Feng L, Lee K A
Department of Biology, Hong Kong University of Science & Technology, Clear Water Bay, Kowloon, Hong Kong, S.A.R. China.
Oncogene. 2001 Jul 12;20(31):4161-8. doi: 10.1038/sj.onc.1204522.
Chromosomal fusion of the N-terminal region of the Ewings Sarcoma Oncogene (EWS-activation-domain, EAD) to the DNA-binding domains of a variety of cellular transcription factors produce oncogenic proteins (EWS-fusion proteins (EFPs)) that cause distinct malignancies. In EFPs, the EAD acts as a potent transcriptional activation domain and this ability is repressed in the context of normal, non-tumorigenic, EWS. Trans-activation by the EAD is therefore a specific characteristic of EFPs and it is thought that EFPs induce tumorigenesis via improper transcriptional activation of cellular genes. Functional elements required for transcriptional activation are dispersed throughout the EAD, as are thirty-one copies of a Degenerate Hexapeptide Repeat (DHR, consensus SYGQQS). This suggests that the EAD contains a highly reiterated functional element related to DHRs. Here we show that in the context of EWS/ATF1, the EFP that causes malignant melanoma of soft parts, trans-cooperation by small regions of the EAD ( approximately 30 residues) results in potent transcriptional activation dependent on the conserved tyrosine residues present in DHRs. These findings provide the first evidence for a role of DHRs in EAD-mediated trans-activation and demonstrate that the EAD represents a novel tyrosine-dependent transcriptional activation domain.
尤文氏肉瘤癌基因（EWS-激活结构域，EAD）N端区域与多种细胞转录因子的DNA结合结构域发生染色体融合，产生致癌蛋白（EWS融合蛋白（EFPs）），引发不同的恶性肿瘤。在EFPs中，EAD作为一个强大的转录激活结构域，而在正常的、非致瘤性的EWS环境中，这种能力受到抑制。因此，EAD的反式激活是EFPs的一个特异性特征，并且认为EFPs通过细胞基因的不适当转录激活诱导肿瘤发生。转录激活所需的功能元件分散在整个EAD中，就像一个简并六肽重复序列（DHR，共有序列SYGQQS）的31个拷贝一样。这表明EAD含有一个与DHRs相关的高度重复的功能元件。在此我们表明，在EWS/ATF1（导致软组织恶性黑色素瘤的EFP）的环境中，EAD的小区域（约30个残基）的反式协同作用导致依赖于DHRs中存在的保守酪氨酸残基的强大转录激活。这些发现为DHRs在EAD介导的反式激活中的作用提供了首个证据，并证明EAD代表一个新的酪氨酸依赖性转录激活结构域。
