BUB1 mediation of caspase-independent mitotic death determines cell fate

作者：Niikura Yohei; Dixit Amruta; Scott Ray; Perkins Guy; Kitagawa Katsumi^*

来源：The Journal of Cell Biology, 2007, 178(2): 283-296.

DOI：10.1083/jcb.200702134

• Antineoplastic Agents
• Antineoplastic Agents, Phytogenic
• Apoptosis Inducing Factor
• Benzoquinones
• Caco-2 Cells
• Caspases
• Cell Line, Tumor
• Chromosomes
• Cold Temperature
• DNA Fragmentation
• DNA-Binding Proteins
• Endodeoxyribonucleases
• Enzyme Activation
• Genomic Instability
• HCT116 Cells
• Hela Cells
• Humans
• Lactams, Macrocyclic
• Mitosis
• Models, Biological
• Nocodazole
• Nuclear Proteins
• Paclitaxel
• Protein Kinases
• Protein-Serine-Threonine Kinases
• RNA, Small Interfering

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-inclucing 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.

• 出版日期2007-7-16