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c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription

Nature Cell Biology volume 7, pages 303–310 (2005)Cite this article

Abstract

The c-Myc oncoprotein regulates transcription of genes that are associated with cell growth, proliferation and apoptosis1. c-Myc levels are modulated by ubiquitin/proteasome-mediated degradation1. Proteasome inhibition leads to c-Myc accumulation within nucleoli2, indicating that c-Myc might have a nucleolar function. Here we show that the proteins c-Myc and Max interact in nucleoli and are associated with ribosomal DNA. This association is increased upon activation of quiescent cells and is followed by recruitment of the Myc cofactor TRRAP, enhanced histone acetylation, recruitment of RNA polymerase I (Pol I), and activation of rDNA transcription. Using small interfering RNAs (siRNAs) against c-Myc and an inhibitor of Myc–Max interactions, we demonstrate that c-Myc is required for activating rDNA transcription in response to mitogenic signals. Furthermore, using the ligand-activated MycER (ER, oestrogen receptor) system, we show that c-Myc can activate Pol I transcription in the absence of Pol II transcription. These results suggest that c-Myc coordinates the activity of all three nuclear RNA polymerases, and thereby plays a key role in regulating ribosome biogenesis and cell growth.

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Figure 1: Localization of c-Myc in the nucleolus is associated with its DNA-binding function.
Figure 2: c-Myc, Max and other c-Myc cofactors associate with E-box-containing regions of rDNA in vivo.
Figure 3: Proteasome inhibition downregulates Pol I transcription.
Figure 4: Recruitment of c-Myc and cofactors to rDNA is required for activated rDNA transcription upon mitogenic stimulation of normal lymphocytes.
Figure 5: MycER activation stimulates pre-rRNA synthesis and enhances histone H4 acetylation at rDNA.

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Acknowledgements

We thank J. Sylvester for providing the rDNA FISH probe, T. Kerppola for providing the BiFC vectors, A. Tikhonenko for providing the chicken c-Myc vector, M. Eilers for providing the Rat1- and U2OS-MycER cell lines, and B. Edgar, R. Eisenman, C. Grandori and R. White for communicating results prior to publication. We also would like to thank F. Godeau and P. Thuriaux for creative discussions. The work was supported by grants from the Swedish Cancer Society to A.W. and L.-G.L. and from the Swedish Children Cancer Foundation, Agrifungen and the Human Frontier Science Program (HFSP) to L.-G.L. I. G. was supported by the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie. A.W. is a senior investigator supported by the Swedish Research Council.

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Author notes

  1. Lars-Gunnar Larsson and Anthony P. H. Wright: These authors contributed equally to this work.

Authors and Affiliations

  1. Södertörns Högskola, Huddinge, S-141 89, Sweden

    Azadeh Arabi, Chiounan Shiue & Anthony P. H. Wright

  2. Department of Biosciences, Karolinska Institute, Huddinge, S-141 57, Sweden

    Azadeh Arabi, Chiounan Shiue & Anthony P. H. Wright

  3. Department of Plant Biology and Forest Genetics, Swedish University of Agricultural Sciences, Uppsala, S-750 07, Sweden

    Siqin Wu, Karin Ridderstråle, Sara Fahlén, Per Hydbring & Lars-Gunnar Larsson

  4. Division of Molecular Biology of the Cell II, German Cancer Research Center, Heidelberg, 69120, Germany

    Holger Bierhoff, Karoly Fatyol & Ingrid Grummt

  5. Department of Genetics and Pathology, The Rudbeck Laboratory, University of Uppsala, Uppsala, S-751 85, Sweden

    Ola Söderberg

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Correspondence to Azadeh Arabi.

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Arabi, A., Wu, S., Ridderstråle, K. et al. c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription. Nat Cell Biol 7, 303–310 (2005). https://doi.org/10.1038/ncb1225

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