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Faithful chromosome segregation is essential for the maintenance of genetic stability during cell division. Eukaryotic cells have evolved a mechanism that delays the onset of anaphase until condensed chromosomes are properly positioned on the mitotic spindle. To further understand the molecular basis of this surveillance mechanism in human cells, we have been studying the role of a spindle checkpoint kinase BubR1 and Adenomatous Polyposis Coli (Apc) in the regulation of genomic stability and tumor suppression. Here we report that whereas ApcMin/+ mice developed many adenomatous polyps, mostly in the small intestine by three months of age, BubR1+/−ApcMin/+ compound mutant mice developed significantly more colonic tumors than that of ApcMin/+ mice. The colonic tumors in BubR1+/−ApcMin/+ mice were in higher grades than those observed in ApcMin/+ mice. BubR1+/−ApcMin/+ MEF cells also proliferated at an accelerated rate and were more resistant to UV-induced cell death than wild-type MEFs or the cells with mutations in single genes. Consistently, induction of p53 and p21 by UV was significantly compromised in BubR1+/−ApcMin/+ MEF cells. Moreover, BubR1+/−ApcMin/+ MEFs slipped through mitosis in the presence of nocodazole and exhibited a higher rate of genomic instability than that of wild-type or BubR1+/− or ApcMin/+ MEFs, which was accompanied by premature separation of sister chromatids. Together, our studies suggest that BubR1 and Apc functionally interact in regulating metaphase/anaphase transition, deregulation of which may play a key role in genomic instability and development and progression of colorectal cancer.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]