泛素连接酶APC/C参与的泛素化与细胞周期调节

Ubiquitin Ligase APC/C in Ubiquitylation and Cell Cycle Regulation

后期促进复合物/细胞周期体(anaphase-promoting complex/cyclosome,APC/C)是一个多功能的泛素连接酶,参与细胞周期、代谢、DNA损伤修复、细胞自噬、凋亡、衰老及肿瘤发生等多种生物学过程。泛素化作为一种重要的翻译后修饰,可通过泛素-蛋白酶体系统(ubiquitin-proteasome system,UPS)调控蛋白质的降解。APC/C的分子量巨大,由多个亚基组成,在细胞周期调控中具有重要地位,可以通过介导细胞周期相关蛋白质的泛素化降解从而精确调控细胞周期的转换,并受共激活分子CDC20或CDH1的调控。了解APC/C的结构和功能,对于研究细胞周期及蛋白质翻译后修饰等生物学事件至关重要。近年,对APC/C分子结构和组成的解析工作取得了极大的进展,其在肿瘤中的作用及潜在的治疗应用也受到了关注。本文将着重对APC/C的组成和结构、参与泛素化的具体过程、在细胞周期中的调控和被调控机制以及参与肿瘤生成的最新研究进展进行综述。

Anaphase-promoting complex/cyclosome（ APC/C） is a multi-functional E3 ubiquitin ligase that takes part in biological processes of cell cycle,metabolism,DNA damage and repair,autophagy,apoptosis,senescence and tumorigenesis. Ubiquitylation,as an important process of post-translational modification,is involved in protein degradation via the ubiquitin-proteasome system（ UPS）. APC/C is a large molecule weight enzyme with multiple subunits,which plays a crucial role in cell cycle regulation,and precisely regulates cell cycle progression by mediating the ubiquitylation of many cell cycle-related proteins. The activity of APC/C is mainly regulated by its co-activator CDC20 or CDH1. In the past decade,the results from a large amount of biochemical,structural,genetic and pharmacology studies have drawn our attention to the role of APC/C and its therapeutic potential in human diseases such as cancer. Understanding the architecture and function of APC/C is a premise to study the biological events including cell cycle and post-translational modification,but the structure of this protein complex remained largely unknown. The recent discovery revealed the molecular and the atomic structure of APC/C,which provided a framework for further investigation. Here we reviewed the recent literatures related to APC/C on its composition and structure,the ubiquitylation process,its regulatory mechanisms in cell cyclecontrol,and its role in tumorigenesis.