Castedo Maria, Perfettini Jean-Luc, Roumier Thomas, Andreau Karine, Medema Rene, Kroemer Guido
CNRS-UMR 8125, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille-Desmoulins, Villejuif F-94805, France.
Oncogene. 2004 Apr 12;23(16):2825-37. doi: 10.1038/sj.onc.1207528.
The current literature is devoid of a clearcut definition of mitotic catastrophe, a type of cell death that occurs during mitosis. Here, we propose that mitotic catastrophe results from a combination of deficient cell-cycle checkpoints (in particular the DNA structure checkpoints and the spindle assembly checkpoint) and cellular damage. Failure to arrest the cell cycle before or at mitosis triggers an attempt of aberrant chromosome segregation, which culminates in the activation of the apoptotic default pathway and cellular demise. Cell death occurring during the metaphase/anaphase transition is characterized by the activation of caspase-2 (which can be activated in response to DNA damage) and/or mitochondrial membrane permeabilization with the release of cell death effectors such as apoptosis-inducing factor and the caspase-9 and-3 activator cytochrome c. Although the morphological aspect of apoptosis may be incomplete, these alterations constitute the biochemical hallmarks of apoptosis. Cells that fail to execute an apoptotic program in response to mitotic failure are likely to divide asymmetrically in the next round of cell division, with the consequent generation of aneuploid cells. This implies that disabling of the apoptotic program may actually favor chromosomal instability, through the suppression of mitotic catastrophe. Mitotic catastrophe thus may be conceived as a molecular device that prevents aneuploidization, which may participate in oncogenesis. Mitotic catastrophe is controlled by numerous molecular players, in particular, cell-cycle-specific kinases (such as the cyclin B1-dependent kinase Cdk1, polo-like kinases and Aurora kinases), cell-cycle checkpoint proteins, survivin, p53, caspases and members of the Bcl-2 family.
目前的文献中缺乏对有丝分裂灾难的明确定义，有丝分裂灾难是一种在有丝分裂期间发生的细胞死亡类型。在此，我们提出有丝分裂灾难是由细胞周期检查点（特别是DNA结构检查点和纺锤体组装检查点）缺陷与细胞损伤共同导致的。在有丝分裂之前或期间未能阻止细胞周期会引发异常染色体分离的尝试，最终导致凋亡默认途径的激活和细胞死亡。在中期/后期转换期间发生的细胞死亡的特征是caspase-2的激活（可因DNA损伤而激活）和/或线粒体膜通透性增加，伴随着凋亡诱导因子、caspase-9和-3激活剂细胞色素c等细胞死亡效应物的释放。尽管凋亡的形态学方面可能不完整，但这些改变构成了凋亡的生化标志。未能对有丝分裂失败执行凋亡程序的细胞可能会在接下来的一轮细胞分裂中不对称分裂，从而产生非整倍体细胞。这意味着凋亡程序的失活实际上可能通过抑制有丝分裂灾难而促进染色体不稳定。因此，有丝分裂灾难可被视为一种防止非整倍体化的分子机制，它可能参与肿瘤发生。有丝分裂灾难受众多分子参与者的控制，特别是细胞周期特异性激酶（如细胞周期蛋白B1依赖性激酶Cdk1、polo样激酶和Aurora激酶）、细胞周期检查点蛋白、生存素、p53、caspases和Bcl-2家族成员。
