EWS/ETS fusions activate telomerase in Ewing's tumors.
EWS/ETS fusions activate telomerase in Ewing's tumors.
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发表时间：
2003-12
期刊：
影响因子：
11.2
通讯作者：
A. Takahashi;F. Higashino;Mariko Aoyagi;Koichi Yoshida;M. Itoh;S. Kyo;T. Ohno;T. Taira;H. Ariga;Kohichi Nakajima;M. Hatta;Masanobu Kobayashi;H. Sano;T. Kohgo;M. Shindoh
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作者：
A. Takahashi;F. Higashino;Mariko Aoyagi;Koichi Yoshida;M. Itoh;S. Kyo;T. Ohno;T. Taira;H. Ariga;Kohichi Nakajima;M. Hatta;Masanobu Kobayashi;H. Sano;T. Kohgo;M. Shindoh
EWS/ETS是在大多数尤文肉瘤中鉴定的嵌合蛋白。虽然EWS/ETS已被证明可以作为转录因子激活转录，但EWS/ETS在转化细胞中的详细靶点尚未阐明。在此，我们证明端粒酶是EWS/ETS融合的新靶点。EWS/E1 AF和EWS/FLI 1转化的NIH 3 T3细胞及两株尤文肉瘤细胞端粒酶活性和端粒酶逆转录酶（telomerase reverse transcriptase，TERT）mRNA表达水平均上调。荧光素酶分析表明EWS/E1 AF和EWS/FLI 1是以ETS结合位点非依赖性方式调控TERT转录的正调控因子。EWS/ETS似乎包含在TERT转录的起始复合物中，并与CREB结合蛋白（CBP）/p300合作。当EWS/FLI 1基因在尤文肉瘤细胞中被RNA干扰后，TERTmRNA的表达水平和端粒酶活性明显降低。这些结果表明，EWS/ETS融合蛋白通过上调TERT基因表达激活尤文氏肿瘤中的人端粒酶活性，可能是作为转录共激活因子。
EWS/ETS is a chimeric protein identified in most Ewing's sarcomas. Although EWS/ETS has been shown to activate transcription as a transcription factor, the detailed targets of EWS/ETS in transformed cells have not been clarified. Herein, we demonstrate that telomerase is a new target of EWS/ETS fusions. Both telomerase activity and the expression level of telomerase reverse transcriptase (TERT) mRNA were up-regulated in NIH3T3 cells transformed by EWS/E1AF and EWS/FLI1 as well as in two Ewing's sarcoma cell lines. Luciferase assay using the TERT promoter revealed that EWS/E1AF and EWS/FLI1 function as positive regulators of TERT transcription in an ETS binding site-independent manner. EWS/ETS appeared to be included in the initiation complex of TERT transcription and to cooperate with CREB-binding protein (CBP)/p300. When EWS/FLI1 was knocked down in Ewing's sarcomas cells by RNA interference, the expression level of TERT mRNA and the telomerase activity were significantly decreased. These findings indicate that EWS/ETS fusion proteins activate human telomerase activity in Ewing's tumors through up-regulation of TERT gene expression, probably as a transcriptional coactivator.