Liu Weijun, Li Wenqi, Fujita Takeo, Yang Qi, Wan Yong
Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213-1863, USA.
Carcinogenesis. 2008 Feb;29(2):263-72. doi: 10.1093/carcin/bgm251. Epub 2008 Jan 3.
As a critical ubiquitin ligase, the anaphase-promoting complex/cyclosome (APC/C) governs cell cycle progression, signaling modulation and the pathogenesis of some human diseases. Recent studies implicate APC in maintaining genomic integrity, but the mechanism by which it plays such a role remains largely unknown. We report here that acute UV radiation triggers proteolysis of CDH1, an activator of APC, which is involved in regulation of apoptosis induced by UV radiation. Depletion of CDH1 by RNA interference enhances the cellular susceptibility to apoptosis in response to UV radiation, whereas overexpression of non-degradable CDH1 delays UV radiation-induced apoptosis. In addition, UV-induced degradation of CDH1 results in the accumulation of cyclin B1 and therefore to increased CDK1 activity, which is believed to enhance UV-induced apoptosis. The present results unveil a novel role for the APC in UV-induced cell death and demonstrate a new regulatory mechanism for APC/CDH1 through proteolysis.
作为一种关键的泛素连接酶，后期促进复合物/细胞周期体（APC/C）调控细胞周期进程、信号转导调节以及一些人类疾病的发病机制。最近的研究表明APC在维持基因组完整性方面发挥作用，但其发挥这种作用的机制在很大程度上仍不清楚。我们在此报告，急性紫外线辐射会触发APC激活剂CDH1的蛋白水解，CDH1参与紫外线辐射诱导的细胞凋亡调控。通过RNA干扰使CDH1缺失会增强细胞对紫外线辐射诱导的细胞凋亡的易感性，而不可降解的CDH1的过表达会延迟紫外线辐射诱导的细胞凋亡。此外，紫外线诱导的CDH1降解导致细胞周期蛋白B1的积累，进而导致CDK1活性增加，这被认为会增强紫外线诱导的细胞凋亡。目前的结果揭示了APC在紫外线诱导的细胞死亡中的新作用，并证明了通过蛋白水解对APC/CDH1的新调控机制。
