A repetitive element containing a critical tyrosine residue is required for transcriptional activation by the EWS/ATF1 oncogene
A repetitive element containing a critical tyrosine residue is required for transcriptional activation by the EWS/ATF1 oncogene
复制标题
DOI：
10.1038/sj.onc.1204522
复制
发表时间：
2001-07-12
期刊：
影响因子：
8
通讯作者：
Lee, KAW
中科院分区：
文献类型：
--
作者：
Feng, L;Lee, KAW
尤文氏肉瘤癌基因的N-末端区域（EWS-活化-结构域，EAD）与多种细胞转录因子的DNA结合结构域的染色体融合产生致癌蛋白（EWS-融合蛋白（EFP）），其引起不同的恶性肿瘤。在EFP中，EAD充当有效的转录激活结构域，并且这种能力在正常、非致瘤性EWS的情况下被抑制。因此，EAD的反式激活是EFP的特定特征，并且认为EFP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，如31个拷贝的简并六肽重复序列（DHR，共有SYCQQS）。这表明EAD含有与DHR相关的高度重复的功能元件。在这里，我们表明，在EWS/ATF 1的背景下，EFP，导致恶性黑色素瘤的软部，trans-cooperation的小区域的EAD（类似于30个残基）导致依赖于DHR中存在的保守酪氨酸残基的有效转录激活，这些发现为DHR在EAD介导的反式激活中的作用提供了第一个证据，并证明EAD代表了一种新的酪氨酸-依赖性转录激活结构域。
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 SYCQQS), 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 (similar to 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.