Department of Urology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abenoku, Osaka 545-8585, Japan.
Curr Pharm Des. 2013;19(22):4131-9. doi: 10.2174/1381612811319220017.
Tumor cells frequently promote the dysregulation of the cell cycle and escape from apoptotic cell death triggered by a number of cellular stresses. Programmed proteolytic degradation of regulatory proteins via the ubiquitin-proteasome pathway is crucial for homeostasis of numerous biological processes. Disruption of this system is one of the factors that promote aberrant cell-proliferation. The small ubiquitin-like protein, NEDD8, has been identified as a fundamental regulator of the activity of the E3 ubiquitin ligases called the SCF complex (consisting of Skp-1, cullin, and F-box protein) or CRL (cullin-RING ubiquitin ligase) which control a final step in ubiquitination of diverse substrates associated with cancer biology. The ubiquitin ligase activity of the SCF complex requires NEDD8 to covalently bind to cullins. To a large extent, exploring the negative regulation system of the NEDD8 pathway is expected to lead to the development of novel anticancer targets. This review focuses on the NEDD8 negative regulation system including chemical compounds such as MLN4924 and protein molecules (e.g. COP9 signalosome, CAND1, inactive mutant of Ubc12 and NUB1/NUB1L) and clarifies possible strategies for targeting the NEDD8 cascade in cancer cells.
肿瘤细胞经常促进细胞周期的失调，并逃避由许多细胞应激触发的细胞凋亡。通过泛素-蛋白酶体途径对调节蛋白进行程序性蛋白水解降解对于许多生物过程的动态平衡至关重要。该系统的破坏是促进异常细胞增殖的因素之一。小泛素样蛋白 NEDD8 已被确定为 E3 泛素连接酶 SCF 复合物（由 Skp-1、cullin 和 F-box 蛋白组成）或 CRL（cullin-RING 泛素连接酶）的基本调节剂，该复合物控制与癌症生物学相关的各种底物泛素化的最后一步。SCF 复合物的泛素连接酶活性需要 NEDD8 与 cullin 共价结合。在很大程度上，探索 NEDD8 途径的负调控系统有望为开发新的抗癌靶标提供依据。这篇综述重点介绍了 NEDD8 的负调控系统，包括化学化合物（如 MLN4924）和蛋白质分子（如 COP9 信号小体、CAND1、Ubc12 的无活性突变体和 NUB1/NUB1L），并阐明了针对癌细胞中 NEDD8 级联的可能策略。
