APC mutations lead to cytokinetic failures in vitro and tetraploid genotypes in Min mice.
Previous research has proposed that genomic instability contributes to cancer progression, with its initiation linked to tetraploid cell formation (Duesberg, P., and R. Li. 2003. Cell Cycle. 2:202-210; Ganem, N.J., Z. Storchova, and D. Pellman. 2007. Curr. Opin. Genet. Dev. 17:157-162). However, there is little direct evidence linking cancer-causing mutations with such events, and it remains controversial whether genomic instability is a cause or an effect of cancer. In this study, we show that adenomatous polyposis coli (APC) mutations found in human colorectal cancers dominantly inhibit cytokinesis by preventing mitotic spindle anchoring at the anaphase cortex and, thus, blocking initiation of the cytokinetic furrow. We find that dividing crypt cells in the small intestines of APC(Min/+) mice exhibit similar mitotic defects, including misoriented spindles and misaligned chromosomes. These defects are observed in normal crypt cells with wild-type levels of beta-catenin and, importantly, are associated with tetraploid genotypes. We provide direct evidence that the dominant activity of APC mutants induces aneuploidy in vivo. Our data support a model whereby tetraploid cells represent a first step in the onset of genomic instability and colorectal cancer.
Caldwell
Christine M
CM
Section of Molecular and Cell Biology, University of California, Davis, Davis, CA 95616, USA.
Green
Rebecca A
RA
Kaplan
Kenneth B
KB
D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D048749:Cytokinesis / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007421:Intestine, Small / Q000166:cytology; D051379:Mice; D008817:Mice, Mutant Strains; D008938:Mitosis; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D053141:Organelle Size; D011123:Polyploidy; D008941:Spindle Apparatus / Q000378:metabolism
D050505:Mutant Proteins