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Identifying Inhibitors of the APC/C Using Yeast Mutants

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The long-term goals of this research are to use mutants of the yeast Saccharomyces cerevisiae to develop novel anti-cancer drugs. The focus of the research will be the spindle checkpoint, which arrests cells in mitosis in response to spindle and microtubule perturbation. Tubulin is a validated target for anti-cancer chemotherapy. A number of natural products, such as taxol, vinblastine and vincristine are effective against a broad spectrum of tumors when used individually or in combination therapy. The drugs have a common mechanism of action; they modulate tubulin polymerization into microtubuies, which activates the spindle checkpoint. The target of the spindle checkpoint is Cdc20, an accessory factor that delivers substrates to the anaphase-promoting complex (APC/C) for ubiquitination and destruction. We have generated strains of yeast defective for APC/C and Cdc20 function and propose to continue screening for compounds that specifically inhibit APCIC activity. We propose to further characterize the six compounds that we haven already identified and to improve their effectiveness using rational drug design. We will expand the analysis to determine if they affect APC/C function and mitosis in cultured human cells. We will prepare extracts from Xenopus oocytes and HeLa cells to determine which step of APC/C activity is affected. We will use ordered arrays of site directed mutants to perform systematic genetic analysis and identify synthetic lethal interactions between a spindle checkpoint mutant, bub3, and all mutants that lack non-essential genes. This will identify possible cellular targets for compounds identified in a bub3 screen by the Seattle Project. We will express the proteins encoded by the interacting genes and determine if they bind the compounds.
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