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 resulting protein-drug complex inhibits the TOR kinase homologs. Both the FKBP12 and the TOR proteins are highly conserved from yeast to man, and genetic and biochemical studies reveal that these proteins are the targets of rapamycin in vivo. Treatment of yeast or mammalian cells with rapamycin inhibits translational initiation of a subset of mRNAs and dramatically represses ribosomal mRNA and tRNA transcription. Furthermore, rapamycin exposure blocks cell cycle progression in the early G1 phase of the cell cycle, driving cells into a G0 state and, ultimately, triggering autophagy. Recent findings reveal that the upstream factors regulating the TOR signaling cascade are involved in detecting amino acids, nutrients, or growth factors. These findings indicate that the TOR proteins function in a signal transduction pathway that coordinates nutritional and mitogenic signals to control protein biosynthesis and degradation.
Cutler
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NS
Department of Genetics, Duke University Medical Center, Durham, NC 27710, USA.
Heitman
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Cardenas
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ME
D000818:Animals; D029721:Drosophila Proteins; D006801:Humans; D020104:Immunophilins / Q000235:genetics / Q000378:metabolism*; D008322:Mammals; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins
D029721:Drosophila Proteins; D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases; C080148:tor protein, Drosophila; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins; D019696:Peptidylprolyl Isomerase; D020123:Sirolimus