Dual roles of human BubR1, a mitotic checkpoint kinase, in the monitoring of chromosomal instability.
In this study, we show that the formation of polyploidy following sustained mitotic checkpoint activation appears to be preceded by the ubiquitin-dependent proteolysis of hBubR1. In addition, the level of hBubR1 is significantly reduced not only in polyploid cells created by sustained mitotic spindle damage, but also in 21 (31.3%) of 67 human colon adenocarcinomas tested. Importantly, the introduction of hBubR1 triggers the apoptosis of polyploid cells formed by aberrant exit from mitosis and inhibits the growth of tumors established with these cells in athymic nude mice. These results suggest that hBubR1-mediated apoptosis prevents the propagation of cells that breach the mitotic checkpoint and that the control of hBubR1 protein level is an important factor in the acquisition of preneoplastic polyploidy.
Shin
Hyun Jin
HJ
Research Institute, National Cancer Center, Goyang, Gyeonggi, 411-764, Korea.
Baek
Kwan Hyuck
KH
Jeon
Ae Hwa
AH
Park
Moon Taek
MT
Lee
Su Jae
SJ
Kang
Chang Mo
CM
Lee
Hyun Sook
HS
Yoo
Seong Ho
SH
Chung
Doo Hyun
DH
Sung
Young Chul
YC
McKeon
Frank
F
Lee
Chang Woo
CW
D000230:Adenocarcinoma / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins; D043171:Chromosomal Instability / Q000235:genetics*; D003001:Cloning, Molecular; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008938:Mitosis / Q000502:physiology; D015739:Nocodazole / Q000494:pharmacology; D010766:Phosphorylation; D011123:Polyploidy; D011489:Protein Denaturation; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D008941:Spindle Apparatus; D014183:Transplantation, Heterologous / Q000473:pathology; D025801:Ubiquitin / Q000378:metabolism
D000970:Antineoplastic Agents; C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; D025801:Ubiquitin; D011494:Protein Kinases; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D020169:Caspases; D015739:Nocodazole