COP1 is a tumour suppressor that causes degradation of ETS transcription factors
COP1 is a tumour suppressor that causes degradation of ETS transcription factors
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DOI：
10.1038/nature10005
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发表时间：
2011-06-16
期刊：
影响因子：
64.8
通讯作者：
Dixit, Vishva M.
中科院分区：
文献类型：
--
作者：
Vitari, Alberto C.;Leong, Kevin G.;Dixit, Vishva M.
原癌基因ETV 1、ETV 4和ETV 5编码E26转化特异性（ETS）家族中的转录因子，该家族包括前列腺癌中最常重排和过表达的基因（1-4）。尽管是发育的关键调节因子，但对其翻译后调节知之甚少。在这里，我们确定了泛素连接酶COP 1（也称为RFWD 2）作为负调控ETV 1，ETV 4和ETV 5的肿瘤抑制因子。ETV 1在前列腺癌中更常发生突变，在被COP 1泛素化后被降解。由前列腺癌易位TMPRSS 2编码的截短ETV 1：ETV 1缺乏关键的COP 1结合基序，并且比野生型ETV 1稳定50倍。几乎所有的患者易位使ETV 1对COP 1不敏感，这意味着这赋予前列腺上皮细胞选择性优势。事实上，小鼠前列腺中COP 1的缺乏会升高ETV 1，并导致细胞增殖、增生和早期前列腺上皮内瘤变增加。COP 1和PTEN的联合缺失增强了小鼠前列腺癌的侵袭性。最后，罕见的人类前列腺癌样本显示COP 1基因的半合子丢失、COP 1蛋白的丢失和ETV 1蛋白的升高，同时缺乏易位事件。这些发现确定COP 1作为肿瘤抑制因子，其下调促进前列腺上皮细胞增殖和肿瘤发生。
The proto-oncogenes ETV1, ETV4 and ETV5 encode transcription factors in the E26 transformation-specific (ETS) family, which includes the most frequently rearranged and overexpressed genes in prostate cancer(1-4). Despite being critical regulators of development, little is known about their post-translational regulation. Here we identify the ubiquitin ligase COP1 (also known as RFWD2) as a tumour suppressor that negatively regulates ETV1, ETV4 and ETV5. ETV1, which is mutated in prostate cancer more often, was degraded after being ubiquitinated by COP1. Truncated ETV1 encoded by prostate cancer translocation TMPRSS2:ETV1 lacks the critical COP1 binding motifs and was 50-fold more stable than wild-type ETV1. Almost all patient translocations render ETV1 insensitive to COP1, implying that this confers a selective advantage to prostate epithelial cells. Indeed, COP1 deficiency in mouse prostate elevated ETV1 and produced increased cell proliferation, hyperplasia, and early prostate intraepithelial neoplasia. Combined loss of COP1 and PTEN enhanced the invasiveness of mouse prostate adenocarcinomas. Finally, rare human prostate cancer samples showed hemizygous loss of the COP1 gene, loss of COP1 protein, and elevated ETV1 protein while lacking a translocation event. These findings identify COP1 as a tumour suppressor whose downregulation promotes prostatic epithelial cell proliferation and tumorigenesis.