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

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.

• Authors: Thijn R Brummelkamp, Sebastian M B Nijman, Annette M G Dirac, René Bernards
• Journal: Nature (Nature) Vol. 424 Issue 6950 Pg. 797-801 (Aug 14 2003) ISSN: 1476-4687 [Electronic] England
• PMID: 12917690 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Apoptosis (drug effects)
• Aspirin (analogs & derivatives, pharmacology)
• Cell Line
• Deubiquitinating Enzyme CYLD
• Humans
• I-kappa B Kinase
• NF-kappa B (antagonists & inhibitors, 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, deficiency, genetics, metabolism)
• Ubiquitin (metabolism)