Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-?B.
In: Nature, Jg. 424 (2003-08-14), Heft 6950, S. 797-801
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Zugriff:
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. [ABSTRACT FROM AUTHOR]
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Titel: |
Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-?B.
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Autor/in / Beteiligte Person: | Brummelkamp, Thijn R. ; Nijman, Sehastian M. B. ; Dirac, Annette M. G. ; Bernards, René |
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Zeitschrift: | Nature, Jg. 424 (2003-08-14), Heft 6950, S. 797-801 |
Veröffentlichung: | 2003 |
Medientyp: | academicJournal |
ISSN: | 0028-0836 (print) |
DOI: | 10.1038/nature01811 |
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