Synergistic Effects of BubR1 and p53 Deficiency in Tumor Formation

Regulation of cell proliferation within an organism is a necessary and complex process involving several proteins serving as controls at various cell cycle phases known as cell cycle checkpoints. One of these checkpoints, the mitotic spindle checkpoint, controls the advancement from metaphase to anaphase during mitosis and monitors the proper attachment of the microtubules to the kinetochore. The spindle checkpoint protein, BubR1 is a protein kinase that localizes to the kinetochores to monitor proper microtubule attachment. BubR1 is able to inhibit the anaphase promoting complex (APC) and delay the onset of anaphase. Concurrent with its role in regulating cell cycle, mutations in BubR1 have been observed in various human cancers. In this work, we examine the effects of BubR1 deficiency at the cellular and organism level using an inbred mouse strain that is deficient for the BubR1 gene expression. We showed that the complete loss of BubR1 resulted in an embryonic lethal phenotype and this phenotype could not be rescued in a p53 deficient background. Additionally, mice heterozygous for BubR1 showed a decreased life expectancy and an increased incidence of tumorigenesis. Furthermore, our data indicates that the loss of BubR1 synergizes with p53 deficiency to increase the susceptibility of cancer formation in mice and alters the tumor spectrum of the p53 deficient mice. Finally we show that the BubR1 deficiency increases cellular growth kinetics and transformation potential of MEFs derived from compound BubR1; p53 mutants. This data provides insight into the importance of BubR1 in the prevention of tumorigensis and its role as a checkpoint protein.