My long-term goal is to understand cell signaling mechanisms to control cell cycle progression in eukaryotic cells. Rapamycin is a potent immunosuppressive and anti-proliferation agent. It is highly effective in treating allograft rejection, autoimmune disorders, fungal infections and cancer. My studies established that Tor1p/Tor2p are the direct targets of rapamycin and led to understanding of the molecular mode of rapamycin action. The target of rapamycin protein or TOR in yeast and its human homolog FKBP12-rapamycin associated protein, FRAP, have recently been identified and shown to be a key regulator in a novel signaling pathway for cell growth, in particular, G1 cell-cycle progression. This pathway is conserved during evolution and delivers signals from growth factors, hormones, cytokines, nutrients and stresses to a cell-cycle checkpoint. The TOR protein family is conserved both structurally and functionally throughout the eukaryotic kingdom. They belong to the phosphatidylinositol kinase (PIK)-related kinase family and have protein a Ser/Thr kinase activity essential for the rapamycin- sensitive growth regulation. However, little is known about TOR protein family as a novel kinase, how its activity is regulated and what the rapamycin-sensitive TOR signaling pathway is composed of. Answering these questions is the next important task in the field, and is the central theme of this proposal. Budding yeast has thus far been a major driving force in the TOR field. This proposed research is aimed at dissecting the mechanisms of TOR signaling with yeast as a model. We will take advantage of all the powerful tools created by the integration of genetics, genomics and molecular biology in S. cerevisiae. Accomplishment of this research should further our general understanding of eukaryotic cell regulation and provide a rational basis for more effective and safer use of rapamycin as a therapeutic agent.
