Colonic tumorigenesis in BubR1+/–ApcMin/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability

CV Rao, YM Yang, MV Swamy, T Liu… - Proceedings of the …, 2005 - National Acad Sciences
CV Rao, YM Yang, MV Swamy, T Liu, Y Fang, R Mahmood, M Jhanwar-Uniyal, W Dai
Proceedings of the National Academy of Sciences, 2005National Acad Sciences
Faithful chromosome segregation is essential for the maintenance of genetic stability during
cell division and it is at least partly monitored by the spindle checkpoint, a surveillance
mechanism preventing the cell from prematurely entering anaphase. The adenomatous
polyposis coli (Apc) gene also plays an important role in regulating genomic stability, as
mutations of Apc cause aneuploidy. Here we show that whereas ApcMin/+ mice developed
many adenomatous polyps, mostly in the small intestine, by 3 mo of age; BubR1+/–ApcMin/+ …
Faithful chromosome segregation is essential for the maintenance of genetic stability during cell division and it is at least partly monitored by the spindle checkpoint, a surveillance mechanism preventing the cell from prematurely entering anaphase. The adenomatous polyposis coli (Apc) gene also plays an important role in regulating genomic stability, as mutations of Apc cause aneuploidy. Here we show that whereas ApcMin/+ mice developed many adenomatous polyps, mostly in the small intestine, by 3 mo of age; BubR1+/–ApcMin/+ compound mutant mice developed 10 times more colonic tumors than ApcMin/+ mice. The colonic tumors in BubR1+/–ApcMin/+ mice were in higher grades than those observed in ApcMin/+ mice. Consistently, BubR1+/–ApcMin/+ murine embryonic fibroblasts (MEFs) contained more β-catenin and proliferated at a faster rate than WT or BubR1+/– MEFs. Moreover, BubR1+/–ApcMin/+ MEFs slipped through mitosis in the presence of nocodazole and exhibited a higher rate of genomic instability than that of WT or BubR1+/– or ApcMin/+ MEFs, 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.
National Acad Sciences