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J. Biol. Chem., Vol. 282, Issue 7, 4253-4264, February 16, 2007

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Withaferin A Strongly Elicits IB Kinase Hyperphosphorylation Concomitant with Potent Inhibition of Its Kinase Activity^*

Mary Kaileh¹, Wim Vanden Berghe², Arne Heyerick^¶, Julie Horion^||, Jacques Piette^||, Claude Libert^**, Denis De Keukeleire^¶, Tamer Essawi, and Guy Haegeman³

From the Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST), Department of Molecular Biology, Ghent University-UGent, K. L. Ledeganckstraat 35, B-9000 Gent, Belgium, Master program in Clinical Laboratory Sciences, Birzeit University, P. O. Box 14, Birzeit, Palestine, ^||Center for Biomedical Integrated Genoproteomics (CBIG), Virology and Immunology Unit, Institute of Pathology B23, B-4000 Liege, Belgium, ^**Department of Molecular Biomedical Research, Flanders Interuniversity for Biotechnology and Ghent University, Technologiepark 927, B-9052 Zwijnaarde, Belgium, and ^¶Laboratory of Pharmacognosy and Phytochemistry, Ghent University-UGent, Harelbekestraat 72, B-9000 Gent, Belgium

The transcription factor NFB plays a critical role in normal and pathophysiological immune responses. Therefore, NFB and the signaling pathways that regulate its activation have become a major focus of drug development programs. Withania somnifera (WS) is a medicinal plant that is widely used in Palestine for the treatment of various inflammatory disorders. In this study we show that the leave extract of WS, as well as its major constituent withaferin A (WA), potently inhibits NFB activation by preventing the tumor necrosis factor-induced activation of IB kinase via a thioalkylation-sensitive redox mechanism, whereas other WS-derived steroidal lactones, such as withanolide A and 12-deoxywithastramonolide, are far less effective. To our knowledge, this is the first communication of IB kinase inhibition by a plant-derived inhibitor, coinciding with MEK1/ERK-dependent Ser-181 hyperphosphorylation. This prevents IB phosphorylation and degradation, which subsequently blocks NFB translocation, NFB/DNA binding, and gene transcription. Taken together, our results indicate that pure WA or WA-enriched WS extracts can be considered as a novel class of NFB inhibitors, which hold promise as novel anti-inflammatory agents for treatment of various inflammatory disorders and/or cancer.

Received for publication, July 14, 2006 , and in revised form, December 6, 2006.

^* This work was supported in part by grants from Interuniversitaire Attractiepolen V and from Geconcerteerde Onderzoeksacties. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Supported by Belgian technical cooperation and L’OREAL-United Nations Educational, Scientific, and Cultural Organization for women in science fellowships.

² A postdoctoral fellow with the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen.

³ To whom correspondence should be addressed. Tel.: 003292645166; Fax: 003292645304; E-mail: Guy.Haegeman{at}UGent.be.

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