Cellular Consequences of Snf5 Tumor Suppressor Loss

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Aberrant expression of genes that regulate growth and differentiation is a critical component of oncogenic transformation. Biallelic inactivation of SNF5, a core component of the SWI/SNF chromatin remodeling complex, is an extremely potent, cancer-promoting event that occurs in the large majority of malignant rhabdoid tumors (MRT), an aggressive cancer of childhood. Our laboratory has developed a mouse model of MRT by eliminating both copies of SNF5. As in children, inactivation of Snf5 in mice leads to the extremely rapid onset of malignant cancers in 100% of mice at a median age of 11 weeks. We have now begun studying the molecular consequences of SNF5 loss in cells isolated from these Snf5 deficient mice. We have recently identified dramatic perturbations of cell cycle regulation, chromosomal stability and apoptosis following loss of Snf5 in primary fibroblasts. Further, we have demonstrated that inactivation of Snf5 leads to increased levels of p53, and that inactivation of p53 results in synergy with Snf5 loss for tumor formation in vivo. The proposed experiments are designed to reveal the mechanistic basis by which Snf5 affects cell cycle progression, determine the genetic pathways that underlie the tumor suppressor activity of Snf5, and to further elucidate the relationship between Snf5 and p53 tumor suppressors. We propose to utilize our model systems, combining data from loss of Snf5 in primary fibroblasts, with data from in vivo deletion of Snf5, to evaluate the function of the Snf5 tumor suppressor and determine how its loss leads to oncogenesis. Elucidating the basis for Snf5 tumor suppressor activity may ultimately lead to novel therapeutic treatments.