Abnormalities of chromosome number are a hallmark of the vast majority of human cancers. A subset of these cancers is associated with mutations in genes encoding for mitotic checkpoint proteins such as BUB1, BUBR1 or MAD2. These checkpoint proteins are part of an intricate regulatory mechanism that prevents aneuploidy by delaying sister chromatid separation until all chromosomes are properly attached to the mitotic spindle apparatus and aligned at the metaphase plate. Therefore, they may contribute to chromosomal instability when defective. Initial attempts to study the possible connection between mitotic checkpoint dysfunction and disease by classical gene knockout approaches in the mouse have been hampered by the early embryonic death of mice lacking BUB3 or MAD2. In an effort to generate a mouse model for mitotic checkpoint dysfunction, we generated mice with a hypomorphic BUBR1 allele (BUBR1 hypo). Mice homozygous for the hypomorphic BUBR1 allele are viable despite a strong reduction of their BUBR 1 protein levels. Preliminary data demonstrate the formation of histological confirmed tumors in several homozygous mutant mice. Detailed analyses of early-passage fibroblasts derived from 13.5-day-old homozygous mutant embryos show that the diminished BUBR1 expression causes premature sister chromatid separation and aneuploidy. In this project we have proposed experiments to elucidate the biological role of BUBR1, and the mechanisms by which BUBR1 dysfunction may lead to malignant cell transformation.
In specific aim one, we will use inducible BUBR1 knockout cell lines to establish the in vivo role of BUBR1 and its critical functional domains.
In specific aim two, we will determine the rates of spontaneous and carcinogen-induced tumor formation in hypomorphic BUBR1 mice, and investigate the effect of BUBR1 dysfunction on chromosomal instability at the organismal level.
In specific aim three, we will identify the tumorigenic pathways able to cooperate with BUBR1 in the formation of tumors. Together these studies will provide valuable insights into the normal function of BUBR1 and help to elucidate how errors in the control of the mitotic spindle assembly checkpoint lead to increased susceptibility to tumor formation.
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