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.
Mayer
Christine
C
Division of Molecular Biology of the Cell II, German Cancer Research Center, D-69120 Heidelberg, Germany.
Zhao
Jian
J
Yuan
Xuejun
X
Grummt
Ingrid
I
D016475:3T3 Cells; D019943:Amino Acid Substitution; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009693:Nucleic Acid Hybridization; D010710:Phosphates / Q000378:metabolism; D010766:Phosphorylation; D035463:Pol1 Transcription Initiation Complex Proteins; D011494:Protein Kinases / Q000378:metabolism*; D021381:Protein Transport; D012318:RNA Polymerase I / Q000378:metabolism; D012335:RNA, Ribosomal / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
D010710:Phosphates; D035463:Pol1 Transcription Initiation Complex Proteins; D012335:RNA, Ribosomal; C428423:RRN3 protein, human; D014157:Transcription Factors; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D012318:RNA Polymerase I; D020123:Sirolimus