PMID:16319058

Citation	Bernier, M, Kwon, YK, Pandey, SK, Zhu, TN, Zhao, RJ, Maciuk, A, He, HJ, Decabo, R and Kole, S (2006) Binding of manumycin A inhibits IkappaB kinase beta activity. J. Biol. Chem. 281:2551-61
Abstract	IkappaB kinase (IKK) catalytic subunits play a key role in cytokinemediated nuclear factor (NF)-kappaB signaling, and a loss of NF-kappaB 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 alpha 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 IKKalpha and IKKbeta constructs, and a striking difference in manumycin A sensitivity was observed. Furthermore, cells expressing wild-type IKKbeta and IKKbeta mutated in the activation loop at Cys-179 exhibited covalent homotypic dimerization of IKKbeta 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 IKKbeta dimers were observed in the presence of manumycin A that could be blocked by dithiothreitol. IKK interaction with the adaptor protein IKKgamma/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.
Links	PubMed Online version:10.1074/jbc.M511878200
Keywords	Amino Acid Substitution; Animals; Cell Line, Tumor; Dimerization; Humans; I-kappa B Kinase/antagonists & inhibitors; I-kappa B Kinase/genetics; Mice; Neoplasms, Experimental/drug therapy; Polyenes/pharmacology; Polyenes/therapeutic use; Polyunsaturated Alkamides; Protein Binding; Transfection; Tumor Necrosis Factor-alpha/pharmacology
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