泛素连接酶Nedd4-1对于PTEN稳定性和定位的调节并非必需。
The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN stability and localization.
作者信息
Fouladkou Fatemeh, Landry Tamara, Kawabe Hiroshi, Neeb Antje, Lu Chen, Brose Nils, Stambolic Vuk, Rotin Daniela
机构信息
Hospital for Sick Children and Biochemistry Department, University of Toronto, MaRS-TMDT, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
出版信息
Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8585-90. doi: 10.1073/pnas.0803233105. Epub 2008 Jun 18.
PTEN is a tumor suppressor frequently mutated in cancer. Recent reports implicated Nedd4-1 as the E3 ubiquitin ligase for PTEN that regulates its stability and nuclear localization. We tested the physiological role of Nedd4-1 as a PTEN regulator by using cells and tissues derived from two independently generated strains of mice with their Nedd4-1 gene disrupted. PTEN stability and ubiquitination were indistinguishable between the wild-type and Nedd4-1-deficient cells, and an interaction between the two proteins could not be detected. Moreover, PTEN subcellular distribution, showing prominent cytoplasmic and nuclear staining, was independent of Nedd4-1 presence. Finally, activation of PKB/Akt, a major downstream target of cytoplasmic PTEN activity, and the ability of PTEN to transactivate the Rad51 promoter, a measure of its nuclear function, were unaffected by the loss of Nedd4-1. Taken together, our results fail to support a role for Nedd4-1 as the E3 ligase regulating PTEN stability and subcellular localization.
PTEN是一种在癌症中经常发生突变的肿瘤抑制因子。最近的报道表明Nedd4-1是PTEN的E3泛素连接酶，可调节其稳定性和核定位。我们通过使用来自两个独立生成的Nedd4-1基因被破坏的小鼠品系的细胞和组织，测试了Nedd4-1作为PTEN调节剂的生理作用。野生型细胞和Nedd4-1缺陷型细胞之间PTEN的稳定性和泛素化没有区别，并且未检测到这两种蛋白质之间的相互作用。此外，PTEN的亚细胞分布显示出明显的细胞质和细胞核染色，与Nedd4-1的存在无关。最后，细胞质PTEN活性的主要下游靶点PKB/Akt的激活以及PTEN反式激活Rad51启动子的能力（衡量其核功能的指标）不受Nedd4-1缺失的影响。综上所述，我们的结果不支持Nedd4-1作为调节PTEN稳定性和亚细胞定位的E3连接酶的作用。
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