Mad2 Overexpression Uncovers a Critical Role for TRIP13 in Mitotic Exit.
Mad2 Overexpression Uncovers a Critical Role for TRIP13 in Mitotic Exit.
复制标题
DOI：
10.1016/j.celrep.2017.05.021
复制
发表时间：
2017-05-30
期刊：
影响因子：
8.8
通讯作者：
Benezra R
中科院分区：
文献类型：
--
作者：
Marks DH;Thomas R;Chin Y;Shah R;Khoo C;Benezra R
有丝分裂检查点通过延迟后期直至所有动粒与微管结合来确保染色体的正确分离。该抑制信号由含有 Mad2 的复合物组成，可抑制后期进展。该复合物可以被p31comet和TRIP13分解；然而，TRIP13 敲除已被证明仅导致轻微的有丝分裂延迟。检查点基因以及 TRIP13 的过度表达与癌症中的染色体不稳定 (CIN) 相关，但 Mad2 过度表达的最初影响是有丝分裂延长和增殖减少。在这里，我们发现TRIP13过表达显着减少了与Mad2过表达相关的有丝分裂延迟，而TRIP13减少显着加剧了有丝分裂延迟，但与微管解聚诱导的有丝分裂延迟无关。 Mad2 过表达和 TRIP13 缺失的结合降低了检查点复合物的分解能力，并显着抑制培养物和肿瘤异种移植物中细胞的增殖。这些结果确定了过表达 Mad2 的细胞对 TRIP13 的意外依赖性。 TRIP13 是一种假定的有丝分裂检查点沉默蛋白。然而，TRIP13 的缺失仅导致轻微的有丝分裂退出表型。马克斯等人。发现 TRIP13 对于 Mad2 过表达细胞的有丝分裂退出至关重要。这两种蛋白在癌症中共同过表达，TRIP13 可能是 Mad2 过表达肿瘤的治疗靶点。
The mitotic checkpoint ensures proper segregation of chromosomes by delaying anaphase until all kinetochores are bound to microtubules. This inhibitory signal is composed of a complex containing Mad2, which inhibits anaphase progression. The complex can be disassembled by p31comet and TRIP13; however, TRIP13 knockdown has been shown to cause only a mild mitotic delay. Overexpression of checkpoint genes, as well as TRIP13, is correlated with chromosomal instability (CIN) in cancer, but the initial effects of Mad2 overexpression are prolonged mitosis and decreased proliferation. Here we show that TRIP13 overexpression significantly reduced, and TRIP13 reduction significantly exacerbated, the mitotic delay associated with Mad2 overexpression but not that induced by microtubule depolymerization. The combination of Mad2 overexpression and TRIP13 loss reduced the ability of checkpoint complexes to disassemble and significantly inhibited the proliferation of cells in culture and tumor xenografts. These results identify an unexpected dependency on TRIP13 in cells overexpressing Mad2. TRIP13 is a putative mitotic checkpoint silencing protein. However, depletion of TRIP13 causes only mild mitotic exit phenotypes. Marks et al. find that TRIP13 becomes critical for mitotic exit in Mad2-overexpressing cells. Both proteins are co-overexpressed in cancer, and TRIP13 may be a therapeutic target in Mad2-overexpressing tumors.
登录
查看更多内容
DOI：
10.1038/nrm3494
发表时间：
2013-01
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1083/jcb.201505114
发表时间：
2015-11-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Nelson CR;Hwang T;Chen PH;Bhalla N
通讯作者：
Bhalla N
影响因子：
9.2
作者：
Mariani, Luca;Chiroli, Elena;Ciliberto, Andrea
通讯作者：
Ciliberto, Andrea
影响因子：
16.8
作者：
Luo, XL;Tang, ZY;Yu, HT
通讯作者：
Yu, HT