Loss of APC induces polyploidy as a result of a combination of defects in mitosis and apoptosis

Dikovskaya, Dina, Schiffmann, David, Newton, Ian P., Oakley, Abigail, Kroboth, Karin, Sansom, Owen J. ORCID: https://orcid.org/0000-0001-9540-3010, Jamieson, Thomas J., Meniel, Valerie, Clarke, Alan Richard ORCID: https://orcid.org/0000-0002-4281-426X and Nathke, Inke S. 2007. Loss of APC induces polyploidy as a result of a combination of defects in mitosis and apoptosis. Journal of cell biology 176 (2) , pp. 183-195. 10.1083/jcb.200610099

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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 β-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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Subjects:	Q Science > Q Science (General) Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher:	Rockefeller University Press,
ISSN:	0021-9525
Last Modified:	25 Oct 2022 10:10
URI:	https://orca.cardiff.ac.uk/id/eprint/61345

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