NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN
NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN
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DOI：
10.1016/j.cell.2006.11.039
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发表时间：
2007-01-12
期刊：
影响因子：
64.5
通讯作者：
Jiang, Xuejun
中科院分区：
文献类型：
--
作者：
Wang, Xinjiang;Trotman, Lloyd C.;Jiang, Xuejun
肿瘤抑制因子 PTEN 是多种细胞过程的关键调节因子，在各种人类癌症中经常发生突变或缺失。 PTEN 表达水平的轻微降低对致癌作用具有深远的影响。在这里，我们证明PTEN水平受到泛素介导的蛋白酶体降解的调节，并将其泛素连接酶纯化为HECT结构域蛋白NEDD4-1。在细胞中，NEDD4-1 通过催化 PTEN 多泛素化来负调节 PTEN 稳定性。与 PTEN 的肿瘤抑制作用一致，NEDD4-1 的过度表达可增强细胞转化。引人注目的是，在 PTEN 遗传背景正常但蛋白水平较低的小鼠癌症模型和多个人类癌症样本中，NEDD4-1 高表达，这表明 NEDD4-1 的异常上调可以在翻译后抑制癌症中的 PTEN。 NEDD4-1表达的消除以PTEN依赖性方式抑制异种移植肿瘤的生长。因此，NEDD4-1 是一种潜在的原癌基因，可通过泛素化对 PTEN 进行负向调节，其范式类似于 Mdm2 和 p53。
The tumor suppressor PTEN, a critical regulator for multiple cellular processes, is mutated or deleted frequently in various human cancers. Subtle reductions in PTEN expression levels have profound impacts on carcinogenesis. Here we show that PTEN level is regulated by ubiquitin-mediated proteasomal degradation, and purified its ubiquitin ligase as HECT-domain protein NEDD4-1. In cells NEDD4-1 negatively regulates PTEN stability by catalyzing PTEN polyubiquitination. Consistent with the tumor-suppressive role of PTEN, overexpression of NEDD4-1 potentiated cellular transformation. Strikingly, in a mouse cancer model and multiple human cancer samples where the genetic background of PTEN was normal but its protein levels were low, NEDD4-1 was highly expressed, suggesting that aberrant upregulation of NEDD4-1 can posttranslationally suppress PTEN in cancers. Elimination of NEDD4-1 expression inhibited xenotransplanted tumor growth in a PTENdependent manner. Therefore, NEDD4-1 is a potential proto-oncogene that negatively regulates PTEN via ubiquitination, a paradigm analogous to that of Mdm2 and p53.