mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability.
In cycling cells, transcription of ribosomal RNA genes by RNA polymerase I (Pol I) is tightly coordinated with cell growth. Here, we show that the mammalian target of rapamycin (mTOR) regulates Pol I transcription by modulating the activity of TIF-IA, a regulatory factor that senses nutrient and growth-factor availability. Inhibition ... of mTOR signaling by rapamycin inactivates TIF-IA and impairs transcription-initiation complex formation. Moreover, rapamycin treatment leads to translocation of TIF-IA into the cytoplasm. Rapamycin-mediated inactivation of TIF-IA is caused by hypophosphorylation of Se 44 (S44) and hyperphosphorylation of Se 199 (S199). Phosphorylation at these sites affects TIF-IA activity in opposite ways, for example, phosphorylation of S44 activates and S199 inactivates TIF-IA. The results identify a new target formTOR-signaling pathways and elucidate the molecular mechanism underlying mTOR-dependent regulation of RNA synthesis.
Mesh Terms:
3T3 Cells, Amino Acid Substitution, Animals, Cell Division, Cell Line, Cell Nucleus, Humans, Mice, Mutagenesis, Site-Directed, Nucleic Acid Hybridization, Phosphates, Phosphorylation, Pol1 Transcription Initiation Complex Proteins, Protein Kinases, Protein Transport, RNA Polymerase I, RNA, Ribosomal, Signal Transduction, Sirolimus, Transcription Factors, Transcription, Genetic
3T3 Cells, Amino Acid Substitution, Animals, Cell Division, Cell Line, Cell Nucleus, Humans, Mice, Mutagenesis, Site-Directed, Nucleic Acid Hybridization, Phosphates, Phosphorylation, Pol1 Transcription Initiation Complex Proteins, Protein Kinases, Protein Transport, RNA Polymerase I, RNA, Ribosomal, Signal Transduction, Sirolimus, Transcription Factors, Transcription, Genetic
Genes Dev.
Date: Feb. 15, 2004
PubMed ID: 15004009
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