Loss of the Cylindromatosis Tumour Suppressor Inhibits Apoptosis by Activating NF-kappaB

Nature. 2003 Aug 14;424(6950):797-801. doi: 10.1038/nature01811.

Abstract

Protein modification by the conjugation of ubiquitin moieties--ubiquitination--plays a major part in many biological processes, including cell cycle and apoptosis. 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 substrates. 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), having no known function, enhances activation of the transcription factor NF-kappaB. We show that CYLD binds to the NEMO (also known as IKKgamma) component of the IkappaB 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-kappaB activity, which suggests a therapeutic intervention strategy to restore growth control in patients suffering from familial cylindromatosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis* / drug effects
  • Aspirin / analogs & derivatives
  • Aspirin / pharmacology
  • Cell Line
  • Deubiquitinating Enzyme CYLD
  • Humans
  • I-kappa B Kinase
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins / metabolism
  • RNA Interference
  • TNF Receptor-Associated Factor 2
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Suppressor Proteins / antagonists & inhibitors
  • Tumor Suppressor Proteins / deficiency*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin / metabolism

Substances

  • NF-kappa B
  • Proteins
  • TNF Receptor-Associated Factor 2
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Proteins
  • Ubiquitin
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • CYLD protein, human
  • Deubiquitinating Enzyme CYLD
  • Aspirin