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Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases

Oncogene volume 25, pages 6384–6391 (2006)Cite this article

Abstract

The target of rapamycin (TOR) signal-transduction pathway is an important mechanism by which eucaryotic cells adjust their protein biosynthetic capacity to nutrient availability. Both in yeast and in mammals, the TOR pathway regulates the synthesis of ribosomal components, including transcription and processing of pre-rRNA, expression of ribosomal proteins and the synthesis of 5S rRNA. Expression of the genes encoding the numerous constituents of ribosomes requires transcription by all three classes of nuclear RNA polymerases. In this review, we summarize recent advances in understanding the interplay among nutrient availability, transcriptional control and ribosome biogenesis. We focus on transcription in response to nutrients, detailing the relevant downstream targets of TOR in yeast and mammals. The critical role of TOR in linking environmental queues to ribosome biogenesis provides an efficient means by which cells alter their overall protein biosynthetic capacity.

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References

  • Barth-Baus D, Stratton CA, Parrott L, Myerson H, Meyuhas O, Templeton DJ et al. (2002). S6 phosphorylation-independent pathways regulate translation of 5′-terminal oligopyrimidine tract-containing mRNAs in differentiating hematopoietic cells. Nucl Acids Res 30: 1919–1928.

    Article  CAS  Google Scholar 

  • Beck T, Hall MN . (1999). The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors. Nature 402: 689–692.

    Article  CAS  Google Scholar 

  • Bodem J, Dobreva G, Hoffmann-Rohrer U, Iben S, Zentgraf H, Delius H et al. (2000). TIF-IA, the factor mediating growth-dependent control of ribosomal RNA synthesis, is the mammalian homolog of yeast Rrn3p. EMBO Rep 1: 171–175.

    Article  CAS  Google Scholar 

  • Buttgereit D, Pflugfelder G, Grummt I . (1985). Growth-dependent regulation of rRNA synthesis is mediated by a transcription initiation factor (TIF-IA). Nucleic Acids Res 13: 8165–8180.

    Article  CAS  Google Scholar 

  • Cardenas ME, Cutler NS, Lorenz MC, Di Como CJ, Heitman J . (1999). The TOR signaling cascade regulates gene expression in response to nutrients. Genes Dev 13: 3271–3279.

    Article  CAS  Google Scholar 

  • Cavanaugh AH, Hirschler-Laszkiewicz I, Hu Q, Dundr M, Smink T, Misteli T et al. (2002). Rrn3 phosphorylation is a regulatory checkpoint for ribosome biogenesis. J Biol Chem 277: 27423–27432.

    Article  CAS  Google Scholar 

  • Claypool JA, French SL, Johzuka K, Eliason K, Vu L, Dodd JA et al. (2003). Tor pathway regulates Rrn3p-dependent recruitment of yeast RNA polymerase I to the promoter but does not participate in alteration of the number of active genes. Mol Cell Biol 15: 946–956.

    Article  Google Scholar 

  • Di Como CJ, Arndt KT . (1996). Nutrients, via the Tor proteins, stimulate the association of Tap42 with type 2A phosphatases. Genes Dev 10: 1904–1916.

    Article  CAS  Google Scholar 

  • Ferrari S, Manfredini R, Tagliafico E, Rossi E, Donelli A, Torelli G et al. (1990). Noncoordinated expression of S6, S11, and S14 ribosomal protein genes in leukemic blast cells. Cancer Res 50: 5825–5828.

    CAS  PubMed  Google Scholar 

  • Gingras AC, Raught B, Sonenberg N . (2001). Regulation of translation initiation by FRAP/mTOR. Genes Dev 15: 807–826.

    Article  CAS  Google Scholar 

  • Grummt I . (2003). Life on a planet of its own: regulation of RNA polymerase I transcription in the nucleolus. Genes Dev 17: 1691–1702.

    Article  CAS  Google Scholar 

  • Grummt I . (2006). Actin and myosin as transcription factors. Curr Opin Genet Dev 16: 191–196.

    Article  CAS  Google Scholar 

  • Grummt I, Smith VA, Grummt F . (1976). Amino acid starvation affects the initiation frequency of nucleolar RNA polymerase. Cell 7: 439–445.

    Article  CAS  Google Scholar 

  • Gstaiger M, Luke B, Hess D, Oakeley EJ, Wirbelauer C, Blondel M et al. (2003). Control of nutrient-sensitive transcription programs by the unconventional prefoldin URI. Science 302: 1208–1212.

    Article  CAS  Google Scholar 

  • Hannan KM, Brandenburger Y, Jenkins A, Sharkey K, Cavanaugh A, Rothblum L et al. (2003). mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF. Mol Cell Biol 23: 8862–8877.

    Article  CAS  Google Scholar 

  • Hara K, Yonezawa K, Weng Q-P, Kozlowski MT, Belham C, Avruch J . (1998). Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem 273: 14484–14494.

    Article  CAS  Google Scholar 

  • Hardwick JS, Kuruvilla FG, Tong JK, Shamji AF, Schreiber SL . (1999). Rapamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins. Proc Natl Acad Sci USA 96: 14866–14870.

    Article  CAS  Google Scholar 

  • Holland EC, Sonenberg N, Pandolfi PP, Thomas G . (2004). Signaling control of mRNA translation in cancer pathogenesis. Oncogene 23: 3138–3144.

    Article  CAS  Google Scholar 

  • Humphrey EL, Shamji AF, Bernstein BE, Schreiber SL . (2004). Rpd3p relocation mediates a transcriptional response to rapamycin in yeast. Chem Biol 11: 295–299.

    Article  CAS  Google Scholar 

  • Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A et al. (2004). Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6: 1122–1128.

    Article  CAS  Google Scholar 

  • James MJ, Zomerdijk JC . (2004). Phosphatidylinositol 3-kinase and mTOR signaling pathways regulate RNA polymerase I transcription in response to IGF-1 and nutrients. J Biol Chem 279: 8911–8918.

    Article  CAS  Google Scholar 

  • Jefferies HB, Fumagalli S, Dennis PB, Reinhard C, Pearson RB, Thomas G . (1997). Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k. EMBO J 16: 3693–3704.

    Article  CAS  Google Scholar 

  • Jiang Y, Broach JR . (1999). Tor proteins and protein phosphatase 2A reciprocally regulate Tap42 in controlling cell growth in yeast. EMBO J 18: 2782–2792.

    Article  CAS  Google Scholar 

  • Jorgensen P, Rupes I, Sharom JR, Schneper L, Brouch JR, Tyers M . (2004). A dynamic transcriptional network communicates growth potential to ribosome synthesis and critical cell size. Genes Dev 18: 2491–2505.

    Article  CAS  Google Scholar 

  • Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H et al. (2003). GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 11: 895–904.

    Article  CAS  Google Scholar 

  • Kimball SR, Shantz LM, Horetsky RL, Jefferson LS . (1999). Leucine regulates translation of specific mRNAs in L6 myoblasts through mTOR-mediated changes in availability of eIF4E and phosphorylation of ribosomal protein S6. J Biol Chem 274: 11647–11652.

    Article  CAS  Google Scholar 

  • Laferté A, Favry E, Sentenac A, Riva M, Carles C, Chedin C . (2006). The transcriptional activity of RNA polymerase I is a key determinant for the level of all ribosome components. Genes Dev 20: 2030–2040.

    Article  Google Scholar 

  • Mahajan PB . (1994). Modulation of transcription of rRNA genes by rapamycin. Int J Immunopharmacol 16: 711–721.

    Article  CAS  Google Scholar 

  • Marion RM, Regev A, Segal E, Barash Y, Koller D, Friedman N et al. (2004). Sfp1 is a stress- and nutrient-sensitive regulator of ribosomal protein gene expression. Proc Natl Acad Sci USA 101: 14315–14322.

    Article  CAS  Google Scholar 

  • Martin DE, Soulard A, Hall MN . (2004). TOR regulates ribosomal protein gene expression via PKA and the Forkhead transcription factor FHL. Cell 119: 969–979.

    Article  CAS  Google Scholar 

  • Mayer C, Zhao J, Yuan X, Grummt I . (2004). mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. Genes Dev 18: 423–434.

    Article  CAS  Google Scholar 

  • Miller G, Panov KI, Friedrich JK, Trinkle-Mulcahy L, Lamond AI, Zomerdijk JC . (2001). hRRN3 Is essential in the SL1-mediated recruitment of RNA polymerase I to rRNA gene promoters. EMBO J 20: 1373–1382.

    Article  CAS  Google Scholar 

  • Moorefield B, Greene EA, Reeder RH . (2000). RNA polymerase I transcription factor Rrn3 is functionally conserved between yeast and human. Proc Natl Acad Sci USA 97: 4724–4729.

    Article  CAS  Google Scholar 

  • Nader GA, McLoughlin TJ, Esser KA . (2005). mTOR function in skeletal muscle hypertrophy: increased ribosomal RNA via cell cycle regulators. Am J Physiol Cell Physiol 289: C1457–C1465.

    Article  CAS  Google Scholar 

  • Naora H, Takai I, Adachi M, Naora H . (1998). Altered cellular responses by varying expression of a ribosomal protein gene: sequential coordination of enhancement and suppression of ribosomal protein S3a gene expression induces apoptosis. J Cell Biol 141: 741–753.

    Article  CAS  Google Scholar 

  • Pende M, Um SH, Mieulet V, Sticker M, Goss VL, Mestan J et al. (2004). S6K1(−/−)/S6K2(−/−) mice exhibit perinatal lethality and rapamycin-sensitive 5′-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol 24: 3112–3124.

    Article  CAS  Google Scholar 

  • Powers T, Walter P . (1999). Regulation of ribosome biogenesis by the rapamycin-sensitive TOR-signaling pathway in Saccharomyces cerevisiae. Mol Biol Cell 10: 987–1000.

    Article  CAS  Google Scholar 

  • Preiss T, Baron-Benhamou J, Ansorge W, Hentze MW . (2003). Homodirectional changes in transcriptome composition and mRNA translation induced by rapamycin and heat shock. Nat Struct Biol 10: 1039–1047.

    Article  CAS  Google Scholar 

  • Proud CG . (2002). Regulation of mammalian translation factors by nutrients. Eur J Biochem 269: 5338–5349.

    Article  CAS  Google Scholar 

  • Rohde J, Cardenas ME . (2003). The tor pathway regulates gene expression by linking nutrient sensing to histone acetylation. Mol Cell Biol 23: 629–635.

    Article  CAS  Google Scholar 

  • Rohde J, Heitman J, Cardenas ME . (2001). The TOR kinases link nutrient sensing to cell growth. J Biol Chem 276: 9583–9586.

    Article  CAS  Google Scholar 

  • Rudra D, Zhao Y, Warner JR . (2005). Central role of Ifh1p-Fhl1p interaction in the synthesis of yeast ribosomal proteins. EMBO J 24: 533–542.

    Article  CAS  Google Scholar 

  • Ruggero D, Pandolfi PP . (2003). Does the ribosome translate cancer? Nat Rev Cancer 3: 179–192.

    Article  CAS  Google Scholar 

  • Schawalder SB, Kabani M, Howald I, Choudhury U, Werner M, Shore D . (2004). Growth-regulated recruitment of the essential yeast ribosomal protein gene activator Ifh1. Nature 432: 1058–1061.

    Article  CAS  Google Scholar 

  • Schmelzle T, Hall MN . (2000). TOR, a central controller of cell growth. Cell 103: 253–262.

    Article  CAS  Google Scholar 

  • Tang H, Hornstein E, Stolovich M, Levy G, Livingstone M, Templeton D et al. (2001). Amino acid-induced translation of TOP mRNAs is fully dependent on phosphatidylinositol 3-kinase-mediated signaling, is partially inhibited by rapamycin, and is independent of S6K1 and rpS6 phosphorylation. Mol Cell Biol 21: 8671–8683.

    Article  CAS  Google Scholar 

  • Volarevic S, Thomas G . (2001). Role of S6 phosphorylation and S6 kinase in cell growth. Prog Nucl Acid Res Mol Biol 65: 101–127.

    Article  CAS  Google Scholar 

  • Warner JR . (1999). The economics of ribosome biosynthesis in yeast. Trends Biochem Sci 24: 437–440.

    Article  CAS  Google Scholar 

  • White RJ . (2005). RNA polymerases I and III, growth control and cancer. Nat Rev 6: 69–78.

    Article  CAS  Google Scholar 

  • Xu G, Kwon G, Cruz WS, Marshall CA, McDaniel ML . (2001). Metabolic regulation by leucine of translation initiation through the mTOR-signaling pathway by pancreatic beta-cells. Diabetes 50: 353–360.

    Article  CAS  Google Scholar 

  • Yuan X, Zhao J, Zentgraf H, Hofmann-Rohrer U, Grummt I. (2002). Multiple interactions between RNA polymerase I, TIF-IA, and TAFI subunits regulate preinitiation complex assembly at the ribosomal gene promoter. EMBO Rep 3: 1082–1087.

    Article  CAS  Google Scholar 

  • Zaragoza D, Ghavidel A, Heitman J, Schultz MC . (1998). Rapamycin induces the G0 program of transcriptional repression in yeast by interfering with the TOR signaling pathway. Mol Cell Biol 18: 4463–4470.

    Article  CAS  Google Scholar 

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Acknowledgements

We apologize to those whose work was not cited or discussed because of space limitations. Work in the authors' laboratory is supported by the Deutsche Forschungsgemeinschaft (SFB/Transregio 5, SP, Epigenetics'), the EU-Network ‘Epigenome’ and the Fonds der Chemischen Industrie.

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  1. Division of Molecular Biology of the Cell II, German Cancer Research Center, Heidelberg, Germany

    C Mayer & I Grummt

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Correspondence to I Grummt.

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Mayer, C., Grummt, I. Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases. Oncogene 25, 6384–6391 (2006). https://doi.org/10.1038/sj.onc.1209883

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