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.

Direct activation of RNA polymerase III transcription by c-Myc

Abstract

The proto-oncogene product c-Myc has a direct role in both metazoan cell growth and division1,2,3,4. RNA polymerase III (pol III) is involved in the generation of transfer RNA and 5S ribosomal RNA, and these molecules must be produced in bulk to meet the need for protein synthesis in growing cells5. We demonstrate here that c-Myc binds to TFIIIB, a pol III-specific general transcription factor, and directly activates pol III transcription. Chromatin immunoprecipitation reveals that endogenous c-Myc is present at tRNA and 5S rRNA genes in cultured mammalian cells. These results suggest that activation of pol III may have a role in the ability of c-Myc to stimulate cell growth.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Pol III-transcribed genes respond to c-Myc in vivo.
Figure 2: Pol III activation by c-Myc does not require pocket proteins or induction of TFIIIC2 or BN51.
Figure 3: Activation of pol III transcription by c-Myc does not depend on induction of pol II transcription.
Figure 4: ChIP assays show that c-Myc interacts with tRNA, 5S rRNA and B2 genes in vivo.
Figure 5: TFIIIB interacts with the N-terminal domain of c-Myc.

References

  1. Dang, C. V. c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol. Cell Biol. 19, 1–11 (1999)

    MathSciNet  CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Elend, M. & Eilers, M. Downstream of Myc—to grow or to cycle? Curr. Biol. 9, R936–R938 (1999)

    CAS  Article  PubMed  Google Scholar 

  3. Schmidt, E. V. The role of c-myc in cellular growth control. Oncogene 18, 2988–2996 (1999)

    CAS  Article  PubMed  Google Scholar 

  4. Grandori, C., Cowley, S. M., James, L. P. & Eisenman, R. N. The Myc/Max/Mad network and the transcriptional control of cell behavior. Annu. Rev. Cell Dev. Biol. 16, 653–699 (2000)

    CAS  Article  PubMed  Google Scholar 

  5. Brown, T. R. P., Scott, P. H., Stein, T., Winter, A. G. & White, R. J. RNA polymerase III transcription: its control by tumour suppressors and its deregulation by transforming agents. Gene Expr. 9, 15–28 (2000)

    CAS  Article  PubMed  Google Scholar 

  6. Rosenwald, I. B. Upregulated expression of the genes encoding translation initiation factors eIF-4E and eIF-2α in transformed cells. Cancer Lett. 102, 113–123 (1996)

    CAS  Article  PubMed  Google Scholar 

  7. Iritani, B. M. & Eisenman, R. N. c-Myc enhances protein synthesis and cell size during B lymphocyte development. Proc. Natl Acad. Sci. USA 96, 13180–13185 (1999)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Johnston, L. A., Prober, D. A., Edgar, B. A., Eisenman, R. N. & Gallant, P. Drosophila myc regulates cellular growth during development. Cell 98, 779–790 (1999)

    CAS  Article  PubMed  Google Scholar 

  9. Schuhmacher, M. et al. Control of cell growth by c-Myc in the absence of cell division. Curr. Biol. 9, 1255–1258 (1999)

    CAS  Article  PubMed  Google Scholar 

  10. Beier, R. et al. Induction of cyclin E-cdk2 kinase activity, E2F-dependent transcription and cell growth by Myc are genetically separable events. EMBO J. 19, 5813–5823 (2000)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Kim, S., Li, Q., Dang, C. V. & Lee, L. A. Induction of ribosomal genes and hepatocyte hypertrophy by adenovirus-mediated expression of c-Myc in vivo. Proc. Natl Acad. Sci. USA 97, 11198–11202 (2000)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Mateyak, M. K., Obaya, A. J., Adachi, S. & Sedivy, J. M. Phenotypes of c-Myc-deficient rat fibroblasts isolated by targeted homologous recombination. Cell Growth Differ. 8, 1039–1048 (1997)

    CAS  PubMed  Google Scholar 

  13. Coller, H. A. et al. Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. Proc. Natl Acad. Sci. USA 97, 3260–3265 (2000)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Boon, K. et al. N-myc enhances the expression of a large set of genes functioning in ribosome biogenesis and protein synthesis. EMBO J. 20, 1383–1393 (2001)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Hirst, S. K. & Grandori, C. Differential activity of conditional MYC and its variant MYC-S in human mortal fibroblasts. Oncogene 19, 5189–5197 (2000)

    CAS  Article  PubMed  Google Scholar 

  16. Winter, A. G. et al. RNA polymerase III transcription factor TFIIIC2 is overexpressed in ovarian tumors. Proc. Natl Acad. Sci. USA 97, 12619–12624 (2000)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Greasley, P. J., Bonnard, C. & Amati, B. Myc induces the nucleolin and BN51 genes: possible implications in ribosome biogenesis. Nucleic Acids Res. 28, 446–453 (2000)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Steiner, P. et al. Identification of a Myc-dependent step during the formation of active G1 cyclin-cdk complexes. EMBO J. 14, 4814–4826 (1995)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. White, R. J., Trouche, D., Martin, K., Jackson, S. P. & Kouzarides, T. Repression of RNA polymerase III transcription by the retinoblastoma protein. Nature 382, 88–90 (1996)

    ADS  CAS  Article  PubMed  Google Scholar 

  20. Scott, P. H. et al. Regulation of RNA polymerase III transcription during cell cycle entry. J. Biol. Chem. 276, 1005–1014 (2001)

    CAS  Article  PubMed  Google Scholar 

  21. Sutcliffe, J. E. et al. RNA polymerase III transcription factor IIIB is a target for repression by pocket proteins p107 and p130. Mol. Cell. Biol. 19, 4255–4261 (1999)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Gu, W., Bhatia, K., Magrath, I. T., Dang, C. V. & Dalla-Favera, R. Binding and suppression of the Myc transcriptional activation domain by p107. Science 264, 251–254 (1994)

    ADS  CAS  Article  PubMed  Google Scholar 

  23. Hoang, A. T. et al. A link between increased transforming activity of lymphoma-derived MYC mutant alleles, their defective regulation by p107, and altered phosphorylation of the c-Myc transactivation domain. Mol. Cell. Biol. 15, 4031–4042 (1995)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Eilers, M., Schirm, S. & Bishop, J. M. The MYC protein activates transcription of the α-prothymosin gene. EMBO J. 10, 133–141 (1991)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Geiduschek, E. P. & Kassavetis, G. A. The RNA polymerase III transcription apparatus. J. Mol. Biol. 310, 1–26 (2001)

    CAS  Article  PubMed  Google Scholar 

  26. Hateboer, G. et al. TATA-binding protein and the retinoblastoma gene product bind to overlapping epitopes on c-Myc and adenovirus E1A protein. Proc. Natl Acad. Sci. USA 90, 8489–8493 (1993)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Cole, M. D. & McMahon, S. B. The Myc oncoprotein: a critical evaluation of transactivation and target gene regulation. Oncogene 18, 2916–2924 (1999)

    CAS  Article  PubMed  Google Scholar 

  28. Eisenman, R. N. Deconstructing Myc. Genes Dev. 15, 2023–2030 (2001)

    CAS  Article  PubMed  Google Scholar 

  29. Schübeler, D. et al. Nuclear localization and histone acetylation: a pathway for chromatin opening and transcriptional activation of the human β-globin locus. Genes Dev. 14, 940–950 (2000)

    PubMed  PubMed Central  Google Scholar 

  30. White, R. J., Gottlieb, T. M., Downes, C. S. & Jackson, S. P. Mitotic regulation of a TATA-binding-protein-containing complex. Mol. Cell. Biol. 15, 1983–1992 (1995)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank C. Ngouenet and Z. Felton-Edkins for technical assistance, and R. Reeder, S. Cowley and C. Yost for critique of this manuscript. This work was funded by grants from CONACYT-Mexico (N.G.), the National Institutes of Health/National Cancer Institute (C.G. and R.N.E.), and from Cancer Research UK (R.J.W.).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Robert N. Eisenman or Robert J. White.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gomez-Roman, N., Grandori, C., Eisenman, R. et al. Direct activation of RNA polymerase III transcription by c-Myc. Nature 421, 290–294 (2003). https://doi.org/10.1038/nature01327

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01327

Further reading

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

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