Labelle Y, Bussières J, Courjal F, Goldring M B
Unité de recherche en génétique humaine et moléculaire, CHUQ, Québec, Canada.
Oncogene. 1999 May 27;18(21):3303-8. doi: 10.1038/sj.onc.1202675.
The EWS/TEC gene fusion generated by the t(9;22) chromosomal translocation found in extraskeletal myxoid chondrosarcomas encodes a fusion protein containing the amino-terminal domain of the EWS protein fused to the whole coding sequence of the orphan nuclear receptor TEC. We have compared the DNA-binding and transcriptional activation properties of various TEC isoforms and the corresponding EWS/TEC fusion proteins. Band-shift experiments show that the full-length TEC receptor can efficiently bind the NGFI-B Response Element (NBRE), whereas an isoform lacking the entire carboxyl-terminal domain of the receptor binds much less efficiently the NBRE. Addition of the amino-terminal domain of EWS to either isoforms does not alter significantly their DNA-binding properties to the NBRE. Co-transfection experiments of COS cells and human chondrocytes indicate that whereas TEC moderately activates transcription from a NBRE-containing promoter, the corresponding EWS/TEC fusion protein is a highly potent transcriptional activator of the same promoter, being approximately 270-fold more active than the native receptor. EWS/TEC may thus exert its oncogenic potential in chrondrosarcomas by activating the transcription of target genes involved in cell proliferation.
在骨外黏液样软骨肉瘤中发现的由t(9;22)染色体易位产生的EWS/TEC基因融合体编码一种融合蛋白，该融合蛋白包含EWS蛋白的氨基末端结构域与孤儿核受体TEC的整个编码序列融合。我们比较了各种TEC异构体以及相应的EWS/TEC融合蛋白的DNA结合和转录激活特性。凝胶迁移实验表明，全长TEC受体能够有效地结合NGFI-B反应元件（NBRE），而缺少受体整个羧基末端结构域的异构体与NBRE的结合效率则低得多。将EWS的氨基末端结构域添加到任何一种异构体中，都不会显著改变它们与NBRE的DNA结合特性。COS细胞和人软骨细胞的共转染实验表明，虽然TEC适度激活来自含NBRE启动子的转录，但相应的EWS/TEC融合蛋白是同一启动子的高效转录激活剂，其活性比天然受体高约270倍。因此，EWS/TEC可能通过激活参与细胞增殖的靶基因转录，在软骨肉瘤中发挥其致癌潜能。
