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Published online
doi:10.1083/jcb.200706015
The Journal of Cell Biology, Vol. 179, No. 2, 255-267
The Rockefeller University Press, 0021-9525 $30.00
© Jeganathan et al.
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Article

Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis



Karthik Jeganathan1, Liviu Malureanu1, Darren J. Baker1, Susan C. Abraham3, and Jan M. van Deursen1,2

1 Department of Pediatrics, 2 Department of Molecular Biology and Biochemistry, and 3 Department of Anatomic Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905

Correspondence to Jan M. van Deursen: vandeursen.jan{at}mayo.edu

The physiological role of the mitotic checkpoint protein Bub1 is unknown. To study this role, we generated a series of mutant mice with a gradient of reduced Bub1 expression using wild-type, hypomorphic, and knockout alleles. Bub1 hypomorphic mice are viable, fertile, and overtly normal despite weakened mitotic checkpoint activity and high percentages of aneuploid cells. Bub1 haploinsufficient mice, which have a milder reduction in Bub1 protein than Bub1 hypomorphic mice, also exhibit reduced checkpoint activity and increased aneuploidy, but to a lesser extent. Although cells from Bub1 hypomorphic and haploinsufficient mice have similar rates of chromosome missegregation, cell death after an aberrant separation decreases dramatically with declining Bub1 levels. Importantly, Bub1 hypomorphic mice are highly susceptible to spontaneous tumors, whereas Bub1 haploinsufficient mice are not. These findings demonstrate that loss of Bub1 below a critical threshold drives spontaneous tumorigenesis and suggest that in addition to ensuring proper chromosome segregation, Bub1 is important for mediating cell death when chromosomes missegregate.

K. Jeganathan, L. Malureanu, and D.J. Baker contributed equally to this paper.

Abbreviations used in this paper: APC/C, anaphase-promoting complex/cyclosome; CENP, centromere protein; ES, embryonic stem; MEF, mouse embryonic fibroblast; NEBD, nuclear envelope breakdown; PMSCS, premature separation of sister chromatids.


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