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首页> 外文期刊>Molecular and Cellular Biology >Tumor-Specific PAX3-FKHR Transcription Factor, but Not PAX3, Activates the Platelet-Derived Growth Factor Alpha Receptor
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Tumor-Specific PAX3-FKHR Transcription Factor, but Not PAX3, Activates the Platelet-Derived Growth Factor Alpha Receptor

机译：肿瘤特异性PAX3-FKHR转录因子而非PAX3激活血小板衍生的生长因子α受体

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摘要

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 (PDGFαR), by recognizing a paired-type homeodomain binding site located in the PDGFαR 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.
机译：t（2; 13）染色体易位发生在肺泡横纹肌肉瘤（一种常见的小儿肌肉肿瘤）中，频率很高。这种易位导致产生了嵌合融合蛋白，该融合蛋白衍生自两种发育受调控的转录因子PAX3和FKHR。 PAX3的两个DNA结合模块（成对结构域和同源结构域）与FKHR的反式激活结构域框内融合。以前，已显示肿瘤特异性PAX3-FKHR与正常被野生型PAX3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PAX3-FKHR是比PAX3更有效的转录激活因子的DNA结合位点已包括PAX3配对域的识别序列。在本报告中，我们通过识别位于PDGFαR启动子中的配对型同源域结合位点，证明了PAX3-FKHR激活生长控制基因的产物，即血小板衍生的生长因子α受体（PDGFαR）的能力。在测试的条件下，单独的PAX3不能介导该启动子的转录激活。这提供了第一个证据，即染色体易位导致PAX3-FKHR的靶基因特异性改变，并提示可能在致癌活性和横纹肌肉瘤发展中起重要作用的转录靶标。

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