Stathmin/Op18 depletion induces genomic instability and leads to premature senescence in human normal fibroblasts
Stathmin/Op18 depletion induces genomic instability and leads to premature senescence in human normal fibroblasts
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DOI：
10.1002/jcb.26401
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发表时间：
2018-02-01
影响因子：
4
通讯作者：
Song, Kiwon
中科院分区：
文献类型：
--
作者：
Shrestha, Deepmala;Kim, Namil;Song, Kiwon
Stathmin/癌蛋白18调节微管动力学并参与有丝分裂的进入和退出。我们分离出stathmin作为KIFC 1的物理相互作用伙伴，KIFC 1是一种负端定向驱动蛋白，在双极纺锤体形成和维持中发挥作用。我们发现stathmin缺失导致IMR-90正常人成纤维细胞中多极纺锤体形成。Stathmin缺失的IMR-90细胞显示早期有丝分裂延迟，但通过形成多极或假双极而设法经历染色体分离。与这些观察结果一致，在stathmin耗尽的IMR-90细胞中，滞后染色体和微核增加，表明stathmin对于维持人类细胞有丝分裂期间的基因组稳定性至关重要。由stathmin耗竭诱导的基因组不稳定性导致在正常IMR-90细胞中没有任何细胞死亡迹象的过早衰老。stathmin和p53的双敲低也不诱导IMR-90细胞中的细胞死亡，而stathmin敲低触发了p53精通的人肺腺癌细胞中的细胞凋亡。我们的研究结果表明，stathmin是必不可少的双极纺锤体的形成，以保持在有丝分裂过程中的基因组稳定性，和stathmin的耗尽防止启动染色体不稳定性诱导衰老在人类正常成纤维细胞。
Stathmin/oncoprotein18 regulates microtubule dynamics and participates in mitotic entry and exit. We isolated stathmin as a physically interacting partner of KIFC1, a minus-end-directed kinesin functioning in bipolar spindle formation and maintenance. We found that stathmin depletion leads to multipolar spindle formation in IMR-90 normal human fibroblasts. Stathmin-depleted IMR-90 cells showed early mitotic delay but managed to undergo chromosome segregation by forming multiple poles or pseudo-bipoles. Consistent with these observations, lagging chromosomes, and micronuclei were elevated in stathmin-depleted IMR-90 cells, demonstrating that stathmin is essential for maintaining genomic stability during mitosis in human cells. Genomic instability induced by stathmin depletion led to premature senescence without any indication of cell death in normal IMR-90 cells. Double knock-down of both stathmin and p53 also did not induce cell death in IMR-90 cells, while the stathmin knock-down triggered apoptosis in p53-proficient human lung adenocarcinoma cells. Our results suggest that stathmin is essential in bipolar spindle formation to maintain genomic stability during mitosis, and the depletion of stathmin prevents the initiation of chromosome instability by inducing senescence in human normal fibroblasts.