Phosphorylation of Def Regulates Nucleolar p53 Turnover and Cell Cycle Progression through Def Recruitment of Calpain3.
Phosphorylation of Def Regulates Nucleolar p53 Turnover and Cell Cycle Progression through Def Recruitment of Calpain3.
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Def 磷酸化通过 Def 募集 Calpain3 调节核仁 p53 周转和细胞周期进展
DOI：
10.1371/journal.pbio.1002555
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发表时间：
2016-09
期刊：
影响因子：
9.8
通讯作者：
Peng J
中科院分区：
文献类型：
--
作者：
Guan Y;Huang D;Chen F;Gao C;Tao T;Shi H;Zhao S;Liao Z;Lo LJ;Wang Y;Chen J;Peng J
消化器官扩展因子（Def）是一种具有双重功能的核仁蛋白：它作为核糖体小亚基处理体的组分用于核糖体的生物发生，并且还通过半胱氨酸蛋白酶钙蛋白酶-3（CAPN 3）介导p53降解。然而，关于Def和CAPN 3之间的确切关系或Def功能的调节，我们一无所知。在这份报告中，我们表明CAPN 3降解p53及其突变蛋白p53 A138 V，p53 M237 I，p53 R248 W和p53 R273 P，但不降解p53 R175 H突变蛋白。重要的是，我们发现Def直接与核仁中的CAPN 3相互作用，并决定了CAPN 3的核仁定位，这是核仁中p53降解的先决条件。此外，我们发现Def通过磷酸化在五个丝氨酸残基：S50，S58，S62，S87和S92处进行修饰。我们进一步表明，在S87和S92同时磷酸化促进Capn 3的核仁定位，这不仅是必不可少的p53的降解，但也是重要的调节细胞周期进程。因此，我们提出，Def-CAPN 3途径作为细胞增殖的核仁检查点，在器官形成过程中通过选择性灭活细胞周期相关底物。
Digestive organ expansion factor (Def) is a nucleolar protein that plays dual functions: it serves as a component of the ribosomal small subunit processome for the biogenesis of ribosomes and also mediates p53 degradation through the cysteine proteinase calpain-3 (CAPN3). However, nothing is known about the exact relationship between Def and CAPN3 or the regulation of the Def function. In this report, we show that CAPN3 degrades p53 and its mutant proteins p53A138V, p53M237I, p53R248W, and p53R273P but not the p53R175H mutant protein. Importantly, we show that Def directly interacts with CAPN3 in the nucleoli and determines the nucleolar localisation of CAPN3, which is a prerequisite for the degradation of p53 in the nucleolus. Furthermore, we find that Def is modified by phosphorylation at five serine residues: S50, S58, S62, S87, and S92. We further show that simultaneous phosphorylations at S87 and S92 facilitate the nucleolar localisation of Capn3 that is not only essential for the degradation of p53 but is also important for regulating cell cycle progression. Hence, we propose that the Def-CAPN3 pathway serves as a nucleolar checkpoint for cell proliferation by selective inactivation of cell cycle-related substrates during organogenesis.
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影响因子：
2
作者：
Chen, Jun;Peng, Jinrong
通讯作者：
Peng, Jinrong
影响因子：
9.2
作者：
Andersen, JS;Lyon, CE;Lamond, AI
通讯作者：
Lamond, AI
影响因子：
4.5
作者：
Charette, J. Michael;Baserga, Susan J.
通讯作者：
Baserga, Susan J.
影响因子：
4.7
作者：
Moretti, D.;Del Bello, B.;Maellaro, E.
通讯作者：
Maellaro, E.
影响因子：
3.5
作者：
Her, GM;Chiang, CC;Wu, JL
通讯作者：
Wu, JL