CHROMATIN TARGETS FOR CANCER THERAPY

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DESCRIPTION: (Applicant's Description) Expression of the adenovirus ElA oncoprotein in budding yeast has provided a useful model for uncovering novel pathways involved in oncoprotein action. Remarkably, multiprotein complexes (SWI/SNF and HAT complexes) that mediate chromatin remodeling and transcriptional regulation are targeted by EIA, leading to the strong prediction that disruption their human counterparts is important in the development of cancer. Indeed, there is evidence from human systems that the development of cancer is associated with loss or disregulation of genes encoding components of several SWI/SNF and HAT complexes. Given the clear role of "chromatin dynamics" in cellular regulation, and its genetic involvement in oncogenesis, the pathways which control chromatin function may contain useful targets for anti-cancer drug therapy. This proposal seeks to extend previous work on oncogenesis-related pathways in yeast, and to identify novel compounds with anti-cancer therapeutic potential. Yeast strains with defined defects in chromatin remodeling functions will be subjected to high throughput screens of two libraries: The "Diversity Set" of approximately 2000 compounds from the National Cancer Institute's Developmental Therapeutics Program, and a library of approximately 6000 ethanolic botanical extracts available through the Markey Center for Cell Signaling at the University of Virginia. The proven utility of Saccharomyces cerevisiae for illuminating novel oncogenesis-related pathways will allow genetic dissection of the action of novel lead compounds from the drug screens. Lead compounds will be tested further in mammalian cell culture systems to examine their potential as therapeutic agents, and their specific effects on mammalian chromatin dynamics.