TOR kinase homologs function in a signal transduction pathway that is conserved from yeast to mammals

Rapamycin is a natural product with potent antifungal and immunosuppressive activities. Rapamycin binds to the FKBP12 prolyl isomerase, and the result ing protein-drug complex inhibits the TOR kinase homologs. Both the FKBP12 and the TOR proteins are highly conserved from yeast to man, and genetic an d biochemical studies reveal that these proteins are the targets of rapamyc in in vivo. Treatment of yeast or mammalian cells with rapamycin inhibits t ranslational initiation of a subset of mRNAs and dramatically represses rib osomal mRNA and tRNA transcription. Furthermore, rapamycin exposure blocks cell cycle progression in the early G1 phase of the cell cycle, driving cel ls into a G0 state and, ultimately, triggering autophagy. Recent findings r eveal that the upstream factors regulating the TOR signaling cascade are in volved in detecting amino acids, nutrients, or growth factors. These findin gs indicate that the TOR proteins function in a signal transduction pathway that coordinates nutritional and mitogenic signals to control protein bios ynthesis and degradation. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.