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.

  • Original Article
  • Published:

Burkitt’s lymphoma-associated c-Myc mutations converge on a dramatically altered target gene response and implicate Nol5a/Nop56 in oncogenesis

Oncogene volume 33, pages 3519–3527 (2014)Cite this article

Subjects

Abstract

Burkitt’s lymphomas (BLs) acquire consistent point mutations in a conserved domain of Myc, Myc Box I. We report that the enhanced transforming activity of BL-associated Myc mutants can be uncoupled from loss of phosphorylation and increased protein stability. Furthermore, two different BL-associated Myc mutations induced similar gene expression profiles independently of T58 phosphorylation, and these profiles are dramatically different from MycWT. Nol5a/Nop56, which is required for ribosomal RNA methylation, was identified as a gene hyperactivated by the BL-associated Myc mutants. We show that Nol5a is necessary for Myc-induced cell transformation, enhances MycWT-induced cell transformation and increases the size of MycWT-induced tumors. Thus, Nol5a expands the link between Myc-induced regulation of nucleolar target genes, which are rate limiting for cell transformation and tumor growth.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Yustein JT, Dang CV . Biology and treatment of Burkitt's lymphoma. Curr Opin Hematol 2007; 14: 375–381.

    Article  PubMed  Google Scholar 

  2. Meyer N, Penn LZ . Reflecting on 25 years with MYC. Nat Rev Cancer 2008; 8: 976–990.

    Article  CAS  PubMed  Google Scholar 

  3. Albert T, Urlbauer B, Kohlhuber F, Hammersen B, Eick D . Ongoing mutations in the N-terminal domain of c-Myc affect transactivation in Burkitt's lymphoma cell lines. Oncogene 1994; 9: 759–763.

    CAS  PubMed  Google Scholar 

  4. Bhatia K, Huppi K, Spangler G, Siwarski D, Iyer R, Magrath I et al. Point mutations in the c-Myc transactivation domain are common in Burkitt's lymphoma and mouse plasmacytomas. Nat Genet 1993; 5: 56–61.

    Article  CAS  PubMed  Google Scholar 

  5. Bhatia K, Spangler G, Gaidano G, Hamdy N, Dalla-Favera R, Magrath I et al. Mutations in the coding region of c-myc occur frequently in acquired immunodeficiency syndrome-associated lymphomas. Blood 1994; 84: 883–888.

    CAS  PubMed  Google Scholar 

  6. Brennscheidt U, Eick D, Kunzmann R, Martens U, Kiehntopf M, Mertelsmann R et al. Burkitt-like mutations in the c-myc gene locus in prolymphocytic leukemia. Leukemia 1994; 8: 897–902.

    CAS  PubMed  Google Scholar 

  7. Clark HM, Yano T, Otsuki T, Jaffe ES, Shibata D, Raffeld M et al. Mutations in the coding region of c-MYC in AIDS-associated and other aggressive lymphomas. Cancer Res 1994; 54: 3383–3386.

    CAS  PubMed  Google Scholar 

  8. Johnston JM, Yu MT, Carroll WL . c-myc hypermutation is ongoing in endemic, but not all Burkitt's lymphoma. Blood 1991; 78: 2419–2425.

    CAS  PubMed  Google Scholar 

  9. Yano T, Sander CA, Clark HM, Dolezal MV, Jaffe ES, Raffeld M et al. Clustered mutations in the second exon of the MYC gene in sporadic Burkitt's lymphoma. Oncogene 1993; 8: 2741–2748.

    CAS  PubMed  Google Scholar 

  10. Chang DW, Claassen GF, Hann SR, Cole MD . The c-Myc transactivation domain is a direct modulator of apoptotic versus proliferative signals. Mol Cell Biol 2000; 20: 4309–4319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hann SR . Role of post-translational modifications in regulating c-Myc proteolysis, transcriptional activity and biological function. Semin Cancer Biol 2006; 16: 288–302.

    Article  CAS  PubMed  Google Scholar 

  12. Vervoorts J, Luscher-Firzlaff JM, Rottmann S, Lilischkis R, Walsemann G, Dohmann K et al. Stimulation of c-MYC transcriptional activity and acetylation by recruitment of the cofactor CBP. EMBO Rep 2003; 4: 484–490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sears RC . The life cycle of C-myc: from synthesis to degradation. Cell Cycle 2004; 3: 1133–1137.

    Article  CAS  PubMed  Google Scholar 

  14. Henriksson M, Bakardjiev A, Klein G, Luscher B . Phosphorylation sites mapping in the N-terminal domain of c-myc modulate its transforming potential. Oncogene 1993; 8: 3199–3209.

    CAS  PubMed  Google Scholar 

  15. Pulverer BJ, Fisher C, Vousden K, Littlewood T, Evan G, Woodgett JR et al. Site-specific modulation of c-Myc cotransformation by residues phosphorylated in vivo. Oncogene 1994; 9: 59–70.

    CAS  PubMed  Google Scholar 

  16. Yeh E, Cunningham M, Arnold H, Chasse D, Monteith T, Ivaldi G et al. A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells. Nat Cell Biol 2004; 6: 308–318.

    Article  CAS  PubMed  Google Scholar 

  17. Hemann MT, Bric A, Teruya-Feldstein J, Herbst A, Nilsson JA, Cordon-Cardo C et al. Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants. Nature 2005; 436: 807–811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang X, Cunningham M, Zhang X, Tokarz S, Laraway B, Troxell M et al. Phosphorylation regulates c-Myc's oncogenic activity in the mammary gland. Cancer Res 2011; 71: 925–936.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Adhikary S, Eilers M . Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol 2005; 6: 635–645.

    Article  CAS  PubMed  Google Scholar 

  20. Dang CV, O'Donnell KA, Zeller KI, Nguyen T, Osthus RC, Li F et al. The c-Myc target gene network. Semin Cancer Biol 2006; 16: 253–264.

    CAS  PubMed  Google Scholar 

  21. Arabi A, Wu S, Ridderstrale K, Bierhoff H, Shiue C, Fatyol K et al. c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription. Nat Cell Biol 2005; 7: 303–310.

    Article  CAS  PubMed  Google Scholar 

  22. Cowling VH, Cole MD . The Myc transactivation domain promotes global phosphorylation of the RNA pol II carboxy-terminal domain independently of direct DNA binding. Mol Cell Biol 2007; 6: 2059–2073.

    Article  Google Scholar 

  23. Gomez-Roman N, Grandori C, Eisenman RN, White RJ . Direct activation of RNA polymerase III transcription by c-Myc. Nature 2003; 421: 290–294.

    Article  CAS  PubMed  Google Scholar 

  24. Grandori C, Gomez-Roman N, Felton-Edkins ZA, Ngouenet C, Galloway DA, Eisenman RN et al. c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I. Nat Cell Biol 2005; 7: 311–318.

    Article  CAS  PubMed  Google Scholar 

  25. Grewal SS, Li L, Orian A, Eisenman RN, Edgar BA . Myc-dependent regulation of ribosomal RNA synthesis during Drosophila development. Nat Cell Biol 2005; 7: 295–302.

    Article  CAS  PubMed  Google Scholar 

  26. Benassi B, Fanciulli M, Fiorentino F, Porrello A, Chiorino G, Loda M et al. c-Myc phosphorylation is required for cellular response to oxidative stress. Mol Cell 2006; 21: 509–519.

    Article  CAS  PubMed  Google Scholar 

  27. Watnick RS, Cheng YN, Rangarajan A, Ince TA, Weinberg RA . Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. Cancer Cell 2003; 3: 219–231.

    Article  CAS  PubMed  Google Scholar 

  28. Hoang AT, Lutterbach B, Lewis BC, Yano T, Chou TY, Barrett JF 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 1995; 15: 4031–4042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR . Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev 2000; 14: 2501–2514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mateyak MK, Obaya AJ, Adachi S, Sedivy JM . Phenotypes of c-Myc-deficient rat fibroblasts isolated by targeted homologous recombination. Cell Growth Differ 1997; 8: 1039–1048.

    CAS  PubMed  Google Scholar 

  31. Tusher VG, Tibshirani R, Chu G . Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 2001; 98: 5116–5121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fernandez PC, Frank SR, Wang L, Schroeder M, Liu S, Greene J et al. Genomic targets of the human c-Myc protein. Genes Dev 2003; 17: 1115–1129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. McMahon SB, Wood MA, Cole MD . The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc. Mol Cell Biol 2000; 20: 556–562.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. van Riggelen J, Yetil A, Felsher DW . MYC as a regulator of ribosome biogenesis and protein synthesis. Nat Rev Cancer 2010; 10: 301–309.

    Article  CAS  PubMed  Google Scholar 

  35. Ruggero D . Revisiting the nucleolus: from marker to dynamic integrator of cancer signaling. Sci Signal 2012; 5: pe38.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Brown SJ, Cole MD, Erives AJ . Evolution of the holozoan ribosome biogenesis regulon. BMC Genomics 2008; 9: 442.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Barna M, Pusic A, Zollo O, Costa M, Kondrashov N, Rego E et al. Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency. Nature 2008; 456: 971–975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dave SS, Fu K, Wright GW, Lam LT, Kluin P, Boerma EJ et al. Molecular diagnosis of Burkitt's lymphoma. N Engl J Med 2006; 354: 2431–2442.

    Article  CAS  PubMed  Google Scholar 

  39. Gautier T, Berges T, Tollervey D, Hurt E . Nucleolar KKE/D repeat proteins Nop56p and Nop58p interact with Nop1p and are required for ribosome biogenesis. Mol Cell Biol 1997; 17: 7088–7098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hayano T, Yanagida M, Yamauchi Y, Shinkawa T, Isobe T, Takahashi N et al. Proteomic analysis of human Nop56p-associated pre-ribosomal ribonucleoprotein complexes. Possible link between Nop56p and the nucleolar protein treacle responsible for Treacher Collins syndrome. J Biol Chem 2003; 278: 34309–34319.

    Article  CAS  PubMed  Google Scholar 

  41. Newman DR, Kuhn JF, Shanab GM, Maxwell ES . Box C/D snoRNA-associated proteins: two pairs of evolutionarily ancient proteins and possible links to replication and transcription. RNA 2000; 6: 861–879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lin CY, Loven J, Rahl PB, Paranal RM, Burge CB, Bradner JE et al. Transcriptional amplification in tumor cells with elevated c-Myc. Cell 2012; 151: 56–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Nie Z, Hu G, Wei G, Cui K, Yamane A, Resch W et al. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 2012; 151: 68–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Goy A, Stewart J, Barkoh BA, Remache YK, Katz R, Sneige N et al. The feasibility of gene expression profiling generated in fine-needle aspiration specimens from patients with follicular lymphoma and diffuse large B-cell lymphoma. Cancer 2006; 108: 10–20.

    Article  CAS  PubMed  Google Scholar 

  45. Vallat LD, Park Y, Li C, Gribben JG . Temporal genetic program following B-cell receptor cross-linking: altered balance between proliferation and death in healthy and malignant B cells. Blood 2007; 109: 3989–3997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Menssen A, Hermeking H . Characterization of the c-MYC-regulated transcriptome by SAGE: identification and analysis of c-MYC target genes. Proc Natl Acad Sci USA 2002; 99: 6274–6279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Schlosser I, Holzel M, Murnseer M, Burtscher H, Weidle UH, Eick D et al. A role for c-Myc in the regulation of ribosomal RNA processing. Nucleic Acids Res 2003; 31: 6148–6156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Shaffer AL, Wright G, Yang L, Powell J, Ngo V, Lamy L et al. A library of gene expression signatures to illuminate normal and pathological lymphoid biology. Immunol Rev 2006; 210: 67–85.

    Article  CAS  PubMed  Google Scholar 

  49. Watson JD, Oster SK, Shago M, Khosravi F, Penn LZ . Identifying genes regulated in a Myc-dependent manner. J Biol Chem 2002; 277: 36921–36930.

    Article  CAS  PubMed  Google Scholar 

  50. Machida YJ, Chen Y, Machida Y, Malhotra A, Sarkar S, Dutta A et al. Targeted comparative RNA interference analysis reveals differential requirement of genes essential for cell proliferation. Mol Biol Cell 2006; 17: 4837–4845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bogomolnaya LM, Pathak R, Cham R, Guo J, Surovtseva YV, Jaeckel L et al. A new enrichment approach identifies genes that alter cell cycle progression in Saccharomyces cerevisiae. Curr Genet 2004; 45: 350–359.

    Article  CAS  PubMed  Google Scholar 

  52. Boisvert FM, van Koningsbruggen S, Navascues J, Lamond AI . The multifunctional nucleolus. Nat Rev Mol Cell Biol 2007; 8: 574–585.

    Article  CAS  PubMed  Google Scholar 

  53. Pandolfi PP . Aberrant mRNA translation in cancer pathogenesis: an old concept revisited comes finally of age. Oncogene 2004; 23: 3134–3137.

    Article  CAS  PubMed  Google Scholar 

  54. Boon K, Caron HN, van Asperen R, Valentijn L, Hermus MC, van Sluis P et al. N-myc enhances the expression of a large set of genes functioning in ribosome biogenesis and protein synthesis. EMBO J 2001; 20: 1383–1393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kim S, Li Q, Dang CV, Lee LA . Induction of ribosomal genes and hepatocyte hypertrophy by adenovirus-mediated expression of c-Myc in vivo. Proc Natl Acad Sci USA 2000; 97: 11198–11202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Perna D, Faga G, Verrecchia A, Gorski MM, Barozzi I, Narang V et al. Genome-wide mapping of Myc binding and gene regulation in serum-stimulated fibroblasts. Oncogene 2012; 31: 1695–1709.

    Article  CAS  PubMed  Google Scholar 

  57. Li Z, Hann SR . Nucleophosmin is essential for c-Myc nucleolar localization and c-Myc-mediated rDNA transcription. Oncogene 2013; 32: 1988–1994.

    Article  CAS  PubMed  Google Scholar 

  58. Alawi F, Lee MN . DKC1 is a direct and conserved transcriptional target of c-MYC. Biochem Biophys Res Commun 2007; 362: 893–898.

    Article  CAS  PubMed  Google Scholar 

  59. Warner JR, McIntosh KB . How common are extraribosomal functions of ribosomal proteins? Mol Cell 2009; 34: 3–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Grisendi S, Mecucci C, Falini B, Pandolfi PP . Nucleophosmin and cancer. Nat Rev Cancer 2006; 6: 493–505.

    Article  CAS  PubMed  Google Scholar 

  61. Cowling VH, Chandriani S, Whitfield ML, Cole MD . A conserved Myc protein domain, MBIV, regulates DNA binding, apoptosis, transformation, and G2 arrest. Mol Cell Biol 2006; 26: 4226–4239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Steve Hann and Chi Dang for providing cell lines. This project was supported by a grant from the National Cancer Institute (CA055248; MDC) and by Award Number T32GM008704 from the National Institute of General Medical Sciences (SAT). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health.

Author information

Author notes

  1. V H Cowling

    Present address: 4Current address: MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee, UK.,

  2. V H Cowling and S A Turner: These authors are co-first authors.

Authors and Affiliations

  1. Department of Pharmacology, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, One Medical Center Drive, NH, Lebanon, USA

    V H Cowling & M D Cole

  2. Department of Genetics, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, One Medical Center Drive, NH, Lebanon, USA

    S A Turner & M D Cole

Authors
  1. V H Cowling
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S A Turner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M D Cole
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M D Cole.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cowling, V., Turner, S. & Cole, M. Burkitt’s lymphoma-associated c-Myc mutations converge on a dramatically altered target gene response and implicate Nol5a/Nop56 in oncogenesis. Oncogene 33, 3519–3527 (2014). https://doi.org/10.1038/onc.2013.338

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.338

Keywords

This article is cited by

Search

Advanced search

Quick links