Arf-induced turnover of the nucleolar nucleophosmin-associated SUMO-2/3 protease Senp3
Arf-induced turnover of the nucleolar nucleophosmin-associated SUMO-2/3 protease Senp3
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DOI：
10.4161/cc.7.21.6930
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发表时间：
2008-11-01
期刊：
影响因子：
4.3
通讯作者：
Sherr, Charles J.
中科院分区：
文献类型：
--
作者：
Kuo, Mei-Ling;den Besten, Willem;Sherr, Charles J.
P19(Arf)抑癌蛋白和SUMO-2/3去结合蛋白Senp3的稳定和亚细胞定位都依赖于它们与丰富的核仁蛋白Npm/B23的结合。Senp3和p19(Arf)在调节靶蛋白包括Npm自身的SUMO化过程中相互拮抗。P19(Arf)蛋白触发Senp3的顺序磷酸化、多泛素化和快速蛋白酶体降解，而这种加速Senp3周转的能力也依赖于Npm的存在。反过来，内源性p19(Arf)和Senp3在Npm缺失的小鼠胚胎成纤维细胞(也缺乏P53)中都是不稳定的，将人NPM蛋白重新导入这些细胞可以逆转这一表型。在这种情况下，保留酸性和寡聚化结构域的NPM突变体可以重新稳定p19(Arf)和Senp3，但这些作用并不严格要求NPM的核仁定位。用shRNAs敲除Senp3可以在单独缺乏p53的细胞中或在缺乏Arf、MDM2和p53基因的三重敲除细胞中模拟p19(Arf)的抗增殖功能。这些发现强化了这样的假设，即p19(Arf)的非p53肿瘤抑制功能可能是通过其拮抗Senp3的能力而介导的，从而通过异常上调细胞内Sumoylated蛋白的水平来诱导细胞周期停滞。
The stabilization and subcellular localization of the p19(Arf) tumor suppressor protein and the SUMO-2/3 deconjugating protease Senp3 each depend upon their binding to the abundant nucleolar protein nucleophosmin (Npm/B23). Senp3 and p19(Arf) antagonize each other's functions in regulating the SUMOylation of target proteins including Npm itself. The p19(Arf) protein triggers the sequential phosphorylation, polyubiquitination and rapid proteasomal degradation of Senp3, and this ability of p19(Arf) to accelerate Senp3 turnover also depends on the presence of Npm. In turn, endogenous p19(Arf) and Senp3 are both destabilized in viable Npm-null mouse embryo fibroblasts ( that also lack p53), and reintroduction of the human NPM protein into these cells reverses this phenotype. NPM mutants that retain their acidic and oligomerization domains can re-stabilize both p19(Arf) and Senp3 in this setting, but the nucleolar localization of NPM is not strictly required for these effects. Knockdown of Senp3 with shRNAs mimics the anti-proliferative functions of p19(Arf) in cells that lack p53 alone or in triple knock-out cells that lack the Arf, Mdm2 and p53 genes. These findings reinforce the hypothesis that the p53-independent tumor suppressive functions of p19(Arf) may be mediated by its ability to antagonize Senp3, thereby inducing cell cycle arrest by abnormally elevating the cellular levels of SUMOylated proteins.