The goals of this program are elucidation of the genetic changes that underlie tumorigenesis and determination of the molecular mechanisms by which these genetic changes cause cancer. A current focus of the program is the mechanisms by which the retinoblastoma (Rb/E2F) pathway suppresses cancer. Mutant mice deficient in individual and combinations of the Rb family of genes, pRb, p107, and p130, will be studied for tumorigenesis, overlapping functions in development, and interactions with other genes in the Rb/E2F pathway. In addition, the roles of the E2F proteins E2F-1 and E2F-3, which are primarily responsible for activation of transcription in the pathway, in tumorigenesis and development will be studied by combining mutations in these genes with those of the Rb family. Deregulation of either E2F-1 or E2F-3 is proapoptotic and their relative contributions to cell growth and cell death will be determined. The p53 dependence of their induction of cell death will be further characterized by crossing in mutations in p53 and/or pl9ARF. Both transcriptional profiling and SNP genomic analysis will be used to characterize the nature of tumors in the p16INK4a/tyrRas melanoma model. The frequency of melanomas in this model varies dramatically between genetic backgrounds. This offers the potential to identify modifier genes by genetic analysis. A new core facility is proposed which will provide both microarray for gene expression profiles and high throughput genetic analysis using SNPs that vary between inbred mouse strains. Loss of heterozygosity when combined with transcription profiles and tumor properties will define at a new and fundamental level tumor-host biology. A similar analysis will be done on tumors arising from mutations in the Rb/E2F pathway whose malignant potential varies dependent upon genetic backgrounds. The profiling technology will also be used to study new possibilities for dominant inhibition of gene expression based on RNA interference (RNAi) in mammalian cells and the relationship between activation of transcription by Oct-1, Oct-2 and OCA-B/Bob-1 and development in B cells.
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