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J. Biol. Chem., Vol. 281, Issue 5, 2551-2561, February 3, 2006

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Binding of Manumycin A Inhibits IB Kinase Activity^*

Michel Bernier¹, Yong-Kook Kwon, Sanjay K. Pandey², Tie-Nian Zhu, Rui-Jing Zhao, Alexandre Maciuk^¶, Hua-Jun He, Rafael DeCabo^||, and Sutapa Kole

From the Diabetes Section, ^¶Bioanalytical Chemistry and Drug Discovery Section, Laboratory of Clinical Investigation, and ^||Laboratory of Experimental Gerontology, NIA, National Institutes of Health, Baltimore, Maryland 21224 and the Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

IB kinase (IKK) catalytic subunits play a key role in cytokinemediated nuclear factor (NF)-B signaling, and a loss of NF-B function appears to inhibit inflammation and oncogenesis. Manumycin A is a potent and selective farnesyltransferase inhibitor with antitumor activity. We found that manumycin A caused a rapid and potent inhibition of IKK activity induced by tumor necrosis factor in a number of cell types. Most unexpectedly, other classes of farnesyltransferase inhibitors had no inhibitory effect. To identify the molecular mechanisms of manumycin A action, cultured human HepG2 hepatoma cells were transiently transfected with various IKK and IKK constructs, and a striking difference in manumycin A sensitivity was observed. Furthermore, cells expressing wild-type IKK and IKK mutated in the activation loop at Cys-179 exhibited covalent homotypic dimerization of IKK in response to manumycin A, whereas substitution of Cys-662 and -716 conferred protection against dimer formation. Direct inhibition of IKK activity and formation of stable IKK dimers were observed in the presence of manumycin A that could be blocked by dithiothreitol. IKK interaction with the adaptor protein IKK/NEMO was disrupted in manumycin A-treated cells. Most importantly, administration of manumycin A to mice xenografted with murine B16F10 tumors caused potent IKK-suppressive effects. Thus, manumycin A with its epoxyquinoid moieties plays an important regulatory function in IKK signaling through pathways distinct from its role as a protein farnesylation inhibitor.

Received for publication, November 3, 2005

^* This work was supported by the Intramural Research Program of the NIA, National Institutes of Health. 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.

² Present address: Isis Pharmaceuticals, Inc., Carlsbad, CA 92008.

¹ To whom correspondence should be addressed: Diabetes Section, NIA, Box 23, 5600 Nathan Shock Dr., Baltimore, MD 21224-6825. Tel.: 410-558-8199; Fax: 410-558-8381; E-mail: Bernierm{at}grc.nia.nih.gov.

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