MTBP plays a crucial role in mitotic progression and chromosome segregation
MTBP plays a crucial role in mitotic progression and chromosome segregation
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DOI：
10.1038/cdd.2010.189
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发表时间：
2011-07-01
影响因子：
12.4
通讯作者：
Iwakuma, T.
中科院分区：
文献类型：
--
作者：
Agarwal, N.;Tochigi, Y.;Iwakuma, T.
小鼠双分钟2(MDM2)结合蛋白(MTBP)与肿瘤细胞增殖有关，但其机制尚不清楚。MTBP在细胞周期进程中的表达分析结果表明，MTBP蛋白在有丝分裂过程中迅速降解。免疫荧光研究表明，在前中期，部分MTBP定位于着丝点。MTBP的过表达延缓了有丝分裂从核膜破裂(NEB)到后期的开始，并导致了染色体的异常分离，如落后染色体、染色体桥和多极染色体分离。相反，MTBP下调导致细胞分裂中期缩短和不充分的有丝分裂停滞，导致染色体异常分离、非整倍体、细胞增殖减少、衰老和细胞死亡，类似于MAD2(有丝分裂停止缺陷2)下调。此外，MTBP的下调抑制了MAD1和MAD2的积累，但不抑制BubR1的积累(出芽不受苯并咪唑相关1的抑制)，而MTBP的过表达则抑制了中期动轴上MAD2的释放。这些结果可能表明，MTBP在早中期在动粒中心招募和/或保留Mad1/MAD2复合体方面具有重要作用，但其降解是沉默有丝分裂检查点所必需的。综上所述，这项研究表明，MTBP在适当的有丝分裂进程和忠实的染色体分离中起着至关重要的作用，为有丝分裂检查点的调控提供了新的见解。《细胞死亡与分化》(2011年)181208-1219DOI：10.1038/cdd.2010.189；2011年1月28日在线发布
Murine double minute 2 (MDM2) binding protein (MTBP) has been implicated in tumor cell proliferation, but the underlying mechanisms remain unclear. The results of MTBP expression analysis during cell cycle progression demonstrated that MTBP protein was rapidly degraded during mitosis. Immunofluorescence studies revealed that a portion of MTBP was localized at the kinetochores during prometaphase. MTBP overexpression delayed mitotic progression from nuclear envelope breakdown (NEB) to anaphase onset and induced abnormal chromosome segregation such as lagging chromosomes, chromosome bridges, and multipolar chromosome segregation. Conversely, MTBP downmodulation caused an abbreviated metaphase and insufficient mitotic arrest, resulting in abnormal chromosome segregation, aneuploidy, decreased cell proliferation, senescence, and cell death, similar to that of Mad2 (mitotic arrest-deficient 2) downmodulation. Furthermore, MTBP downmodulation inhibited the accumulation of Mad1 and Mad2, but not BubR1 (budding uninhibited by benzimidazoles related 1), on the kinetochores, whereas MTBP overexpression inhibited the release of Mad2 from the metaphase kinetochores. These results may imply that MTBP has an important role in recruiting and/or retaining the Mad1/Mad2 complex at the kinetochores during prometaphase, but its degradation is required for silencing the mitotic checkpoint. Together, this study indicates that MTBP has a crucial role in proper mitotic progression and faithful chromosome segregation, providing new insights into regulation of the mitotic checkpoint. Cell Death and Differentiation (2011) 18, 1208-1219; doi:10.1038/cdd.2010.189; published online 28 January 2011