The ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner.
The ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner.
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发表时间：
2000-12
影响因子：
4
通讯作者：
Jian Zhao;T. Tenev;Luis M. Martins;Julian Downward;N. R. Lemoine
中科院分区：
文献类型：
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作者：
Jian Zhao;T. Tenev;Luis M. Martins;Julian Downward;N. R. Lemoine
Survivin 是一种人类凋亡蛋白抑制剂 (IAP)，在细胞周期调节和细胞凋亡抑制中发挥重要作用。生存素在细胞周期的 G(2)/M 期期间在细胞中表达，随后在 G(1) 期 mRNA 和蛋白质水平迅速下降。有人提出，生存素的细胞周期依赖性表达在转录水平上受到调节。在这项研究中，我们证明了泛素-蛋白酶体途径参与生存素的翻译后调节。 Survivin是一种短寿命蛋白质，半衰期约为30分钟，蛋白酶体抑制剂可极大地稳定体内的survivin。生存素基因在 CMV 启动子控制下的表达不能阻止细胞周期依赖性蛋白质降解。蛋白酶体抑制剂可以阻止存活蛋白在 G(1) 期的降解，并且可以在体内检测到多泛素化衍生物。杆状病毒 IAP 重复 (BIR) 结构域内关键氨基酸残基的突变或 N 末端或 C 末端的截短使生存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节生存素降解，并且结构变化极大地破坏了生存素蛋白的稳定性。
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.