Abstract |
Cell growth, subject to temporal and spatial constraints, is a highly regulated process controlled in response to internal and external growth signals. We are studying signalling pathways that control cell growth in the yeast Saccaromyces cerevisiae and in mammalian cells. Within the last years, we have discovered novel signalling pathways involving the yeast TOR1 and TOR2 proteins. The TORs are the targets of the immunosuppressive and anti-cancer drug rapamycin, and the founding members of the phosphatidylinositol kinase-related protein kinase (PIKK) family. TOR signalling patways control cell growth by positively regulating many anabolic processes including translation, transcription, and ribosome biogenesis, and by negatively regulating many catabolic processes such as protein and RNA degradation, all in response to nutrients. The TORs and TOR signalling pathways are structurally and functionally conserved in plants, flies, worms, and mammals. In higher eukaryotes, TOR regulates cell growth in conjunction with the insulin/PI3K signalling pathway, and thereby integrates nutrient and growth factor signals. Thus, the TOR signalling pathways play a central role in controlling cell growth. The goal of the proposed research is 1) to characterize futher two structurally and functionally distinct TOR signalling complexes, TORC1 and TORC2, which we recently identified in yeast and mammalian cells, 2) to identify novel TOR effector pathways and targets involved in ribosome biogenesis, mRNA degradation, and metabolism, and 3) to exploit information derived from yeast to identify and characterize TOR signalling pathways in mammalian cells. Dysfunction of signalling pathways controlling cell growth results in cells of altered size and, in turn, causes developmental errors and a wide variety of pathological conditions. Our findings may lead to novel drugs for the treatment of, for example, cancer, diabetes, immune disorders, obesity and ageing. |