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PMID:15767571

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Citation

Rao, CV, Yang, YM, Swamy, MV, Liu, T, Fang, Y, Mahmood, R, Jhanwar-Uniyal, M and Dai, W (2005) Colonic tumorigenesis in BubR1+/-ApcMin/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability. Proc. Natl. Acad. Sci. U.S.A. 102:4365-70

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 beta-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.

Links

PubMed PMC555497 Online version:10.1073/pnas.0407822102

Keywords

Animals; Cell Cycle Proteins; Cells, Cultured; Chromosome Segregation/genetics; Colonic Neoplasms/etiology; Colonic Neoplasms/genetics; Colonic Neoplasms/pathology; Colonic Polyps/etiology; Colonic Polyps/genetics; Colonic Polyps/pathology; Gene Expression; Genes, APC; Genomic Instability; Mice; Mice, Mutant Strains; Mitosis/genetics; Mutation; Protein Kinases/genetics; Protein-Serine-Threonine Kinases

Significance

Annotations

Gene product Qualifier GO ID GO term name Evidence Code with/from Aspect Notes Status


See also

References

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