Niikura Yohei, Dixit Amruta, Scott Ray, Perkins Guy, Kitagawa Katsumi
Department of Molecular Pharmacology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
J Cell Biol. 2007 Jul 16;178(2):283-96. doi: 10.1083/jcb.200702134. Epub 2007 Jul 9.
The spindle checkpoint that monitors kinetochore-microtubule attachment has been implicated in tumorigenesis; however, the relation between the spindle checkpoint and cell death remains obscure. In BUB1-deficient (but not MAD2-deficient) cells, conditions that activate the spindle checkpoint (i.e., cold shock or treatment with nocodazole, paclitaxel, or 17-AAG) induced DNA fragmentation during early mitosis. This mitotic cell death was independent of caspase activation; therefore, we named it caspase-independent mitotic death (CIMD). CIMD depends on p73, a homologue of p53, but not on p53. CIMD also depends on apoptosis-inducing factor and endonuclease G, which are effectors of caspase-independent cell death. Treatment with nocodazole, paclitaxel, or 17-AAG induced CIMD in cell lines derived from colon tumors with chromosome instability, but not in cells from colon tumors with microsatellite instability. This result was due to low BUB1 expression in the former cell lines. When BUB1 is completely depleted, aneuploidy rather than CIMD occurs. These results suggest that cells prone to substantial chromosome missegregation might be eliminated via CIMD.
监测动粒与微管附着情况的纺锤体检查点与肿瘤发生有关;然而,纺锤体检查点与细胞死亡之间的关系仍不清楚。在BUB1缺陷型(而非MAD2缺陷型)细胞中,激活纺锤体检查点的条件(即冷休克或用诺考达唑、紫杉醇或17-AAG处理)会在有丝分裂早期诱导DNA片段化。这种有丝分裂细胞死亡不依赖于半胱天冬酶激活;因此,我们将其命名为非半胱天冬酶依赖性有丝分裂死亡(CIMD)。CIMD依赖于p53的同源物p73,而非p53。CIMD还依赖于凋亡诱导因子和核酸内切酶G,它们是非半胱天冬酶依赖性细胞死亡的效应因子。用诺考达唑、紫杉醇或17-AAG处理可在源自具有染色体不稳定性的结肠肿瘤的细胞系中诱导CIMD,但在源自具有微卫星不稳定性的结肠肿瘤的细胞中则不会。这一结果是由于前一种细胞系中BUB1表达较低。当BUB1完全缺失时,会出现非整倍体而非CIMD。这些结果表明,易于发生大量染色体错分离的细胞可能会通过CIMD被清除。