期刊
JOURNAL OF CELL BIOLOGY
卷 176, 期 2, 页码 183-195出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200610099
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- Medical Research Council [G0301154] Funding Source: Medline
- Medical Research Council [G0301154] Funding Source: researchfish
- MRC [G0301154] Funding Source: UKRI
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 inter-kinetochore 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 HCT1 16 cells that have constitutively active P-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.
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