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Impaired Bub1 Function In vivo Compromises Tension-Dependent Checkpoint Function Leading to Aneuploidy and Tumorigenesis

¹ Curriculum in Genetics, ² Department of Genetics and the Lineberger Comprehensive Cancer Center, and ³ Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Requests for reprints: Terry Van Dyke, University of North Carolina, 102 Mason Farm Road, CB 7295, Chapel Hill, NC 27514. Phone: 919-962-2145; Fax: 919-843-3160; E-mail: tvdlab{at}med.unc.edu.

Key Words: aneuploidy • Bub1 • tumorigenesis

Bub1 is a serine/threonine kinase originally described as a core component of the spindle assembly checkpoint (SAC) mechanism in yeast. Bub1 binding at kinetochores has been reported to be required for SAC function and localization of other SAC components. A proper SAC is believed to be essential for murine embryonic development, as all previously described null mutations in SAC components in mice cause embryonic lethality. We produced mice harboring a Bub1 mutant allele lacking exons 2 and 3, resulting in a hypomorphic mutant expressed at <5% of wild-type levels. Despite this significant reduction, homozygous mutant animals are viable on a mixed 129P2/B6 or FVB background but display increased tumorigenesis with aging, whereas mice with a C57Bl/6J background die perinatally. Bub1 mutant murine embryonic fibroblasts (MEFs) display defects in chromosome congression to the metaphase plate, severe chromosome missegregation, and aneuploidy accompanied by high levels of premature senescence. Mutant MEFs have a robust SAC in response to nocodazole treatment but an impaired response to Taxol. Mutant MEFs also show reduced kinetochore localization of BubR1, but not of Mad2. The significant reduction in SAC response to Taxol, but not nocodazole, coupled with the reduced binding of BubR1, but not Mad2, indicates that Bub1 is particularly critical for the SAC response to a lack of tension on kinetochores. Thus, Bub1 is essential for proper chromosome segregation, a defect that can lead to severe phenotypes, including perinatal lethality and a predisposition to cancer. [Cancer Res 2009;69(1):45–54]