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:

Mutation of an IKK phosphorylation site within the transactivation domain of REL in two patients with B-cell lymphoma enhances REL's in vitro transforming activity

Oncogene volume 26, pages 2685–2694 (2007)Cite this article

Abstract

The human c-rel proto-oncogene (REL) encodes a subunit of the nuclear factor-kappaB (NF-κB) transcription factor. In this report, we have identified an identical point mutation in two human B-cell lymphomas (follicular (FL) and mediastinal) that changes serine (Ser)525 (TCA) to proline (Pro) (CCA) within the REL transactivation domain. This mutation was not identified in a similarly sized cohort of healthy individuals. In the mediastinal B-cell lymphoma, the mutation in REL is of germ-line origin. In both tumors, the S525P mutant allele is over-represented. REL-S525P shows enhanced in vitro transforming activity in chicken spleen cells. REL-S525P has a reduced ability to activate the human manganese superoxide dismutase (MnSOD) promoter in A293 cells; however, the MnSOD protein shows increased expression in REL-S525P-transformed chicken spleen cells as compared to wild-type REL-transformed cells. Ser525 is a site for phosphorylation by IκB kinase (IKK) in vitro. The S525P mutation reduces IKKα- and tumor necrosis factor (TNF)α-stimulated transactivation by a GAL4-REL protein. Furthermore, REL-S525P-transformed chicken spleen cells are more resistant to TNFα-induced cell death than cells transformed by wild-type REL. These results suggest that the S525P mutation contributes to the development of human B-cell lymphomas by affecting an IKKα-regulated transactivation activity of REL.

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 2
Figure 1
Figure 5
Figure 3
Figure 4
Figure 6
Figure 7

Similar content being viewed by others

References

  • Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MM . (2002). Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 46: 3151–3158.

    Article  CAS  Google Scholar 

  • Bryder D, Ramsfjell V, Dybedal I, Theilgaard-Mönch K, Högerkorp C-M, Adolfsson J et al. (2001). Self-renewal of multipotent long-term repopulating hematopoietic stem cells is negatively regulated by Fas and tumor necrosis factor activation. J Exp Med 194: 941–952.

    Article  CAS  Google Scholar 

  • Feuerhake F, Kutok JL, Monti S, Chen W, LaCasce AS, Cattoretti G et al. (2005). NF-κB activity, function and target gene signatures in primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma subtypes. Blood 106: 1392–1399.

    Article  CAS  Google Scholar 

  • Fognani C, Rondi R, Romano A, Blasi F . (2000). c-Rel-TD kinase: a serine/threonine kinase binding in vivo and in vitro c-Rel and phosphorylating its transactivation domain. Oncogene 19: 2224–2232.

    Article  CAS  Google Scholar 

  • Gilmore TD, Cormier C, Jean-Jacques J, Gapuzan M-E . (2001). Malignant transformation of primary chicken spleen cells by human transcription factor c-Rel. Oncogene 20: 7098–7103.

    Article  CAS  Google Scholar 

  • Gilmore TD, Kalaitzidis D, Liang M-C, Starczynowski DT . (2004). The c-Rel transcription factor and B-cell proliferation: a deal with the devil. Oncogene 23: 2275–2286.

    Article  CAS  Google Scholar 

  • Harris J, Olière S, Sharma S, Sun Q, Lin R, Hiscott J et al. (2006). Nuclear accumulation of cRel following C-terminal phosphorylation by TBK1/IKKɛ. J Immunol 177: 2527–2535.

    Article  CAS  Google Scholar 

  • Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J et al. (1999). The World Health Organization classification of neoplastic diseases of hematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November, 1997. Ann Oncol 10: 1419–1432.

    Article  CAS  Google Scholar 

  • Joos S, Granzow M, Holtgreve-Grez H, Siebert R, Harder L, Martín-Subero JL et al. (2003). Hodgkin's lymphoma cell lines are characterized by frequent aberrations on chromosomes 2p and 9p including REL and JAK2. Int J Cancer 103: 489–495.

    Article  CAS  Google Scholar 

  • Kalaitzidis D, Davis RE, Rosenwald A, Staudt LM, Gilmore TD . (2002). The human B-cell lymphoma cell line RC-K8 has multiple genetic alterations that dysregulate the Rel/NF-κB signal transduction pathway. Oncogene 21: 8759–8768.

    Article  CAS  Google Scholar 

  • Köntgen F, Grumont RJ, Strasser A, Metcalf D, Li R, Tarlinton D et al. (1995). Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression. Genes Dev 9: 1965–1977.

    Article  Google Scholar 

  • Kralova J, Liss AS, Bargmann W, Pendleton C, Varadarajan J, Ulug E et al. (2002). Differential regulation of the inhibitor of apoptosis ch-IAP1 by v-rel and the proto-oncogene c-rel. J Virol 76: 11960–11970.

    Article  CAS  Google Scholar 

  • Lawrence T, Bebien M, Liu GY, Nizet V, Karin M . (2005). IKKα limits macrophage NF-κB activation and contributes to the resolution of inflammation. Nature 434: 1138–1143.

    Article  CAS  Google Scholar 

  • Liang M-C, Bardhan S, Li C, Pace EA, Porco Jr JA, Gilmore TD . (2003). Jesterone dimer, a synthetic derivative of the fungal metabolite jesterone, blocks activation of transcription factor nuclear factor κB by inhibiting the inhibitor of κB kinase. Mol Pharmacol 64: 123–131.

    Article  CAS  Google Scholar 

  • Martin AG, Fresno M . (2000). Tumor necrosis factor-α activation of NF-κB requires the phosphorylation of Ser-471 in the transactivation domain of c-Rel. J Biol Chem 275: 24383–24391.

    Article  CAS  Google Scholar 

  • Martin AG, San-Antonio B, Fresno M . (2001). Regulation of nuclear factor κB transactivation: implications of phosphatidylinositol 3-kinase and protein kinase Cζ in c-Rel activation by tumor necrosis factor α. J Biol Chem 276: 15840–15849.

    Article  CAS  Google Scholar 

  • Martín-Subero JI, Gesk S, Harder L, Sonoki T, Tucker PW, Schlegelberger B et al. (2002). Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma. Blood 99: 1474–1477.

    Article  Google Scholar 

  • Martín-Subero JI, Knippschild U, Harder L, Barth TF, Riemke J, Grohmann S et al. (2003). Segmental chromosomal aberrations and centrosome amplifications: pathogenetic mechanisms in Hodgkin and Reed–Sternberg cells of classical Hodgkin's lymphoma? Leukemia 17: 2214–2219.

    Article  Google Scholar 

  • Mittlemann F (ed). (1995). International System for Human Cytogenetic Nomenclature (ISCN). Karger: Basel, Switzerland.

    Google Scholar 

  • Neiman PE, Grbic JJ, Polony TS, Kimmel R, Bowers SJ, Delrow J et al. (2003). Functional genomic analysis reveals distinct neoplastic phenotypes associated with c-myb mutation in the bursa of Fabricius. Oncogene 22: 1073–1086.

    Article  CAS  Google Scholar 

  • Rhodes DR, Kalyana-Sundaram S, Mahavisno V, Barrette TR, Ghosh D, Chinnaiyan AM . (2005). Mining for regulatory programs in the cancer transcriptome. Nat Genet 37: 579–583.

    Article  CAS  Google Scholar 

  • Sánchez-Valdepeñas C, Martín AG, Ramakrishnan P, Wallach D, Fresno M . (2006). NF-κB-inducing kinase is involved in the activation of the CD28 responsive element through phosphorylation of c-Rel and regulation of its transactivating activity. J Immunol 176: 4666–4674.

    Article  Google Scholar 

  • Sasaki CY, Barberi TJ, Ghosh P, Longo DL . (2005). Phosphorylation of RelA/p65 on serine 536 defines an IκBα-independent NF-κB pathway. J Biol Chem 280: 34538–34547.

    Article  CAS  Google Scholar 

  • Scheidereit C . (2006). IκB kinase (IKK) complexes: gateways to NF-κB activation and transcription. Oncogene 25: 6685–6705.

    Article  CAS  Google Scholar 

  • Schlegelberger B, Metzke S, Harder S, Zühlke-Jenisch R, Zhang Y, Siebert R . (1999). Classical molecular cytogenetics of tumor cells. In: Wegner R (ed). Diagnostic Cytogenetics. Springer-Verlag: New York, NY, pp. 151–185.

    Chapter  Google Scholar 

  • Starczynowski DT, Reynolds JG, Gilmore TD . (2003). Deletion of either C-terminal transactivation subdomain enhances the in vitro transforming activity of human transcription factor REL in chicken spleen cells. Oncogene 22: 6928–6936.

    Article  CAS  Google Scholar 

  • Starczynowski DT, Reynolds JG, Gilmore TD . (2005). Mutations of tumor necrosis factor α-responsive serine residues within the C-terminal transactivation domain of human transcription factor REL enhance its in vitro transforming ability. Oncogene 24: 7355–7368.

    Article  CAS  Google Scholar 

  • van Dongen JJM, Langerak AW, Brüggemann M, Evans PAS, Hummel M, Lavender FL et al. (2003). Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombination in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98–3936. Leukemia 17: 2257–2317.

    Article  CAS  Google Scholar 

  • Yu SH, Chiang WC, Shih HM, Wu KJ . (2004). Stimulation of c-Rel transcriptional activity by PKA catalytic subunit β. J Mol Med 82: 621–628.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K Bandick, C Becher, D Schuster and P Chall for technical assistance, and thank members of German Lymphoma Reference Pathologists Panel for providing and reviewing samples within the Network ‘Molecular Mechanisms in Malignant Lymphoma’. DTS was partially supported by a Pre-doctoral Fellowship from the Natural Sciences & Engineering Research Council of Canada, and JAA was partially supported by the Boston University Undergraduate Research Opportunities Program. This work was supported by NIH Grant CA47763 (TDG) and Deutsche Krebshilfe project grant 70-3173-Tr3 (RS, LH, CP).

Author information

Author notes

  1. D T Starczynowski

    Present address: BC Cancer Research Centre, Vancouver, BC, Canada

  2. D T Starczynowski and H Trautmann: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Biology, Boston University, Boston, MA, USA

    D T Starczynowski, J A Africa, J R Leeman & T D Gilmore

  2. Department of Medicine (Hematology & Oncology), University Hospital Schleswig-Holstein, Kiel, Germany

    H Trautmann & C Pott

  3. Institute of Human Genetics, University Hospital Schleswig-Holstein, Kiel, Germany

    L Harder & R Siebert

  4. Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Kiel, Germany

    N Arnold

Authors
  1. D T Starczynowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Trautmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Pott
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L Harder
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N Arnold
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J A Africa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J R Leeman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R Siebert
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. T D Gilmore
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T D Gilmore.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Starczynowski, D., Trautmann, H., Pott, C. et al. Mutation of an IKK phosphorylation site within the transactivation domain of REL in two patients with B-cell lymphoma enhances REL's in vitro transforming activity. Oncogene 26, 2685–2694 (2007). https://doi.org/10.1038/sj.onc.1210089

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210089

Keywords

This article is cited by

Search

Advanced search

Quick links