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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Degradation of p57Kip2 mediated by SCFSkp2-dependent ubiquitylation.
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Degradation of p57Kip2 mediated by SCFSkp2-dependent ubiquitylation.

机译：由SCFSkp2依赖性泛素化介导的p57Kip2降解。

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摘要

The abundance of the cyclin-dependent kinase (CDK) inhibitor p57Kip2, an important regulator of cell cycle progression, is thought to be controlled by the ubiquitin-proteasome pathway. The Skp1/Cul1/F-box (SCF)-type E3 ubiquitin ligase complex SCFSkp2 has now been shown to be responsible for regulating the cellular level of p57Kip2 by targeting it for ubiquitylation and proteolysis. The elimination of p57Kip2 was impaired in Skp2-/- cells, resulting in abnormal accumulation of the protein. Coimmunoprecipitation analysis also revealed that Skp2 interacts with p57Kip2 in vivo. Overexpression of WT Skp2 promoted degradation of p57Kip2, whereas expression of a dominant negative mutant of Skp2 prolonged the half-life of p57Kip2. Mutation of the threonine residue (Thr-310) of human p57Kip2 that is conserved between the COOH-terminal QT domains of p57Kip2 and p27Kip1 prevented the effect of Skp2 on the stability of p57Kip2, suggesting that phosphorylation at this site is required for SCFSkp2-mediated ubiquitylation. Finally, the purified recombinant SCFSkp2 complex mediated p57Kip2 ubiquitylation in vitro in a manner dependent on the presence of the cyclin E-CDK2 complex. These observations thus demonstrate that the SCFSkp2 complex plays an important role in cell-cycle progression by determining the abundance of p57Kip2 and that of the related CDK inhibitor p27Kip1.
机译：细胞周期蛋白依赖性激酶（CDK）抑制剂p57Kip2是细胞周期进程的重要调节剂，其丰度被认为是由泛素-蛋白酶体途径控制的。 Skp1 / Cul1 / F-box（SCF）型E3泛素连接酶复合物SCFSkp2已显示可通过靶向p57Kip2的泛素化和蛋白水解作用来调节其细胞水平。 Skp2-/-细胞中p57Kip2的消除受到损害，导致蛋白质异常积聚。免疫共沉淀分析还显示，Skp2在体内与p57Kip2相互作用。 WT Skp2的过表达促进p57Kip2的降解，而Skp2显性负突变体的表达延长了p57Kip2的半衰期。在p57Kip2和p27Kip1的COOH末端QT结构域之间保守的人p57Kip2的苏氨酸残基（Thr-310）突变阻止了Skp2对p57Kip2稳定性的影响，这表明SCFSkp2介导需要该位点的磷酸化泛素化。最后，纯化的重组SCFSkp2复合物在体外以依赖于细胞周期蛋白E-CDK2复合物的方式介导p57Kip2泛素化。因此，这些观察结果表明，SCFSkp2复合物通过确定p57Kip2和相关CDK抑制剂p27Kip1的丰度，在细胞周期进程中起重要作用。

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