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.

  • Letter
  • Published:

Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB

Nature volume 424, pages 797–801 (2003)Cite this article

Abstract

Protein modification by the conjugation of ubiquitin moieties—ubiquitination—plays a major part in many biological processes, including cell cycle and apoptosis1. The enzymes that mediate ubiquitin-conjugation have been well-studied, but much less is known about the ubiquitin-specific proteases that mediate de-ubiquitination of cellular substrates2,3. To study this gene family, we designed a collection of RNA interference vectors to suppress 50 human de-ubiquitinating enzymes, and used these vectors to identify de-ubiquitinating enzymes in cancer-relevant pathways. We report here that inhibition of one of these enzymes, the familial cylindromatosis tumour suppressor gene (CYLD)4, having no known function, enhances activation of the transcription factor NF-κB. We show that CYLD binds to the NEMO (also known as IKKγ) component of the IκB kinase (IKK) complex, and appears to regulate its activity through de-ubiquitination of TRAF2, as TRAF2 ubiquitination can be modulated by CYLD. Inhibition of CYLD increases resistance to apoptosis, suggesting a mechanism through which loss of CYLD contributes to oncogenesis. We show that this effect can be relieved by aspirin derivatives that inhibit NF-κB activity5, which suggests a therapeutic intervention strategy to restore growth control in patients suffering from familial cylindromatosis.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Genome-wide DUB knockdown screen.
Figure 2: CYLD is an antagonist of NF-κB signalling.
Figure 3: CYLD loss protects against TNF-α induced apoptosis.
Figure 4: Anti-apoptotic effects of CYLD loss can be reversed by aspirin.

Similar content being viewed by others

References

  1. Wilkinson, K. D. Ubiquitination and deubiquitination: Targeting of proteins for degradation by the proteasome. Semin. Cell Dev. Biol. 11, 141–148 (2000)

    Article  CAS  Google Scholar 

  2. Chung, C. H. & Baek, S. H. Deubiquitinating enzymes: Their diversity and emerging roles. Biochem. Biophys. Res. Commun. 266, 633–640 (1999)

    Article  CAS  Google Scholar 

  3. D'Andrea, A. & Pellman, D. Deubiquitinating enzymes: A new class of biological regulators. Crit. Rev. Biochem. Mol. Biol. 33, 337–352 (1998)

    Article  CAS  Google Scholar 

  4. Bignell, G. R. et al. Identification of the familial cylindromatosis tumour-suppressor gene. Nature Genet. 25, 160–165 (2000)

    Article  CAS  Google Scholar 

  5. Yin, M. J., Yamamoto, Y. & Gaynor, R. B. The anti-inflammatory agents aspirin and salicylate inhibit the activity of IκB kinase-β. Nature 396, 77–80 (1998)

    Article  ADS  CAS  Google Scholar 

  6. Nakamura, T., Hillova, J., Mariage-Samson, R. & Hill, M. Molecular cloning of a novel oncogene generated by DNA recombination during transfection. Oncogene Res. 2, 357–370 (1988)

    CAS  PubMed  Google Scholar 

  7. Papa, F. R. & Hochstrasser, M. The yeast DOA4 gene encodes a deubiquitinating enzyme related to a product of the human tre-2 oncogene. Nature 366, 313–319 (1993)

    Article  ADS  CAS  Google Scholar 

  8. Brummelkamp, T. R., Bernards, R. & Agami, R. A system for stable expression of short interfering RNAs in mammalian cells. Science 296, 550–553 (2002)

    Article  ADS  CAS  Google Scholar 

  9. Karin, M., Cao, Y., Greten, F. R. & Li, Z. W. NF-κB in cancer: From innocent bystander to major culprit. Nature Rev. Cancer 2, 301–310 (2002)

    Article  CAS  Google Scholar 

  10. Smahi, A. et al. The NF-κB signalling pathway in human diseases: From incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes. Hum. Mol. Genet. 11, 2371–2375 (2002)

    Article  CAS  Google Scholar 

  11. Trompouki, E. et al. CYLD is a deubiquitinating enzyme that negatively regulates NF-kB activation by TNFR family members. Nature 424, 793–796 (2003)

    Article  ADS  CAS  Google Scholar 

  12. Bradley, J. R. & Pober, J. S. Tumor necrosis factor receptor-associated factors (TRAFs). Oncogene 20, 6482–6491 (2001)

    Article  CAS  Google Scholar 

  13. Chung, J. Y., Park, Y. C., Ye, H. & Wu, H. All TRAFs are not created equal: Common and distinct molecular mechanisms of TRAF-mediated signal transduction. J. Cell Sci. 115, 679–688 (2002)

    CAS  PubMed  Google Scholar 

  14. Shi, C. S. & Kehrl, J. H. TNF-induced GCKR and SAPK activation depends upon the E2/E3 complex Ubc13-Uev1A/TRAF2. J. Biol. Chem. 18, 15429–15434 (2003)

    Article  Google Scholar 

  15. Wang, C. et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412, 346–351 (2001)

    Article  ADS  CAS  Google Scholar 

  16. Holtmann, H., Hahn, T. & Wallach, D. Interrelated effects of tumor necrosis factor and interleukin 1 on cell viability. Immunobiology 177, 7–22 (1988)

    Article  CAS  Google Scholar 

  17. Wang, C. Y., Mayo, M. W. & Baldwin, A. S. Jr TNF- and cancer therapy-induced apoptosis: Potentiation by inhibition of NF-κB. Science 274, 784–787 (1996)

    Article  ADS  CAS  Google Scholar 

  18. Liu, Z. G., Hsu, H., Goeddel, D. V. & Karin, M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-κB activation prevents cell death. Cell 87, 565–576 (1996)

    Article  CAS  Google Scholar 

  19. De Smaele, E. et al. Induction of gadd45β by NF-κB downregulates pro-apoptotic JNK signalling. Nature 414, 308–313 (2001)

    Article  ADS  CAS  Google Scholar 

  20. Baud, V. & Karin, M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol. 11, 372–377 (2001)

    Article  CAS  Google Scholar 

  21. Rossi, A. et al. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase. Nature 403, 103–108 (2000)

    Article  ADS  CAS  Google Scholar 

  22. Dajee, M. et al. NF-κB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421, 639–643 (2003)

    Article  ADS  CAS  Google Scholar 

  23. van Balkom, I. D. & Hennekam, R. C. Dermal eccrine cylindromatosis. J. Med. Genet. 31, 321–324 (1994)

    Article  CAS  Google Scholar 

  24. Schmidt-Ullrich, R. et al. NF-κB activity in transgenic mice: Developmental regulation and tissue specificity. Development 122, 2117–2128 (1996)

    CAS  PubMed  Google Scholar 

  25. Schmidt-Ullrich, R. et al. Requirement of NF-κB/Rel for the development of hair follicles and other epidermal appendices. Development 128, 3843–3853 (2001)

    CAS  PubMed  Google Scholar 

  26. Agami, R. & Bernards, R. Distinct initiation and maintenance mechanisms cooperate to induce G1 cell cycle arrest in response to DNA damage. Cell 102, 55–66 (2000)

    Article  CAS  Google Scholar 

  27. Chen, G., Cao, P. & Goeddel, D. V. TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90. Mol. Cell 9, 401–410 (2002)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Lens, A. Lund and J. Borst for reagents, and M. Madiredjo for assistance. This work was supported by the Centre for Biomedical Genetics (CBG) and the Netherlands Organization for Scientific Research (NWO). A.D. was supported by a long-term fellowship from EMBO.

Author information

Author notes

  1. Thijn R. Brummelkamp, Sebastian M. B. Nijman and Annette M. G. Dirac: These authors contributed equally to this work

Authors and Affiliations

  1. Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Thijn R. Brummelkamp, Sebastian M. B. Nijman, Annette M. G. Dirac & René Bernards

Authors
  1. Thijn R. Brummelkamp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sebastian M. B. Nijman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Annette M. G. Dirac
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. René Bernards
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to René Bernards.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brummelkamp, T., Nijman, S., Dirac, A. et al. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB. Nature 424, 797–801 (2003). https://doi.org/10.1038/nature01811

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01811

Search

Advanced 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