Marks Daniel Henry, Thomas Rozario, Chin Yvette, Shah Riddhi, Khoo Christine, Benezra Robert
Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
Cell Rep. 2017 May 30;19(9):1832-1845. doi: 10.1016/j.celrep.2017.05.021.
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 p31 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.
有丝分裂检查点通过延迟后期直到所有动粒都与微管结合，来确保染色体的正确分离。这种抑制信号由包含Mad2的复合物组成，该复合物抑制后期进程。该复合物可被p31和TRIP13拆解；然而，已表明敲低TRIP13仅会导致轻微的有丝分裂延迟。检查点基因以及TRIP13的过表达与癌症中的染色体不稳定性（CIN）相关，但Mad2过表达的初始效应是有丝分裂延长和增殖减少。在这里，我们表明，TRIP13过表达显著降低，而TRIP13减少则显著加剧了与Mad2过表达相关的有丝分裂延迟，但对微管解聚诱导的延迟没有影响。Mad2过表达和TRIP13缺失的组合降低了检查点复合物的拆解能力，并显著抑制了培养细胞和肿瘤异种移植中细胞的增殖。这些结果确定了过表达Mad2的细胞对TRIP13存在意想不到的依赖性。
