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J. Biol. Chem., Vol. 277, Issue 26, 23573-23581, June 28, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/26/23573    most recent M200842200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Swinney, D. C. Articles by Huber, M. Search for Related Content PubMed PubMed Citation Articles by Swinney, D. C. Articles by Huber, M. Social Bookmarking                      What's this?

A Small Molecule Ubiquitination Inhibitor Blocks NF-B-dependent Cytokine Expression in Cells and Rats^*

David C. Swinney, Yi-Zheng Xu, Liliana E. Scarafia, Ina Lee, Amy Y. Mak, Qing-Fen Gan, Chakkodabylu S. Ramesha, Mary A. Mulkins, Jim Dunn, On-Yee So, Teresa Biegel, Marie Dinh, Pamela Volkel, Jim Barnett, Stacie A. Dalrymple, Simon Lee, and Martin Huber

From the Inflammatory and Viral Diseases Unit, Roche Bioscience, Palo Alto, California 94304

A small molecule inhibitor of NF-B-dependent cytokine expression was discovered that blocked tumor necrosis factor (TNF) -induced IB degradation in MM6 cells but not the degradation of -catenin in Jurkat cells. Ro106-9920 blocked lipopolysaccharide (LPS)-dependent expression of TNF, interleukin-1, and interleukin-6 in fresh human peripheral blood mononuclear cells with IC₅₀ values below 1 µM. Ro106-9920 also blocked TNF production in a dose-dependent manner following oral administration in two acute models of inflammation (air pouch and LPS challenge). Ro106-9920 was observed to inhibit an ubiquitination activity that does not require TRCP but associates with IB and will ubiquitinate IB S32E,S36E (IBee) specifically at lysine 21 or 22. Ro106-9920 was identified in a cell-free system as a time-dependent inhibitor of IBee ubiquitination with an IC₅₀ value of 2.3 ± 0.09 µM. The ubiquitin E3 ligase activity is inhibited by cysteine-alkylating reagents, supported by E2UBCH7, and requires cIAP2 or a cIAP2-associated protein for activity. These activities are inconsistent with what has been reported for SCF^TRCP, the putative E3 for IB ubiquitination. Ro106-9920 was observed to be selective for IBee ubiquitination over the ubiquitin-activating enzyme (E1), E2UBCH7, nonspecific ubiquitination of cellular proteins, and 97 other molecular targets. We propose that Ro106-9920 selectively inhibits an uncharacterized but essential ubiquitination activity associated with LPS- and TNF-induced IB degradation and NF-B activation.

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