CELLULAR PHARMACOLOGY OF RAPAMYCIN

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DESCRIPTION: Rapamycin is a bacterially-derived macrolide that is currently undergoing clinical and preclinical evaluations as an immunosuppressant and cancer chemotherapeutic agent. Both the immunosuppressive and anticancer properties of rapamycin are attributed to the inhibition of a signaling pathway required for the passage of proliferating cells from G1 into S phase. A pivotal step toward understanding the anti-proliferative mechanism of rapamycin was the identification of the protein whose function is inhibited when cells are exposed to this drug. The mammalian Target of Rapamycin (mTOR) is a member of a novel family of high molecular weight kinases termed phosphatidylinositol 3-kinase-related kinases (PIKKs). The members of the PIKK family play crucial roles in cell-cycle regulation and chromosome maintenance, and their dysfunction leads to disregulated growth, genomic instability, and cancer. The overall objectives of this proposal are to define the signaling pathway governed by mTOR, and to identify the cell-cycle-related parameters that determine sensitivity or resistance of transformed cells to the anti-proliferative effects of rapamycin. The preliminary studies offer biochemical and genetic evidence that mTOR regulates the translation of mRNAs whose protein products are needed to drive the cell through G1 and into S phase. The current project will extend this research through implementation of three specific aims: (1) to define the role of PHAS-1 in cell growth inhibition by rapamycin, (2) to elucidate upstream regulators of mTOR function in mitogen-stimulated cells, (3) to investigate the interactions of the mTOR-dependent signaling pathway with the cell-cycle control machinery in nontransformed and transformed cells. The completion of these aims may significantly advance ther knowledge of the cellular pharmacology of rapamycin, and will facilitate the development of novel antiproliferative agents targeted against mTOR itself or other components of the mTOR-dependent signaling pathway.