Dual roles of human BubR1, a mitotic checkpoint kinase, in the monitoring of chromosomal instability

• 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
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/S1535-6108(03)00302-7

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.