共 30 条
Colonic tumorigenesis in BubR1+/- ApcMin/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability
被引:141
作者:
Rao, CV
[1
]
Yang, YM
Swamy, MV
Liu, TY
Fang, YQ
Mahmood, R
Jhanwar-Uniyal, M
Dai, W
机构:
[1] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK 73104 USA
[2] New York Med Coll, Dept Med, Valhalla, NY 10595 USA
[3] New York Med Coll, Dept Pathol, Valhalla, NY 10595 USA
[4] Albert Einstein Coll Med, Core Facil Histopathol, Bronx, NY 10461 USA
来源:
关键词:
polyposis;
genetic instability;
colon cancer;
spindle checkpoint;
mitosis;
D O I:
10.1073/pnas.0407822102
中图分类号:
O [数理科学和化学];
P [天文学、地球科学];
Q [生物科学];
N [自然科学总论];
学科分类号:
07 ;
0710 ;
09 ;
摘要:
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.
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页码:4365 / 4370
页数:6
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