Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents, Phytogenic / pharmacology
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Apoptosis Inducing Factor / metabolism
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Benzoquinones / pharmacology
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Caco-2 Cells
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Caspases / metabolism*
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Caspases / ultrastructure
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Cell Line, Tumor
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Chromosomes / genetics
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Chromosomes / metabolism
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Cold Temperature
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DNA Fragmentation / drug effects
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DNA-Binding Proteins / metabolism
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Endodeoxyribonucleases / metabolism
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Enzyme Activation
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Genomic Instability
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HCT116 Cells
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HeLa Cells
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Humans
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Lactams, Macrocyclic / pharmacology
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Mitosis / physiology*
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Models, Biological
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Nocodazole / pharmacology
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Nuclear Proteins / metabolism
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Paclitaxel / pharmacology
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Protein Kinases / ultrastructure
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Protein Serine-Threonine Kinases
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RNA, Small Interfering / pharmacology
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Tumor Protein p73
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Tumor Suppressor Proteins / metabolism
Substances
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Antineoplastic Agents
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Antineoplastic Agents, Phytogenic
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Apoptosis Inducing Factor
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Benzoquinones
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DNA-Binding Proteins
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Lactams, Macrocyclic
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Nuclear Proteins
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RNA, Small Interfering
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TP73 protein, human
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Tumor Protein p73
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Tumor Suppressor Proteins
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tanespimycin
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Protein Kinases
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BUB1 protein, human
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Bub1 spindle checkpoint protein
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Protein Serine-Threonine Kinases
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Endodeoxyribonucleases
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endonuclease G
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Caspases
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Paclitaxel
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Nocodazole