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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.

Original publication

DOI

10.1038/nature01811

Type

Journal article

Journal

Nature

Publication Date

14/08/2003

Volume

424

Pages

797 - 801

Keywords

Apoptosis, Aspirin, Cell Line, Deubiquitinating Enzyme CYLD, Humans, I-kappa B Kinase, NF-kappa B, Protein Binding, Protein-Serine-Threonine Kinases, Proteins, RNA Interference, TNF Receptor-Associated Factor 2, Transfection, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha, Tumor Suppressor Proteins, Ubiquitin