The identification of tumor suppressor genes has led to new insights into the mechanisms of human cancer development. The normal functions of these genes often lie in the control of gene expression, especially in the realm of cell cycle control and cellular differentiation. Several recent studies have implicated aberrant activity of chromatin remodeling complexes in the development of human cancer. Mutations in the INI1/SNF5/BAF47 gene, a component of the SWI/SNF chromatin remodeling complex, occur in virtually all malignant rhabdoid tumors (MRTs). The SWI/SNF complex acts as a global transcriptional activator that alters nucleosome positioning on DMAvia an energy-dependent mechanism. During the previous funding period, we have determined that loss of SNF5 expression affects cell cycle regulation and replicative senescence through changes in P21WAF1/CIP1 and p16INK4A expression. However, we also found the loss of SNF5 did not globally inactivate DNA damage checkpoints in MRTs. We also developed a genetically engineered mouse model for MRT development that indicates that SNF5 loss does not inactivate the activities of the pRb family in MRT development. Our studies also suggest that MRTs may arise from a population of neural progenitor cells. Based on these studies, we hypothesize that SNF5 controls normal cell cycle arrest by recruitment of specific transcription factors to the promoters of specific cell cycle regulatory genes. Wefurther hypothesize that loss of SNF5 expression and the concomitant disruptjon of normal growth regulation during a narrow window of neural cell development promotes rhabdoid oncogenesis. To test this hypothesis, we propose 3 specific aims. In the first, we will investigate the mechanism of SNF5-induced growth arrest in MRT cell lines using RT-PCR arrays in our cell culture model. The second specific aim will identify downstream targets of SNF5 associated with MRT development using a combination of ChlP-chjp and gene expression array analyses. In the third specific aim, we will determine the role of Snf5 inactivation in neural cell development and malignant rhabdoid tumorigenesis using novel genetically engineered mouse models. The dissection of the role SNF5 plays in MRT development will broaden our understanding of its normal biological and biochemical activities, provide new insights into the function of the SWI/SNF complex in cell cycle regulation and normal development and identify new avenues of treatment for this highly aggressive tumor.
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