Mitotic catastrophe constitutes a special case of apoptosis whose suppression entails aneuploidy
Mitotic catastrophe constitutes a special case of apoptosis whose suppression entails aneuploidy
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DOI：
10.1038/sj.onc.1207572
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发表时间：
2004-05-27
期刊：
影响因子：
8
通讯作者：
Kroemer, G
中科院分区：
文献类型：
--
作者：
Castedo, M;Perfettini, JL;Kroemer, G
当DNA结构检查点失活时，例如当检查点激酶Chk2被抑制时，细胞周期进程中的冲突或DNA损伤可导致有丝分裂灾难。在这种情况下，由于半胱天冬酶的激活和随后的线粒体损伤，细胞在细胞周期的中期死亡。这些现象的分子排序表明，有丝分裂突变以p53独立的方式发生，涉及细胞色素c释放上游的caspase-2的初级激活，随后是caspase-3的激活和染色质凝聚。通过RNA干扰或假底物抑制剂抑制caspase-2以及阻断线粒体膜透性可以防止有丝分裂灾难，并允许细胞在中期之后进一步进行细胞周期，导致细胞分裂不对称。当Chk2和caspase同时受到抑制时，由非同步细胞融合产生的异核细胞可以分裂成三个或更多的子细胞。这种由抑制有丝分裂突变引起的多极分裂，导致细胞质（异细胞增多症）、DNA（异核增多症）和染色体（非整倍体）的不对称分布。同样，在DNA损伤诱导的有丝分裂突变模型中，抑制细胞凋亡导致非整倍体细胞的产生。我们的研究结果描绘了一个分子途径，通过该途径，DNA损伤、未能阻止细胞周期和抑制凋亡可能有利于可能参与肿瘤发生的细胞遗传学异常的发生。
A conflict in cell cycle progression or DNA damage can lead to mitotic catastrophe when the DNA structure checkpoints are inactivated, for instance when the checkpoint kinase Chk2 is inhibited. Here we show that in such conditions, cells die during the metaphase of the cell cycle, as a result of caspase activation and subsequent mitochondrial damage. Molecular ordering of these phenomena reveals that mitotic catastrophe occurs in a p53-independent manner and involves a primary activation of caspase-2, upstream of cytochrome c release, followed by caspase-3 activation and chromatin condensation. Suppression of caspase-2 by RNA interference or pseudosubstrate inhibitors as well as blockade of the mitochondrial membrane permeabilization prevent the mitotic catastrophe and allow cells to further proceed the cell cycle beyond the metaphase, leading to asymmetric cell division. Heterokarya generated by the fusion of nonsynchronized cells can be driven to divide into three or more daughter cells when Chk2 and caspases are simultaneously inhibited. Such multipolar divisions, resulting from suppressed mitotic catastrophe, lead to the asymmetric distribution of cytoplasm (anisocytosis), DNA (anisokaryosis) and chromosomes (aneuploidy). Similarly, in a model of DNA damage-induced mitotic catastrophe, suppression of apoptosis leads to the generation of aneuploid cells. Our findings delineate a molecular pathway through which DNA damage, failure to arrest the cell cycle and inhibition of apoptosis can favor the occurrence of cytogenetic abnormalities that are likely to participate in oncogenesis.