Loss of spindle assembly checkpoint-mediated inhibition of Cdc20 promotes tumorigenesis in mice.
Loss of spindle assembly checkpoint-mediated inhibition of Cdc20 promotes tumorigenesis in mice.
复制标题
DOI：
10.1083/jcb.200904020
复制
发表时间：
2009-06-15
期刊：
影响因子：
--
通讯作者：
Zhang P
中科院分区：
文献类型：
--
作者：
Li M;Fang X;Wei Z;York JP;Zhang P
基因组不稳定性是人类癌症的一个标志。纺锤体组装检查点（SAC）是一种重要的细胞机制，通过阻止姐妹染色单体的过早分离来防止染色体的错误分离，从而防止非整倍体。因此，SAC就像DNA损伤检查点一样，对基因组稳定性至关重要。在这项研究中，我们报告的生成和分析的小鼠携带Cdc 20等位基因，其中三个残基的相互作用与Mad 2的关键突变为丙氨酸。突变的Cdc 20蛋白（AAA-Cdc 20）不再被Mad 2抑制以响应SAC激活，导致SAC功能障碍和非整倍性。另外一种Cdc 20抑制剂BubR 1的额外表达不能挽救这种功能障碍。此外，我们发现Cdc 20 AAA/AAA小鼠在妊娠晚期死亡，但Cdc 20 +/AAA小鼠是存活的。重要的是，Cdc 20 +/AAA小鼠以高度加速的速率发生自发性肿瘤，表明SAC介导的Cdc 20抑制是一种重要的肿瘤抑制机制。
Genomic instability is a hallmark of human cancers. Spindle assembly checkpoint (SAC) is a critical cellular mechanism that prevents chromosome missegregation and therefore aneuploidy by blocking premature separation of sister chromatids. Thus, SAC, much like the DNA damage checkpoint, is essential for genome stability. In this study, we report the generation and analysis of mice carrying a Cdc20 allele in which three residues critical for the interaction with Mad2 were mutated to alanine. The mutant Cdc20 protein (AAA-Cdc20) is no longer inhibited by Mad2 in response to SAC activation, leading to the dysfunction of SAC and aneuploidy. The dysfunction could not be rescued by the additional expression of another Cdc20 inhibitor, BubR1. Furthermore, we found that Cdc20AAA/AAA mice died at late gestation, but Cdc20+/AAA mice were viable. Importantly, Cdc20+/AAA mice developed spontaneous tumors at highly accelerated rates, indicating that the SAC-mediated inhibition of Cdc20 is an important tumor-suppressing mechanism.
登录
查看更多内容
DOI：
10.1083/jcb.200706015
发表时间：
2007-10-22
期刊：
The Journal of cell biology
影响因子：
--
作者：
Jeganathan K;Malureanu L;Baker DJ;Abraham SC;van Deursen JM
通讯作者：
van Deursen JM
影响因子：
64.8
作者：
Cahill, DP;Lengauer, C;Vogelstein, B
通讯作者：
Vogelstein, B
影响因子：
21.3
作者：
Kitagawa, R;Rose, AM
通讯作者：
Rose, AM
影响因子：
4
作者：
Chi, Ya-Hui;Jeang, Kuan-Teh
通讯作者：
Jeang, Kuan-Teh
影响因子：
16
作者：
Gorr, IH;Boos, D;Stemmann, O
通讯作者：
Stemmann, O