Collections > Electronic Theses and Dissertations > Characterization of the Tumor Suppressor Capabilities of SWI/SNF Complex Member BAF155 in Cancer Cell Lines and Cooperation of SNF5 and p53 Pathways
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Tumorigenesis is often attributed to aberrant gene expression leading to altered cell cycle control, abnormal differentiation, and inefficient DNA repair. The activity of chromatin remodeling complexes is vital to maintaining proper control of such gene expression. The SWI/SNF chromatin remodeling complex is responsible for remodeling up to 6% of the human genome, with many of those genes known to be associated with cell cycle control. Therefore, impaired or defective activity of this complex could encourage tumor development. Little is known, however, of how SWI/SNF accomplishes those tasks and the differing roles of the distinct members of the complex. Composed of more than ten members, several components are now known to have tumor suppressive roles, as their absence correlates with tumorigenic phenotypes. We propose also that core SWI/SNF member, BAF155, is also likely to be involved in controlling tumor progression. I have utilized two carcinoma cell lines lacking endogenous BAF155 expression to explore the role of BAF155 in cell cycle control and found that re-expression of BAF155 in these cells leads to a reduction in cell number due to replicative senescence. These BAF155 null cells were also found to be sensitive to Rb-mediated cell cycle arrest. This data imply a role for SWI/SNF member BAF155 in cell cycle control and in turn, tumor progression. To determine the pathways in which SWI/SNF core member SNF5 suppresses tumor progression we utilized mouse models to explore the relationship between the p53 pathway and that of SNF5/INI1 in controlling tumor progression and found that while double heterozygous mice still develop p53 wild type SNF5 null rhabdoid tumors similar to their SNF5+/- littermates, SNF5 loss of heterozygosity is accelerated on a p53+/- background leading to reduced latency and increased penetrance of p53 null SNF5 null rhabdoid tumors in alternate anatomical locations as well as the formation of lymphomas. The resulting rhabdoid tumors were found to express a pattern of markers similar to the human rhabdoid phenotype, solidifying this model as an appropriate recapitulation of human rhabdoid tumors. These studies shed light on the specific roles of SWI/SNF chromatin remodeling complex in tumor suppression.