Abstract
Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene initiate a majority of colorectal cancers. Acquisition of chromosomal instability is an early event in these tumors. We provide evidence that the loss of APC leads to a partial loss of interkinetochore tension at metaphase and alters mitotic progression. Furthermore, we show that inhibition of APC in U2OS cells compromises the mitotic spindle checkpoint. This is accompanied by a decrease in the association of the checkpoint proteins Bub1 and BubR1 with kinetochores. Additionally, APC depletion reduced apoptosis. As expected from this combination of defects, tetraploidy and polyploidy are consequences of APC inhibition in vitro and in vivo. The removal of APC produced the same defects in HCT116 cells that have constitutively active beta-catenin. These data show that the loss of APC immediately induces chromosomal instability as a result of a combination of mitotic and apoptotic defects. We suggest that these defects amplify each other to increase the incidence of tetra- and polyploidy in early stages of tumorigenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenomatous Polyposis Coli Protein / deficiency*
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Adenomatous Polyposis Coli Protein / genetics
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Apoptosis / physiology*
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Caspase 3 / metabolism
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Cell Cycle Proteins
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Cell Line, Tumor
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Chromatin / chemistry
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Chromatin / metabolism
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Cyclin B / metabolism
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Cyclin B1
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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HCT116 Cells
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Histones / analysis
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Humans
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Intestinal Mucosa / metabolism
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Intestines / chemistry
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Intestines / pathology
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Mice
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Mice, Transgenic
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Mitosis / drug effects
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Mitosis / genetics
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Mitosis / physiology*
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Models, Biological
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Nocodazole / pharmacology
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Paclitaxel / pharmacology
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Polyploidy*
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases
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RNA, Small Interfering / genetics
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Spindle Apparatus / metabolism
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Staurosporine / pharmacology
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beta Catenin / analysis
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beta Catenin / metabolism
Substances
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Adenomatous Polyposis Coli Protein
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Bub1b protein, mouse
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CCNB1 protein, human
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Ccnb1 protein, mouse
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Cell Cycle Proteins
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Chromatin
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Cyclin B
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Cyclin B1
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Cyclin-Dependent Kinase Inhibitor p21
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Histones
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RNA, Small Interfering
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beta Catenin
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Protein Kinases
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BUB1 protein, human
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Bub1 protein, mouse
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Bub1 spindle checkpoint protein
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Protein Serine-Threonine Kinases
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Caspase 3
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Staurosporine
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Paclitaxel
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Nocodazole