Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Front Biosci (Landmark Ed). 2012 Jun 1;17(6):2197-212. doi: 10.2741/4045.
The Ubiquitin Proteasome System (UPS) is a major regulator of protein abundance in the cell. The UPS influences the functions of multiple biological processes by targeting key regulators for destruction. E3 ubiquitin ligases are a vital component of the UPS machinery, working with E1 and E2 enzymes to bind substrates and facilitate the transfer of ubiquitin molecules onto the target protein. This poly-ubiquitination, in turn, directs the modified proteins for proteolysis by the 26S proteasome. As the UPS regulates the degradation of multiple oncogenes and tumor suppressors, the dysregulation of this pathway is known to promote various diseases including cancer. While E1 and E2 enzymes have only been minimally linked to cancer development, burgeoning amounts of evidence have implicated loss or gain of E3 function as a key factor in cancer initiation and progression. This review will examine the literature on two SCF-type E3 ligases, SCFFbw7 and SCFbeta-TRCP. In particular, we will highlight novel substrates recently identified for these two E3 ligases, and further discuss how UPS regulation of these targets may promote carcinogenesis.
泛素蛋白酶体系统（UPS）是细胞内蛋白质丰度的主要调节剂。UPS 通过靶向关键调节剂进行破坏来影响多种生物过程的功能。E3 泛素连接酶是 UPS 机制的重要组成部分，与 E1 和 E2 酶一起作用，结合底物并促进泛素分子转移到靶蛋白上。这种多泛素化反过来又将修饰后的蛋白质定向到 26S 蛋白酶体进行降解。由于 UPS 调节多种癌基因和肿瘤抑制因子的降解，该途径的失调被认为会促进包括癌症在内的各种疾病。虽然 E1 和 E2 酶与癌症的发展只有最小的联系，但越来越多的证据表明 E3 功能的丧失或获得是癌症发生和进展的关键因素。本综述将检查关于两种 SCF 型 E3 连接酶，SCFFbw7 和 SCFbeta-TRCP 的文献。特别是，我们将重点介绍这两种 E3 连接酶最近确定的新底物，并进一步讨论 UPS 对这些靶标的调节如何促进致癌作用。
