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- Title
Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-?B.
- Authors
Brummelkamp, Thijn R.; Nijman, Sehastian M. B.; Dirac, Annette M. G.; Bernards, René
- 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-?B. We show that CYLD binds to the NEMO (also known as IKK?) component of the I?B 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-?B activity, which suggests a therapeutic intervention strategy to restore growth control in patients suffering from familial cylindromatosis.
- Subjects
PROTEINS; APOPTOSIS; RNA; ENZYMES; TUMOR suppressor genes
- Publication
Nature, 2003, Vol 424, Issue 6950, p797
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature01811