STRUCTURE/FUNCTION OF THE TARGETS OF RAPAMYCIN--THE

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Rapamycin is a natural product with anti-microbial, immunosuppressive, and anti-neoplastic activities via its ability to inhibit signal transduction. In both yeast and mammalian cells, rapamycin action is mediated by association with the peptidyl proIy1 isomerase, FKBP12. The FKBP12-rapamycin complex inhibits G1 to 5 phase cell cycle progression, but the mechanisms of cell cycle arrest are unknown. Genetic studies in yeast first implicated the T0R1 and T0R2 gene products as targets of the FKBP12-rapamycin complex. Recently, a mammalian TOR homolog (mTOR) has been identified. The highest degree of identity resides in a carboxy terminal domain with homology to lipid and protein kinases. mTOR autophosphorylates, and this activity is inhibited by FKBP12-rapamycin, but only one other candidate substrate (PHAS-1) has been identified. The TOR proteins have three known functions. One, shared by TOR1 and TOR2, is required for signaling translation initiation and G1 cell cycle progression. This function is conserved in mammalian cells and leads to activation of p70s6k. The second function of TOR2, is the control, via the RH01 and RH02 GTPases, of polarized distribution of the actin cytoskeleton during the cell cycle. Finally, a role for mTOR in preventing apoptosis has been suggested by studies in which rapamycin accelerates apoptosis in cancer cells. However, the precise roles of the TOR proteins in these functions are not yet well understood. The candidate has identified a novel toxic domain of the TOR proteins and proposes to identify effectors of the TOR proteins in yeast and mammalian cells and to study the mechanisms by which the TOR proteins regulate cell cycle progression and apoptosis. Such studies should provide information on the mechanisms of action of the novel TOR inhibitor rapamycin and thereby provide a sound biochemical basis for further analysis of rapamycin and other TOR inhibitors as novel chemotherapy agents.