Division of Medical Genetics, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Foggia, Italy; PhD Program, Experimental and Regenerative Medicine, University of Foggia, Foggia, Italy.
Unit of Cellular Networks and Molecular Therapeutic Targets, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
Cancer Lett. 2020 Mar 31;473:98-106. doi: 10.1016/j.canlet.2019.12.042. Epub 2020 Jan 2.
The faithful inheritance of chromosomes is essential for the propagation of organisms. In eukaryotes, central to this process is the mitotic spindle. Recently, we have identified TRIM8 as a gene aberrantly expressed in gliomas whose expression reduces the clonogenic potential in the patients' glioma cells. TRIM8 encodes an E3 ubiquitin ligase involved in various pathological processes, including hypertrophy, antiviral defense, encephalopathy, and cancer development. To gain insights into the TRIM8 functions, we characterized the TRIM8 interactome in primary mouse embryonic neural stem cells using proteomics. We found that TRIM8 interacts with KIFC1, and KIF11/Eg5, two master regulators of mitotic spindle assembly and cytoskeleton reorganization. By exploring the TRIM8 role in the mitotic spindle machinery, we showed that TRIM8 localizes at the mitotic spindle during mitosis and plays a role in centrosome separation at the beginning of mitosis with a subsequent delay of the mitotic progression and impact on chromosomal stability.
染色体的忠实遗传对于生物的繁衍至关重要。在真核生物中，有丝分裂纺锤体是这一过程的核心。最近，我们发现 TRIM8 在神经胶质瘤中异常表达，其表达降低了患者神经胶质瘤细胞的集落形成能力。TRIM8 编码一种 E3 泛素连接酶，参与多种病理过程，包括肥大、抗病毒防御、脑病和癌症发展。为了深入了解 TRIM8 的功能，我们使用蛋白质组学方法在原代小鼠胚胎神经干细胞中对 TRIM8 相互作用组进行了表征。我们发现 TRIM8 与 KIFC1 和 KIF11/Eg5 相互作用，这两种蛋白是有丝分裂纺锤体组装和细胞骨架重排的主要调节剂。通过探索 TRIM8 在有丝分裂纺锤体机制中的作用，我们表明 TRIM8 在有丝分裂期间定位于有丝分裂纺锤体上，并在有丝分裂开始时在中心体分离中发挥作用，随后导致有丝分裂进程延迟，并影响染色体稳定性。
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