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.

FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas

This article has been updated

Abstract

BCL6 is the product of a proto-oncogene implicated in the pathogenesis of human B-cell lymphomas1,2. By binding specific DNA sequences, BCL6 controls the transcription of a variety of genes involved in B-cell development, differentiation and activation. BCL6 is overexpressed in the majority of patients with aggressive diffuse large B-cell lymphoma (DLBCL), the most common lymphoma in adulthood, and transgenic mice constitutively expressing BCL6 in B cells develop DLBCLs similar to the human disease3,4. In many DLBCL patients, BCL6 overexpression is achieved through translocation (40%) or hypermutation of its promoter (15%). However, many other DLBCLs overexpress BCL6 through an unknown mechanism. Here we show that BCL6 is targeted for ubiquitylation and proteasomal degradation by a SKP1–CUL1–F-box protein (SCF) ubiquitin ligase complex that contains the orphan F-box protein FBXO11 (refs 5, 6). The gene encoding FBXO11 was found to be deleted or mutated in multiple DLBCL cell lines, and this inactivation of FBXO11 correlated with increased levels and stability of BCL6. Similarly, FBXO11 was either deleted or mutated in primary DLBCLs. Notably, tumour-derived FBXO11 mutants displayed an impaired ability to induce BCL6 degradation. Reconstitution of FBXO11 expression in FBXO11-deleted DLBCL cells promoted BCL6 ubiquitylation and degradation, inhibited cell proliferation, and induced cell death. FBXO11-deleted DLBCL cells generated tumours in immunodeficient mice, and the tumorigenicity was suppressed by FBXO11 reconstitution. We reveal a molecular mechanism controlling BCL6 stability and propose that mutations and deletions in FBXO11 contribute to lymphomagenesis through BCL6 stabilization. The deletions/mutations found in DLBCLs are largely monoallelic, indicating that FBXO11 is a haplo-insufficient tumour suppressor gene.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: FBXO11 controls the ubiquitylation and degradation of BCL6.
Figure 2: DLBCL cell lines with FBXO11 deletions or an FBXO11 mutation display increased levels and stability of BCL6.
Figure 3: Human DLBCLs with FBXO11 mutations display increased levels of BCL6, and FBXO11 tumour-derived mutants have impaired abilities to induce BCL6 degradation.
Figure 4: Expression of FBXO11 in FBXO11 -null cells promotes BCL6 ubiquitylation and degradation, inhibits cell proliferation and induces apoptosis.

Change history

  • 04 January 2012

    The labelling of Fig. 1a was corrected.

References

  1. Ci, W., Polo, J. M. & Melnick, A. B-cell lymphoma 6 and the molecular pathogenesis of diffuse large B-cell lymphoma. Curr. Opin. Hematol. 15, 381–390 (2008)

    Article  CAS  Google Scholar 

  2. Staudt, L. M. & Dave, S. The biology of human lymphoid malignancies revealed by gene expression profiling. Adv. Immunol. 87, 163–208 (2005)

    Article  CAS  Google Scholar 

  3. Baron, B. W. et al. The human BCL6 transgene promotes the development of lymphomas in the mouse. Proc. Natl Acad. Sci. USA 101, 14198–14203 (2004)

    Article  ADS  CAS  Google Scholar 

  4. Cattoretti, G. et al. Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice. Cancer Cell 7, 445–455 (2005)

    Article  CAS  Google Scholar 

  5. Cardozo, T. & Pagano, M. The SCF ubiquitin ligase: insights into a molecular machine. Nature Rev. Mol. Cell Biol. 5, 739–751 (2004)

    Article  CAS  Google Scholar 

  6. Skaar, J. R., D’Angiolella, V., Pagan, J. K. & Pagano, M. SnapShot: F Box Proteins II. Cell 137, 1358 (2009)

    Article  Google Scholar 

  7. Niu, H., Ye, B. H. & Dalla-Favera, R. Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. Genes Dev. 12, 1953–1961 (1998)

    Article  CAS  Google Scholar 

  8. Phan, R. T., Saito, M., Kitagawa, Y., Means, A. R. & Dalla-Favera, R. Genotoxic stress regulates expression of the proto-oncogene Bcl6 in germinal center B cells. Nature Immunol. 8, 1132–1139 (2007)

    Article  CAS  Google Scholar 

  9. Benmaamar, R. & Pagano, M. Involvement of the SCF complex in the control of Cdh1 degradation in S-phase. Cell Cycle 4, 1230–1232 (2005)

    Article  CAS  Google Scholar 

  10. Piva, R. et al. In vivo interference with Skp1 function leads to genetic instability and neoplastic transformation. Mol. Cell. Biol. 22, 8375–8387 (2002)

    Article  CAS  Google Scholar 

  11. Yen, H. C. & Elledge, S. J. Identification of SCF ubiquitin ligase substrates by global protein stability profiling. Science 322, 923–929 (2008)

    Article  ADS  CAS  Google Scholar 

  12. Skaar, J. R. & Pagano, M. Control of cell growth by the SCF and APC/C ubiquitin ligases. Curr. Opin. Cell Biol. 21, 816–824 (2009)

    Article  CAS  Google Scholar 

  13. Jin, J. et al. Systematic analysis and nomenclature of mammalian F-box proteins. Genes Dev. 18, 2573–2580 (2004)

    Article  CAS  Google Scholar 

  14. Edgar, R., Domrachev, M. & Lash, A. E. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30, 207–210 (2002)

    Article  CAS  Google Scholar 

  15. Kato, M. et al. Frequent inactivation of A20 in B-cell lymphomas. Nature 459, 712–716 (2009)

    Article  ADS  CAS  Google Scholar 

  16. D’Angiolella, V. et al. SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation. Nature 466, 138–142 (2010)

    Article  ADS  Google Scholar 

  17. Duan, S. et al. mTOR generates an auto-amplification loop by triggering the βTrCP- and CK1α-dependent degradation of DEPTOR. Mol. Cell 44, 317–324 (2011)

    Article  CAS  Google Scholar 

  18. Bloom, J., Amador, V., Bartolini, F., DeMartino, G. & Pagano, M. Proteasome-mediated degradation of p21 via N-terminal ubiquitinylation. Cell 115, 71–82 (2003)

    Article  CAS  Google Scholar 

  19. Latres, E. et al. Role of the F-box protein Skp2 in lymphomagenesis. Proc. Natl Acad. Sci. USA 98, 2515–2520 (2001)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank W. Carroll, S. Shaham and L. Staudt for sharing unpublished results; A. Melnick, Y. Sun and Y. Xiong for reagents; L. Cerchietti, Y. Cheng, E. Dehan, V. Donato, N. V. Dorello, S. N. Yang and Z. Yao for advice and/or contributions to this work. M.P. is grateful to T. M. Thor and K. E. Davidson, and L.C. to Zuzana S. for continuous support. This work was supported by grants from the National Institutes of Health to M.P. (R01-GM57587, R37-CA76584 and R21-CA161108) and M.S. (PO1-CA092625), a grant from Susan G. Komen for the Cure to S.D., a Lymphoma Research Foundation Fellowship to J.K.P. and grants from AIRC and ERC (ERC-2009-StG-Proposal No242965-LUNELY) to R.C. M.P. is an Investigator with the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

Authors

Contributions

S.D., L.C. and J.K.P. planned and performed most experiments and helped to write the manuscript. M.P. coordinated the study, oversaw the results and wrote the manuscript. C.M., P.F.d.C. and R.C. provided the DLBCL tumour samples and some DLBCL cell lines, and performed some experiments. M.R. generated several constructs. B.C. and M.S. provided the HD-SNP data in Supplementary Fig. 10. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Roberto Chiarle or Michele Pagano.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-14 with legends, Supplementary Tables 1-3 and additional references. (PDF 9357 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Duan, S., Cermak, L., Pagan, J. et al. FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas. Nature 481, 90–93 (2012). https://doi.org/10.1038/nature10688

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10688

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

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