Surveillance mechanism linking Bub1 loss to the p53 pathway

Bub1 is a kinase believed to function primarily in the mitotic spindle checkpoint. Mutation or aberrant Bub1 expression is associated with chromosomal instability, aneuploidy, and human cancer. We now find that targeting Bub1 by RNAi or simian virus 40 (SV40) large T antigen in normal human diploid...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2007-05, Vol.104 (20), p.8334-8339
Main Authors: Gjoerup, Ole V, Wu, Jiaping, Chandler-Militello, Devin, Williams, Grace L, Zhao, Jean, Schaffhausen, Brian, Jat, Parmjit S, Roberts, Thomas M
Format: Article
Language:English
Subjects:
Aneuploidy
Antigens, Viral, Tumor - metabolism
Biological Sciences
Cancer
Cell culture techniques
Cell division
Cell growth
Cell Line
Cell lines
Cell Proliferation
Cellular Senescence
Chromosomes
Cyclin-Dependent Kinase Inhibitor p21 - metabolism
Fibroblasts
Fibroblasts - cytology
Fibroblasts - metabolism
HeLa cells
Humans
Kinases
Protein Binding
Protein Kinases - deficiency
Protein-Serine-Threonine Kinases
Retinoblastoma Protein - metabolism
Simian virus 40
Simian virus 40 - immunology
Spindle Apparatus - metabolism
Time Factors
Tumor Suppressor Protein p53 - metabolism
Tumors
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Summary:Bub1 is a kinase believed to function primarily in the mitotic spindle checkpoint. Mutation or aberrant Bub1 expression is associated with chromosomal instability, aneuploidy, and human cancer. We now find that targeting Bub1 by RNAi or simian virus 40 (SV40) large T antigen in normal human diploid fibroblasts results in premature senescence. Interestingly, cells undergoing replicative senescence were also low in Bub1 expression, although ectopic Bub1 expression in presenescent cells was insufficient to extend lifespan. Premature senescence caused by lower Bub1 levels depends on p53. Senescence induction was blocked by dominant negative p53 expression or depletion of p21CIP¹, a p53 target. Importantly, cells with lower Bub1 levels and inactivated p53 became highly aneuploid. Taken together, our data highlight a role for p53 in monitoring Bub1 function, which may be part of a more general spindle checkpoint surveillance mechanism. Our data support the hypothesis that Bub1 compromise triggers p53-dependent senescence, which limits the production of aneuploid and potentially cancerous cells.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0703164104