Castedo Maria, Perfettini Jean-Luc, Roumier Thomas, Valent Alexander, Raslova Hana, Yakushijin Kenichi, Horne David, Feunteun Jean, Lenoir Gilbert, Medema René, Vainchenker William, Kroemer Guido
CNRS-UMR 8125, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France.
Oncogene. 2004 May 27;23(25):4362-70. doi: 10.1038/sj.onc.1207572.
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.
当DNA结构检查点失活时，例如检查点激酶Chk2受到抑制，细胞周期进程中的冲突或DNA损伤会导致有丝分裂灾难。我们在此表明，在这种情况下，细胞在细胞周期的中期死亡，这是半胱天冬酶激活及随后线粒体损伤的结果。这些现象的分子顺序显示，有丝分裂灾难以不依赖p53的方式发生，涉及细胞色素c释放上游的半胱天冬酶-2的初级激活，随后是半胱天冬酶-3激活和染色质凝聚。通过RNA干扰或假底物抑制剂抑制半胱天冬酶-2以及阻断线粒体膜通透性可防止有丝分裂灾难，并使细胞在中期之后进一步进行细胞周期，导致不对称细胞分裂。当Chk2和半胱天冬酶同时受到抑制时，由不同步细胞融合产生的异核体可被驱动分裂为三个或更多子细胞。这种由受抑制的有丝分裂灾难导致的多极分裂会导致细胞质（细胞大小不等）、DNA（核大小不等）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灾难模型中，细胞凋亡的抑制会导致非整倍体细胞的产生。我们的研究结果描绘了一条分子途径，通过这条途径，DNA损伤、无法阻止细胞周期以及细胞凋亡的抑制可能会促进细胞遗传学异常的发生，而这些异常很可能参与肿瘤发生。
