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 spindl...

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Bibliographic Details
Published in:Cancer cell 2003-12, Vol.4 (6), p.483-497
Main Authors: Shin, Hyun-Jin, Baek, Kwan-Hyuck, Jeon, Ae-Hwa, Park, Moon-Taek, Lee, Su-Jae, Kang, Chang-Mo, Lee, Hyun-Sook, Yoo, Seong-Ho, Chung, Doo-Hyun, Sung, Young-Chul, McKeon, Frank, Lee, Chang-Woo
Format: Article
Language:English
Subjects:
Adenocarcinoma - metabolism
Adenocarcinoma - physiopathology
Animals
Antineoplastic Agents - pharmacology
Apoptosis - physiology
Caspases - metabolism
Cell Cycle Proteins
Chromosomal Instability - genetics
Cloning, Molecular
Colonic Neoplasms - metabolism
Colonic Neoplasms - physiopathology
hBubR1 protein
HeLa Cells
Humans
Immunohistochemistry
Mice
Mitosis - physiology
Nocodazole - pharmacology
Phosphorylation
Polyploidy
Protein Denaturation
Protein Kinases - metabolism
Protein-Serine-Threonine Kinases
Spindle Apparatus
Transplantation, Heterologous - pathology
Ubiquitin - metabolism
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Summary: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.
ISSN:1535-6108
1878-3686
DOI:10.1016/S1535-6108(03)00302-7