Raparnycin is a potent immunosuppressive antibiotic currently being used for kidney transplants. It is also under clinical trials for transplantation of other organs as well as treatment of leukemia. When complexed with its immunophilin receptor FKBP12, rapamycin binds to and inhibits Tor, the target of raparnycin protein, an intracellular signaling kinase essential for cell growth and functions. However, the overall biological functions of Tor remain poorly understood. Our long-term goal is to understand the cellular functions of Tor and how rapamycin interferes with different aspects of Tor functions. Tor is highly conserved throughout eukaryotic kingdom. Thus, study of Tor in yeast should provide new important insights into the mechanism of Tor signaling. This knowledge should also contribute to the overall understanding of the basic control of cell growth and proliferation, and help evaluate additional benefits as well as potential side effects of rapamycin as a transplantation medicine. In this proposal, we will examine several new aspects of Tor functions. Specifically, we will examine the mechanism of signaling by Tor leading to control of transcription in response to extracellular and intracellular cues. Accomplishment of these research objectives may have significant implications in transplantation medicine as well as understanding and treatment of metabolic disorders, cancer and fungal infection.
