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Published online January 16, 2007
doi:10.1083/jcb.200610099
The Journal of Cell Biology, Vol. 176, No. 2, 183-195
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Dikovskaya et al.
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Article

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

Dina Dikovskaya1, David Schiffmann1, Ian P. Newton1, Abigail Oakley1, Karin Kroboth1, Owen Sansom2, Thomas J. Jamieson2, Valerie Meniel3, Alan Clarke3, and Inke S. Näthke1

1 Division of Cell and Developmental Biology, University of Dundee, Dundee DD1 5EH, Scotland, UK
2 Cancer Research UK, Beatson Laboratories, Glasgow G61 1BD, Scotland, UK
3 School of Biosciences, Cardiff University, Cardiff CF10 3US, Wales, UK

Correspondence to Inke S. Näthke: inke{at}lifesci.dundee.ac.uk

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.

Abbreviations used in this paper: APC, adenomatous polyposis coli; IQR, interquartile range; PE, phycoerythrin; RFP, red fluorescent protein; TCF, T cell factor.


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