Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Nutrient regulates Tor1 nuclear localization and association with rDNA promoter

Nature volume 442, pages 1058–1061 (2006)Cite this article

Abstract

TOR is the target of the immunosuppressant rapamycin and a key regulator of cell growth. It modulates diverse cellular processes in the cytoplasm and nucleus1,2,3,4,5, including the expression of amino acid transporters, ribosomal RNAs and ribosomal proteins. Despite considerable recent progress, little is known about the spatial and temporal regulation of TOR signalling, particularly that leading into the nucleus. Here we show that Tor1 is dynamically distributed in the cytoplasm and nucleus in yeast. Tor1 nuclear localization is nutrient dependent and rapamycin sensitive: starvation or treatment with rapamycin causes Tor1 to exit from the nucleus. Tor1 nuclear localization is critical for 35S rRNA synthesis, but not for the expression of amino acid transporters and ribosomal protein genes. We show further that Tor1 is associated with 35S ribosomal DNA (rDNA) promoter chromatin in a rapamycin- and starvation-sensitive manner; this association is necessary for 35S rRNA synthesis and cell growth. These results indicate that the spatial regulation of TOR complex 1 (TORC1) might be involved in differential control of its target genes. TOR is known as a classic cytoplasmic kinase that mediates the cytoplasm-to-nucleus signalling by controlling the localization of transcription factors. Our data indicate that TOR might be more intimately involved in gene regulation than previously thought.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Tor1 is dynamically distributed in the cytoplasm and nucleus in a rapamycin- and nutrient-sensitive manner.
Figure 2: Tor1 nuclear localization is critical for cell growth and 35S rRNA synthesis.
Figure 4: Tor1 binding to the 35S rDNA promoter is important for cell growth and 35S rRNA synthesis.
Figure 3: Tor1 binds to the 35S rDNA promoter in a rapamycin-sensitive manner.

References

  1. Abraham, R. TOR signaling: an odyssey from cellular stress to the cell growth machinery. Curr. Biol. 15, R139–R141 (2005)

    Article  CAS  Google Scholar 

  2. Harris, T. E. & Lawrence, J. C. Jr . TOR signaling. Sci. STKE 2003, re15 (2003)

    PubMed  Google Scholar 

  3. Shamji, A., Nghiem, P. & Schreiber, S. Integration of growth factor and nutrient signaling: implications for cancer biology. Mol. Cell 12, 271–280 (2003)

    Article  CAS  Google Scholar 

  4. Schmelzle, T. & Hall, M. N. TOR, a central controller of cell growth. Cell 103, 253–262 (2000)

    Article  CAS  Google Scholar 

  5. Schneper, L., Duvel, K. & Broach, J. Sense and sensibility: nutritional response and signal integration in yeast. Curr. Opin. Microbiol. 7, 624–630 (2004)

    Article  CAS  Google Scholar 

  6. Loewith, R. et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 10, 457–468 (2002)

    Article  CAS  Google Scholar 

  7. Wedaman, K. P. et al. Tor kinases are in distinct membrane-associated protein complexes in Saccharomyces cerevisiae. Mol. Biol. Cell 14, 1204–1220 (2003)

    Article  CAS  Google Scholar 

  8. Drenan, R. M., Liu, X., Bertram, P. G. & Zheng, X. F. S. FKBP12-rapamycin-associated protein or mammalian target of rapamycin (FRAP/mTOR) localization in the endoplasmic reticulum and the Golgi apparatus. J. Biol. Chem. 279, 772–778 (2004)

    Article  CAS  Google Scholar 

  9. Desai, B. N., Myers, B. R. & Schreiber, S. L. FKBP12-rapamycin-associated protein associates with mitochondria and senses osmotic stress via mitochondrial dysfunction. Proc. Natl Acad. Sci. USA 99, 4319–4324 (2002)

    Article  ADS  CAS  Google Scholar 

  10. Rout, M. & Kilmartin, J. in Cell Biology: A Laboratory Handbook (ed. Celis, J. E.), 2nd edn 120–128 (Academic, San Diego, 1998)

    Google Scholar 

  11. Pemberton, L. F., Blobel, G. & Rosenblum, J. S. Transport routes through the nuclear pore complex. Curr. Opin. Cell Biol. 10, 392–399 (1998)

    Article  CAS  Google Scholar 

  12. Carvalho, J., Bertram, P. G., Wente, S. R. & Zheng, X. F. S. Phosphorylation Regulates the Interaction between Gln3p and the Nuclear Import Factor Srp1p. J. Biol. Chem. 276, 25359–25365 (2001)

    Article  CAS  Google Scholar 

  13. Zheng, X. F., Florentino, D., Chen, J., Crabtree, G. R. & Schreiber, S. L. TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin. Cell 82, 121–130 (1995)

    Article  CAS  Google Scholar 

  14. Chan, T. F., Carvalho, J., Riles, L. & Zheng, X. F. S. A chemical genomics approach toward understanding the global functions of TOR. Proc. Natl Acad. Sci. USA 97, 13227–13232 (2000)

    Article  ADS  CAS  Google Scholar 

  15. Bertram, P. G. et al. Tripartite regulation of Gln3p by TOR, Ure2p and phosphatases. J. Biol. Chem. 275, 35727–35733 (2000)

    Article  CAS  Google Scholar 

  16. Cardenas, M., Cutler, N., Lorenz, M., Di Como, C. & Heitman, J. The TOR signaling cascade regulates gene expression in response to nutrients. Genes Dev. 13, 3271–3279 (1999)

    Article  CAS  Google Scholar 

  17. Jorgensen, P. et al. A dynamic transcriptional network communicates growth potential to ribosome synthesis and critical cell size. Genes Dev. 18, 2491–2505 (2004)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Moss, T. & Stefanovsky, V. Y. At the center of eukaryotic life. Cell 109, 545–548 (2002)

    Article  CAS  Google Scholar 

  21. Warner, J. R. The economics of ribosome biosynthesis in yeast. Trends Biochem. Sci. 24, 437–440 (1999)

    Article  CAS  Google Scholar 

  22. Udem, S. & Warner, J. Ribosomal RNA synthesis in Saccharomyces cerevisiae. J. Mol. Biol. 65, 227–242 (1972)

    Article  CAS  Google Scholar 

  23. Claypool, J. A. et al. 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. Biol. Cell 15, 946–956 (2004)

    Article  CAS  Google Scholar 

  24. Tsang, C. K., Bertram, P. G., Ai, W., Drenan, R. & Zheng, X. F. S. Chromatin-mediated regulation of nucleolar structure and RNA Pol I localization by TOR. EMBO J. 22, 6045–6056 (2003)

    Article  CAS  Google Scholar 

  25. Beck, T. & Hall, M. N. The TOR signaling pathway controls nuclear localization of nutrient-regulated transcriptional factors. Nature 402, 689–692 (1999)

    Article  ADS  CAS  Google Scholar 

  26. Duvel, K., Santhanam, A., Garrett, S., Schneper, L. & Broach, J. Multiple roles of Tap42 in mediating rapamycin-induced transcriptional changes in yeast. Mol. Cell 11, 1467–1478 (2003)

    Article  Google Scholar 

  27. Martin, D., Soulard, A. & Hall, M. TOR regulates ribosomal protein gene expression via PKA and the Forkhead transcription factor FHL1. Cell 119, 969–979 (2004)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Schawalder, S. et al. Growth-regulated recruitment of the essential yeast ribosomal protein gene activator Ifh1. Nature 432, 1058–1061 (2004)

    Article  ADS  CAS  Google Scholar 

  30. Bertram, P. G. et al. Convergence of TOR-nitrogen and Snf1-glucose signaling pathways onto Gln3. Mol. Cell. Biol. 22, 1246–1252 (2002)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. H. Cho for generating the KOG1-MYC9 strain, M. Rout and S. Wente for advice on the purification of yeast nuclei, and H. Sesaki and R. Jensen for Tim23 antibody. This work was supported by an NIH grant to X.F.S.Z. Author Contributions The immunofluorescence experiments were performed by C.K.T. and M.W. Mutagenesis and rapamycin sensitivity assays were performed by H.L. and M.W. Subcellular fractionation, northern blotting and 35S rRNA assays were performed by H.L. ChIP assays were performed by C.K.T. and H.L. Tor1 antibody was generated and characterized by P.G.B. The data were analyzed and interpreted by H.L., C.K.T., M.W., P.G.B. and X.F.S.Z. The data images for the figures were prepared by H.L., C.K.T., M.W. and P.G.B. The manuscript was written by H.L., C.K.T. and X.F.S.Z.

Author information

Author notes

  1. Hong Li, Chi Kwan Tsang and Marcus Watkins: *These authors contributed equally to this work

Authors and Affiliations

  1. Department of Pharmacology, Robert Wood Johnson Medical School, 675 Hoes Lane, New Jersey, 08854, Piscataway, USA

    Hong Li, Chi Kwan Tsang & X. F. Steven Zheng

  2. Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Missouri, 63110, St Louis, USA

    Marcus Watkins & Paula G. Bertram

Authors
  1. Hong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chi Kwan Tsang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marcus Watkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paula G. Bertram
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. X. F. Steven Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to X. F. Steven Zheng.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Li, H., Tsang, C., Watkins, M. et al. Nutrient regulates Tor1 nuclear localization and association with rDNA promoter. Nature 442, 1058–1061 (2006). https://doi.org/10.1038/nature05020

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05020

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing