Zhao J, Tenev T, Martins L M, Downward J, Lemoine N R
ICRF Molecular Oncology Unit, Imperial College School of Medicine, Hammersmith Campus, Du Cane Road, London W12 ONN, UK.
J Cell Sci. 2000 Dec;113 Pt 23:4363-71. doi: 10.1242/jcs.113.23.4363.
Survivin, a human inhibitor of apoptosis protein (IAP), plays an important role in both cell cycle regulation and inhibition of apoptosis. Survivin is expressed in cells during the G(2)/M phase of the cell cycle, followed by rapid decline of both mRNA and protein levels at the G(1) phase. It has been suggested that cell cycle-dependent expression of survivin is regulated at the transcriptional level. In this study we demonstrate involvement of the ubiquitin-proteasome pathway in post-translational regulation of survivin. Survivin is a short-lived protein with a half-life of about 30 minutes and proteasome inhibitors greatly stabilise survivin in vivo. Expression of the survivin gene under the control of the CMV promoter cannot block cell cycle-dependent degradation of the protein. Proteasome inhibitors can block survivin degradation during the G(1) phase and polyubiquitinated derivatives can be detected in vivo. Mutation of critical amino acid residues within the baculovirus IAP repeat (BIR) domain or truncation of the N terminus or the C terminus sensitises survivin to proteasome degradation. Together, these results indicate that the ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner and structural changes greatly destabilise the survivin protein.
存活素是一种人类凋亡抑制蛋白（IAP），在细胞周期调控和凋亡抑制中均发挥重要作用。存活素在细胞周期的G(2)/M期表达于细胞中，随后在G(1)期mRNA和蛋白水平均迅速下降。有人提出，存活素的细胞周期依赖性表达在转录水平受到调控。在本研究中，我们证明了泛素-蛋白酶体途径参与存活素的翻译后调控。存活素是一种半衰期约为30分钟的短命蛋白，蛋白酶体抑制剂在体内能极大地稳定存活素。在巨细胞病毒（CMV）启动子控制下的存活素基因表达并不能阻断该蛋白的细胞周期依赖性降解。蛋白酶体抑制剂可在G(1)期阻断存活素降解，且在体内可检测到多聚泛素化衍生物。杆状病毒IAP重复序列（BIR）结构域内关键氨基酸残基的突变或N端或C端的截短会使存活素对蛋白酶体降解敏感。总之，这些结果表明泛素-蛋白酶体途径以细胞周期依赖性方式调控存活素降解，且结构变化会极大地使存活素蛋白不稳定。
