The identification of human tumor suppressor genes has led to new insights into the mechanisms of human cancer development. Isolation of the first tumor suppressor genes resulted from studies of pediatric malignancies including the RB and WT1 genes. In the case of rhabdoid tumors, frequent LOH on chromosome 22 has led to the discovery of a novel tumor suppressor gene designated INI1/hSNF5/BAF47. This gene codes for the human homolog of the yeast SNF5 gene, a member of the SWI/SNF chromatin remodeling complex. The SWI/SNF complex acts as a global transcriptional activator that alters nucleosome positioning on DNA in an energy-dependent manner. The role of altered chromatin remodeling during neoplastic progression has gained increasing recognition over the last several years. Recent reports strongly support the notion that INI1/hSNF5/BAF47 acts as a prototypical tumor suppressor gene. These include demonstrations that mutations and deletions occur in rhabdoid tumors, choroid plexus tumors and rhabdomyosarcomas, that LOH drives the removal of the remaining wild-type allele, that families carrying germline mutations develop these tumors at a high frequency and that germline inactivation in mice leads to the development of rhabdoid-like tumors. We have found that re- expression of SNF5 in rhabdoid tumor cell lines causes growth inhibition accompanied by a dramatic rise in p16INK4A protein levels. Based on these preliminary studies as well as the known functions of the SWI/SNF complex and other relevant scientific literature, we hypothesize that alterations in the INI1/SNF5 component of the hSWI/SNF complex contribute to human tumor development by blocking the induction of p16INK4A and disrupting normal cell cycle control. In this application, we will test this hypothesis by determining the mechanism by which loss of activity of this gene affects p16INK4A protein levels using biochemical, biological and animal model assays.
In Specific Aim number 1, we will determine the cell cycle control pathways regulated by INI1/SNF5 and the relevant domains for these activities.
In Specific Aim number 2, we will ascertain the biochemical effects of INI1/SNF5 loss on SWI/SNF function and whether the protein directly interacts with the p16INK4A promoter.
In Specific Aim number 3, we will develop a mouse model for choroid plexus carcinomas by crossing TAg transgenic mice to SNF5+/- mice. The characterization of the INI1/SNF5 gene role in regulation of gene expression will broaden our understanding of tumor suppressor gene functions, provide important clues about the role of chromatin remodeling complexes in normal and neoplastic development and impact upon treatment and detection of these devastating pediatric cancers.
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