Colonic tumorigenesis in BubR1+/-ApcMin/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability.
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.
Rao
Chinthalapally V
CV
Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA. cv-rao@ouhsc.edu
Yang
Yang-Ming
YM
Swamy
Malisetty V
MV
Liu
Tongyi
T
Fang
Yuqiang
Y
Mahmood
Radma
R
Jhanwar-Uniyal
Meena
M
Dai
Wei
W
D000818:Animals; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D020090:Chromosome Segregation / Q000235:genetics*; D003110:Colonic Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D003111:Colonic Polyps / Q000209:etiology / Q000235:genetics / Q000473:pathology; D015870:Gene Expression; D017491:Genes, APC; D042822:Genomic Instability; D051379:Mice; D008817:Mice, Mutant Strains; D008938:Mitosis / Q000235:genetics; D009154:Mutation; D011494:Protein Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases
C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; D011494:Protein Kinases; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases