Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency.
A compromised spindle checkpoint is thought to play a key role in genetic instability that predisposes cells to malignant transformation. Loss of function mutations of BubR1, an important component of the spindle checkpoint, have been detected in human cancers. Here we show that BubR1(+/-) mouse embryonic fibroblasts are defective in spindle checkpoint activation, contain a significantly reduced amount of securin and Cdc20, and exhibit a greater level of micronuclei than do wild-type cells. RNA interference-mediated down-regulation of BubR1 also greatly reduced securin level. Moreover, compared with wild-type littermates, BubR1(+/-) mice rapidly develop lung as well as intestinal adenocarcinomas in response to challenge with carcinogen. BubR1 is thus essential for spindle checkpoint activation and tumor suppression.
Dai
Wei
W
Division of Molecular Carcinogenesis, Department of Medicine, New York Medical College, Valhalla, New York, USA.
Wang
Qi
Q
Liu
Tongyi
T
Swamy
Malisetty
M
Fang
Yuqiang
Y
Xie
Suqing
S
Mahmood
Radma
R
Yang
Yang-Ming
YM
Xu
Ming
M
Rao
Chinthalapally V
CV
D000236:Adenoma / Q000473:pathology; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering / Q000235:genetics; D008941:Spindle Apparatus / Q000502:physiology
C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; D034741:RNA, Small Interfering; D011494:Protein Kinases; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases