Most human cancers have an abnormal chromosome content, also known as aneuploidy. However, the molecular defects underlying the development of aneuploidy and its role in tumorigenesis remain largely unclear. The spindle assembly checkpoint is a surveillance mechanism that ensures accurate segregation of mitotic chromosomes by delaying anaphase onset until each kinetochore has properly attached to the mitotic spindle. In certain cancers with aneuploidy, mutations have been identified in the mitotic checkpoint genes Bub1, BubR1 and Mad2. Epigenetic downregulation of Bub1 and BubR1 expression has also been observed in aneuploid tumors. To study the role of Bub1 in mitosis, development and tumorigenesis, we produced a series of mice in which expression of Bub1 is reduced in a graded fashion by the use of wild-type, knockout and hypomorphic alleles. Preliminary studies of these mice show that Bub1 prevents aneuploidy and spontaneous tumor development in a dose dependent fashion. Cells from animals with relatively low amounts of Bub1 exhibit defective mitotic checkpoint activity, frequent chromosome missegregation, increased survival after chromosome missegregation and massive aneuploidy. The overall goal of this proposal is to dissect the mitotic functions of Bub1 at the molecular, cellular and organismal levels, and to determine the mechanisms by which Bub1 dysfunction promotes tumorigenesis.
In specific aim one, we will use mutant mouse strains to establish the physiological functions and critical functional domains of Bub1.
Specific aim two focuses on a novel interaction between Bub1 and Skp1, a core component of SCF-type E3 ligases. We will examine the functional significance of this interaction by using a knockin mouse model expressing a mutant form of Bub1 that cannot bind Skp1 as well as in vitro ubiquitination assays.
In specific aim three, we will use our allelic series of Bub1 mice to establish the mechanism by which Bub1-promotes tumorigenesis and to identify cancer genes that cooperate with Bub1 in tumor development. The information gained from these studies will improve our understanding of the mechanisms by which this key mitotic regulator maintains chromosomal stability and prevents cancer. We believe this information will ultimately lead to improved detection, prevention and treatment of cancer in humans.
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