Rapamycin induces the G0 program of transcriptional repression in yeast by interfering with the TOR signaling pathway.
The macrolide antibiotic rapamycin inhibits cellular proliferation by interfering with the highly conserved TOR (for target of rapamycin) signaling pathway. Growth arrest of budding yeast cells treated with rapamycin is followed by the program of molecular events that characterizes entry into G0 (stationary phase), including the induction of polymerase (Pol) II genes typically expressed only in G0. Normally, progression into G0 is characterized by transcriptional repression of the Pol I and III genes. Here, we show that rapamycin treatment also causes the transcriptional repression of Pol I and III genes. The down-regulation of Pol III transcription is TOR dependent. While it coincides with translational repression by rapamycin, transcriptional repression is due in part to a translation-independent effect that is evident in extracts from a conditional tor2 mutant. Biochemical experiments reveal that RNA Pol III and probably transcription initiation factor TFIIIB are targets of repression by rapamycin. In view of previous evidence that TFIIIB and Pol III are inhibited when protein phosphatase 2A (PP2A) function is impaired, and that PP2A is a component of the TOR pathway, our results suggest that TOR signaling regulates Pol I and Pol III transcription in response to nutrient growth signals.
Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.
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Zaragoza
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Ghavidel
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Heitman
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Schultz
D000935:Antifungal Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D016193:G1 Phase; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011090:Polyenes / Q000494:pharmacology*; D014176:Protein Biosynthesis; D012320:RNA Polymerase III / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus; D013696:Temperature; D014158:Transcription, Genetic / Q000187:drug effects
D000935:Antifungal Agents; D018797:Cell Cycle Proteins; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011090:Polyenes; D012320:RNA Polymerase III; D029701:Saccharomyces cerevisiae Proteins; D020123:Sirolimus; C081135:TOR2 protein, S cerevisiae