BUB3 that dissociates from BUB1 activates caspase-independent mitotic death (CIMD).

BUB3 that dissociates from BUB1 activates caspase-independent mitotic death (CIMD).
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DOI:
10.1038/cdd.2009.207
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发表时间:
2010-06
影响因子:
12.4
通讯作者:
Kitagawa, K.
Kitagawa, K.
中科院分区:
生物学1区
文献类型:
--
作者:
Niikura, Y.;Ogi, H.;Kikuchi, K.;Kitagawa, K.

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细胞死亡机制,防止非整倍体所造成的纺锤体检查点的失败,最近已经成为一个重要的监管模式。我们以前确定了一种新的类型的有丝分裂细胞死亡,称为半胱天冬酶非依赖性有丝分裂死亡(CIMD),这是诱导早期有丝分裂的部分BUB 1(纺锤体检查点蛋白)耗尽和缺陷的kinetochore-microtubule附件。在这项研究中,我们已经表明,逃脱CIMD的存活细胞具有异常的细胞核,并且我们已经确定了BUB 1耗尽激活CIMD的分子机制。BUB 3(BUB 1相互作用物和纺锤体检查点蛋白)与p73(p53的同源物)特异性地在其中发生CIMD的细胞中相互作用。从BUB 1中释放的BUB 3与p73结合,在p73上Y 99被c-Abl酪氨酸激酶磷酸化,导致CIMD的激活。这些结果有力地支持了CIMD是通过诱导倾向于大量染色体错误分离的细胞死亡来保护细胞免于非整倍性的细胞死亡机制的假设。
The cell death mechanism that prevents aneuploidy caused by a failure of the spindle checkpoint has recently emerged as an important regulatory paradigm. We previously identified a novel type of mitotic cell death, termed caspase-independent mitotic death (CIMD), which is induced during early mitosis by partial BUB1 (a spindle checkpoint protein) depletion and defects in kinetochore–microtubule attachment. In this study, we have shown that survived cells that escape CIMD have abnormal nuclei, and we have determined the molecular mechanism by which BUB1 depletion activates CIMD. BUB3 (a BUB1 interactor and a spindle checkpoint protein) interacts with p73 (a homolog of p53) specifically in cells wherein CIMD occurs. BUB3 that is freed from BUB1 associates with p73 on which Y99 is phosphorylated by c-Abl tyrosine kinase, resulting in the activation of CIMD. These results strongly support the hypothesis that CIMD is the cell death mechanism protecting cells from aneuploidy by inducing the death of cells prone to substantial chromosome missegregation.
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