In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 102, No. 12 ( 2005-03-22), p. 4365-4370
Abstract:
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 Apc Min /+ mice developed many adenomatous polyps, mostly in the small intestine, by 3 mo of age; BubR1 +/– Apc Min /+ compound mutant mice developed 10 times more colonic tumors than Apc Min /+ mice. The colonic tumors in BubR1 +/– Apc Min /+ mice were in higher grades than those observed in Apc Min /+ mice. Consistently, BubR1 +/– Apc Min /+ murine embryonic fibroblasts (MEFs) contained more β-catenin and proliferated at a faster rate than WT or BubR1 +/– MEFs. Moreover, BubR1 +/– Apc Min /+ MEFs slipped through mitosis in the presence of nocodazole and exhibited a higher rate of genomic instability than that of WT or BubR1 +/– or Apc Min /+ 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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0407822102
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2005
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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