The mitotic checkpoint describes molecular controls that monitor chromosome segregation, a process that ensures the faithful transfer of a cell's genome to its progeny. Should any of these steps fail, the mitotic checkpoint triggers a cell cycle arrest to provide additional time to complete the process before cell division. Arguably more important to tumorigenesis, but largely unexplored, is a second function of the mitotic checkpoint- inducing cell death when division occurs without proper chromosome segregation. Recently, the mitotic checkpoint has come under increased scrutiny because many cancer cells show chromosomal aneuploidy, at least some of which can be explained by a genetically dominant chromosome instability (GIN) phenotype. This chromosome instability may in fact be acting early in tumorigenesis to promote the rapid loss and gain of tumor suppressors and proto-oncogenes, respectively. Taken together, these findings suggest a critical link between the mitotic checkpoint and cancer pathways. This is a proposal to decipher the mechanisms underlying the second function of the mitotic checkpoint, that of killing cells which undergo abnormal chromosome segregation. Preliminary data support the hypothesis that cells showing abnormal chromosome segregation are killed in a manner dependent on signaling from two mitotic checkpoint proteins, BUB1 and MAD3L, to the tumor suppressor p53. We want to determine how BUB 1 and MAD3L, which appear to monitor successive phases of chromosome segregation, signal failures and whether both of these signals act through p53 stabilization. Finally, we will develop murine models that test the consequences of defects in the mitotic checkpoint on tumorigenesis, as well as develop models to further decipher the biochemical pathways between the checkpoint signaling molecules and p53. We anticipate that these studies will address an important hypothesis for the generation of cancers and contribute to our understanding and prevention of these diseases.
