A F Shamji1, F G Kuruvilla, S L Schreiber. 1. Howard Hughes Medical Institute, Center for Genomics Research, Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
Abstract
BACKGROUND: In all organisms, nutrients are primary regulators of signaling pathways that control transcription. In Saccharomyces cerevisiae, the Tor proteins regulate the transcription of genes sensitive to the quality of available nitrogen and carbon sources. Formation of a ternary complex of the immunosuppressant rapamycin, its immunophilin receptor Fpr1p and Tor1p or Tor2p results in the nuclear import of several nutrient- and stress-responsive transcription factors. RESULTS: We show that treating yeast cells with rapamycin results in a broader modulation of functionally related gene sets than previously understood. Using chemical epistasis and vector-based global expression analyses, we partition the transcriptional program induced by rapamycin among five effectors (TAP42, MKS1, URE2, GLN3, GAT1) of the Tor proteins, and identify how the quality of carbon and nitrogen sources impinge upon components of the program. Biochemical data measuring Ure2p phosphorylation coupled with the partition analysis indicate that there are distinct signaling branches downstream of the Tor proteins. CONCLUSIONS: Whole-genome transcription profiling reveals a striking similarity between shifting to low-quality carbon or nitrogen sources and treatment with rapamycin. These data suggest that the Tor proteins are central sensors of the quality of carbon and nitrogen sources. Depending on which nutrient is limited in quality, the Tor proteins can modulate a given pathway differentially. Integrating the partition analysis of the transcriptional program of rapamycin with the biochemical data, we propose a novel architecture of Tor protein signaling and of the nutrient-response network, including the identification of carbon discrimination and nitrogen discrimination pathways.
BACKGROUND: In all organisms, nutrients are primary regulators of signaling pathways that control transcription. In Saccharomyces cerevisiae, the Tor proteins regulate the transcription of genes sensitive to the quality of available nitrogen and carbon sources. Formation of a ternary complex of the immunosuppressant rapamycin, its immunophilin receptor Fpr1p and Tor1p or Tor2p results in the nuclear import of several nutrient- and stress-responsive transcription factors. RESULTS: We show that treating yeast cells with rapamycin results in a broader modulation of functionally related gene sets than previously understood. Using chemical epistasis and vector-based global expression analyses, we partition the transcriptional program induced by rapamycin among five effectors (TAP42, MKS1, URE2, GLN3, GAT1) of the Tor proteins, and identify how the quality of carbon and nitrogen sources impinge upon components of the program. Biochemical data measuring Ure2p phosphorylation coupled with the partition analysis indicate that there are distinct signaling branches downstream of the Tor proteins. CONCLUSIONS: Whole-genome transcription profiling reveals a striking similarity between shifting to low-quality carbon or nitrogen sources and treatment with rapamycin. These data suggest that the Tor proteins are central sensors of the quality of carbon and nitrogen sources. Depending on which nutrient is limited in quality, the Tor proteins can modulate a given pathway differentially. Integrating the partition analysis of the transcriptional program of rapamycin with the biochemical data, we propose a novel architecture of Tor protein signaling and of the nutrient-response network, including the identification of carbon discrimination and nitrogen discrimination pathways.