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 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 p21(CIP1), 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.
Gjoerup
Ole V
OV
Molecular Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. ovg27@pitt.edu
Wu
Jiaping
J
Chandler-Militello
Devin
D
Williams
Grace L
GL
Zhao
Jean
J
Schaffhausen
Brian
B
Jat
Parmjit S
PS
Roberts
Thomas M
TM
D000782:Aneuploidy; D000957:Antigens, Viral, Tumor / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D011494:Protein Kinases / Q000172:deficiency*; D017346:Protein Serine-Threonine Kinases; D016160:Retinoblastoma Protein / Q000378:metabolism; D013539:Simian virus 40 / Q000276:immunology; D008941:Spindle Apparatus / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000957:Antigens, Viral, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases