJ;Azuma M;Hickstein DD
EWSR1 与 ETS 转录因子 FLI1 融合导致尤文肉瘤恶性转化的机制尚不清楚。我们证明，将人类或斑马鱼 EWSR1/FLI1 mRNA 注射到发育中的斑马鱼胚胎中会导致有丝分裂缺陷，导致多极和有丝分裂纺锤体紊乱。 HeLa 细胞中人 EWSR1/FLI1 的表达也会导致有丝分裂缺陷，以及极光激酶 B（有丝分裂进展的关键调节因子）的错误定位。由于这些有丝分裂异常与斑马鱼胚胎和 HeLa 细胞中 EWSR1 敲低所观察到的异常相似，因此我们研究了 EWSR1/FLI1 是否与 EWSR1 相互作用并干扰其功能。 EWSR1 与 EWSR1/FLI1 共免疫沉淀，EWSR1 的过表达可挽救 EWSR1/FLI1 转染的 HeLa 细胞中的有丝分裂缺陷。尤文肉瘤中 EWSR1/FLI1 和 EWSR1 之间的这种相互作用可能诱导有丝分裂缺陷，导致基因组不稳定和随后的恶性转化。
The mechanism whereby the fusion of EWSR1 with the ETS transcription factor FLI1 contributes to malignant transformation in Ewing sarcoma remains unclear. We demonstrate that injection of human or zebrafish EWSR1/FLI1 mRNA into developing zebrafish embryos leads to mitotic defects with multipolar and disorganized mitotic spindles. Expression of human EWSR1/FLI1 in HeLa cells also results in mitotic defects, along with mislocalization of Aurora kinase B, a key regulator of mitotic progression. Since these mitotic abnormalities mimic those observed with knockdown of EWSR1 in zebrafish embryos and HeLa cells, we investigated whether EWSR1/FLI1 interacts with EWSR1 and interferes with its function. EWSR1 coimmunoprecipitates with EWSR1/FLI1, and overexpression of EWSR1 rescues the mitotic defects in EWSR1/FLI1-transfected HeLa cells. This interaction between EWSR1/FLI1 and EWSR1 in Ewing sarcoma may induce mitotic defects leading to genomic instability and subsequent malignant transformation.