Tumor-specific PAX3-FKHR transcription factor, but not PAX3, activates the platelet-derived growth factor alpha receptor
Tumor-specific PAX3-FKHR transcription factor, but not PAX3, activates the platelet-derived growth factor alpha receptor
复制标题
DOI：
10.1128/mcb.18.7.4118
复制
发表时间：
1998-07-01
影响因子：
5.3
通讯作者：
Wang, CY
中科院分区：
文献类型：
--
作者：
Epstein, JA;Song, BL;Wang, CY
t（2;13）染色体易位在腺泡状横纹肌肉瘤中发生率很高，腺泡状横纹肌肉瘤是一种常见的儿童肌肉肿瘤。这种易位导致产生源自两种发育调节转录因子PAX 3和FKHR的嵌合融合蛋白。PAX 3的两个DNA结合模块（配对结构域和同源结构域）与FKHR的反式激活结构域在读框内融合。以前，肿瘤特异性PAX 3-FKHR已被证明与野生型PAX 3通常识别的DNA序列结合，并表现出相对增强的转录活性。用于证明PAX 3-FKHR是比PAX 3更有效的转录激活因子的DNA结合位点包括PAX 3配对结构域的识别序列。在这份报告中，我们证明了PAX 3-FKHR的能力，激活产品的生长控制基因，血小板衍生生长因子α受体（PDGF α R），通过识别一个配对型同源结构域结合位点位于PDGF α R启动子。PAX 3单独不能在测试条件下介导该启动子的转录激活。这提供了染色体易位导致PAX 3-FKHR靶基因特异性改变的第一个证据，并表明转录靶点可能在致癌活性和横纹肌肉瘤发展中起重要作用。
The t(2;13) chromosomal translocation occurs at a high frequency in alveolar rhabdomyosarcoma, a common pediatric tumor of muscle. This translocation results in the production of a chimeric fusion protein derived from two developmentally regulated transcription factors, PAX3 and FKHR. The two DNA binding modules, the paired domain and the homeodomain, of PAX3 are fused in frame to the transactivation domain of FKHR. Previously, tumor-specific PAX3-FKHR has been shown to bind to DNA sequences normally recognized by wild-type PAX3 and to exhibit relatively enhanced transcriptional activity. The DNA binding sites used to demonstrate that PAX3-FKHR is a more potent transcriptional activator than PAX3 have included recognition sequences for the paired domain of PAX3. In this report, we demonstrate the ability of PAX3-FKHR to activate the product of a growth control gene, platelet-derived growth factor alpha receptor (PDGF alpha R), by recognizing a paired-type homeodomain binding site located in the PDGF alpha R promoter. PAX3 alone cannot mediate transcriptional activation of this promoter under the conditions tested. This provides the first evidence that chromosomal translocation results in altered target gene specificity of PAX3-FKHR and suggests a transcriptional target that may play a significant role in oncogenic activity and rhabdomyosarcoma development.