The ultimate goal of this program is to elucidate the molecular nature of processes controlling human cancer in order to further its prevention, diagnosis and treatment. The function of tumor suppressor genes Rb and related genes p107 and p130, p53, and Wilms' WTI in normal physiology and in suppressing the development of tumors will be analyzed using gene targeting methods to generate mutant mice. The Rb protein interacts with the E2F family of transcription factors in controlling cell division. These types of interactions will be studied both by generating mouse strains deficient in the E2F-2 and E2F-3 proteins and by analyzing the biochemistry of cell cycle control using cell lines established from these and other strains. The WT1 protein binds DNA in a sequence-specific fashion and transcription of genes critical for normal kidney cell growth and development. Proteins which interact directly with the WT1 protein in mediating its effects on suppressing tumor growth will be sought. In addition, genes regulated by WT1 will be identified. The WT2 locus also suppresses development of kidney tumors and the gene responsible for this activity will be identified. Loss of p53 activity from a tumor cell renders it multidrug resistant. The relationship between p53 status and tumor cell phenotype will be further investigated. The tumor suppressor protein Rb, p53 and WT1 as well as the oncogene Myc all either bind DNA in a sequence-specific fashion or are part of a complex that has this property. The mechanisms by which these proteins as well as the Oct-1 and Oct-2 transcription factors regulate initiation of transcription will be investigated, both in vitro and in vivo. The unique function of Oct-1 and Oct-2 proteins in development of B cells will be analyzed to identify the nature of protein-protein interactions which determine this specificity. Finally, a method to design novel transcription factors to regulate specific endogenous genes in a dominant fashion will be tested.
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