Binding of Manumycin A Inhibits IκB Kinase β Activity
| Autor: | Michel Bernier, Sanjay K. Pandey, Tienian Zhu, Rui-Jing Zhao, Hua-Jun He, Alexandre Maciuk, Sutapa Kole, Rafael deCabo, Yong-Kook Kwon |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
biology
Chemistry Farnesyltransferase Farnesyltransferase inhibitor Signal transducing adaptor protein Cell Biology IκB kinase Transfection medicine.disease_cause Biochemistry Dithiothreitol Cell biology chemistry.chemical_compound Prenylation biology.protein medicine Carcinogenesis Molecular Biology |
| Zdroj: | Journal of Biological Chemistry. 281:2551-2561 |
| ISSN: | 0021-9258 |
| Popis: | IκB kinase (IKK) catalytic subunits play a key role in cytokinemediated nuclear factor (NF)-κB signaling, and a loss of NF-κB 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 α 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 IKKα and IKKβ constructs, and a striking difference in manumycin A sensitivity was observed. Furthermore, cells expressing wild-type IKKβ and IKKβ mutated in the activation loop at Cys-179 exhibited covalent homotypic dimerization of IKKβ 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 IKKβ dimers were observed in the presence of manumycin A that could be blocked by dithiothreitol. IKK interaction with the adaptor protein IKKγ/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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|