IDENTIFYING INHIBITORS OF THE APC/C USING YEAST MUTANTS

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DESCRIPTION: (Applicant's Description) The long term goals of this research is to use mutants of the yeast Saccharomyces cerevesiae as a sensitive detection system to deve1op anti-cancer drugs. Drugs such as taxo1, vinb1astine and vincristine are effective against certain type of tumors and have an increased spectrum of efficiency when used in combination therapy. The drugs have a common target in that they bind tubulin and inhibit microtubu1e function. In the absence of microtubule function, cells arrest in the cell cycle under the control of the spindle checkpoint. The ultimate target of the checkpoint is the anaphase-promoting complex or the APC/C. Most components of the APC/C are conserved from yeast to humans. I propose to use temperature sensitive APC/C mutants, enfeebled for APC/C function to screen for compounds that cause the mutants to die. Genetic analysis and phenotypic characterization will be used to show that the compounds affect the APC/C. The information gained from these studies will be used in future rational drug design to synthesize compounds that inhibit a fu1ly functional APC/C in both yeast and mammalian cells.