Trim32 Facilitates Degradation of MYCN on Spindle Poles and Induces Asymmetric Cell Division in Human Neuroblastoma Cells
Trim32 Facilitates Degradation of MYCN on Spindle Poles and Induces Asymmetric Cell Division in Human Neuroblastoma Cells
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DOI：
10.1158/0008-5472.can-14-0169
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发表时间：
2014-10-01
期刊：
影响因子：
11.2
通讯作者：
Kaneko, Yasuhiko
中科院分区：
文献类型：
--
作者：
Izumi, Hideki;Kaneko, Yasuhiko
不对称细胞分裂（ACD）是发育和组织稳态过程中的一个生理过程。ACD产生两个不等的子细胞：一个具有干/祖细胞活性，另一个具有分化潜力。最近的研究表明，ACD对自我更新和分化之间的平衡的错误调节可能导致果蝇神经母细胞的肿瘤发生。然而，人类癌症干细胞样细胞是否表现出ACD仍然是未知的。在这里，使用人神经母细胞瘤细胞作为ACD模型，我们发现MYCN在有丝分裂期间通过GSK-3 β磷酸化在纺锤体两极积累。与此同时，ACD相关的泛素连接酶Trim32通过CDK1/细胞周期蛋白B介导的磷酸化被募集到纺锤体极。在有丝分裂过程中，Trim32在纺锤体极与MYCN相互作用，促进纺锤体极蛋白酶体降解MYCN并诱导ACD。Trim32还抑制神经母细胞瘤起始细胞的球体形成，这表明ACD的机制产生最终死亡的分化的神经母细胞瘤细胞。因此，Trim32是ACD的正调节因子，其对MYCN起作用，并且应该被认为是肿瘤抑制剂候选物。我们的发现为ACD的机制提供了新的见解，并阐明了其对人类肿瘤发生的贡献。(C)2014年AACR。
Asymmetric cell division (ACD) is a physiologic process during development and tissue homeostasis. ACD produces two unequal daughter cells: one has stem/progenitor cell activity and the other has potential for differentiation. Recent studies showed that misregulation of the balance between self-renewal and differentiation by ACD may lead to tumorigenesis in Drosophila neuroblasts. However, it is still largely unknown whether human cancer stem-like cells exhibit ACD or not. Here, using human neuroblastoma cells as an ACD model, we found that MYCN accumulates at spindle poles by GSK-3 beta phosphorylation during mitosis. In parallel, the ACD-related ubiquitin ligase Trim32 was recruited to spindle poles by CDK1/cyclin B-mediated phosphorylation. Trim32 interacted with MYCN at spindle poles during mitosis, facilitating proteasomal degradation of MYCN at spindle poles and inducing ACD. Trim32 also suppressed sphere formation of neuroblastoma-initiating cells, suggesting that the mechanisms of ACD produce differentiated neuroblastoma cells that will eventually die. Thus, Trim32 is a positive regulator of ACD that acts against MYCN and should be considered as a tumor-suppressor candidate. Our findings offer novel insights into the mechanisms of ACD and clarify its contributions to human tumorigenesis. (C) 2014 AACR.