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

Dina Dikovskaya, David Schiffmann, Ian P. Newton, Abigail Oakley, Karin Kroboth, Owen Sansom, Thomas J. Jamieson, Valerie Meniel, Alan Clarke, Inke S. Nathke

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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 ß-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.

    © 2007 Dikovskaya et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

    Original languageEnglish
    Pages (from-to)183-195
    Number of pages13
    JournalJournal of Cell Biology
    Volume176
    Issue number2
    DOIs
    Publication statusPublished - 16 Jan 2007

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