mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability (original) (raw)

1. Christine Mayer1,
2. Jian Zhao1,
3. Xuejun Yuan, and
4. Ingrid Grummt2
5. Division of Molecular Biology of the Cell II, German Cancer Research Center, D-69120 Heidelberg, Germany

Abstract

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 Ser 44 (S44) and hyperphosphorylation of Ser 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 for mTOR-signaling pathways and elucidate the molecular mechanism underlying mTOR-dependent regulation of rRNA synthesis.

• RNA polymerase I
• TIF-IA
• mTOR
• transcription
• phosphorylation
• PP2A

Footnotes

• Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.285504.

• ↵1 These authors conributed equally to this work.

• ↵2 Corresponding author.
  ↵2 E-MAIL I.Grummt{at}DKFZ-Heidelberg.de; FAX 0049-6221-423404.

• • Accepted January 16, 2004.
  • Received September 16, 2003.

• Cold Spring Harbor Laboratory Press

•