Kaurane diterpene, kamebakaurin, inhibits NF-κB by directly targeting the DNA-binding activity of p50 and blocks the expression of antiapoptotic NF-κB target genes
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- Kaurane diterpene, kamebakaurin, inhibits NF-κB by directly targeting the DNA-binding activity of p50 and blocks the expression of antiapoptotic NF-κB target genes
- Jeong Hyung Lee; Tae Hyeon Koo; Bang Yeon Hwang; Jung Joon Lee
- Bibliographic Citation
- Journal of Biological Chemistry, vol. 277, no. 21, pp. 18411-18420
- Publication Year
- Kaurane diterpenes have been identified from numerous medicinal plants, which have been used for treatment of inflammation and cancer, however, their molecular mechanism of action remains unclear. We have previously shown that kamebakaurin and other three kaurane diterpenes selectively inhibit activation of transcription factor NF-KκB, a central mediator of apoptosis and immune responses. We here demonstrate that kamebakaurin is a potent inhibitor of NF-κB NF-κB activation by directly targeting DNA-binding activity of p50. Kamebakaurin prevented the activation of NF-κB by different stimuli in various cell types. Kamebakaurin did not prevent either stimuli-induced degradation of IκB-α or nuclear translocation of NF-κB, however, it significantly interfered DNA binding activity of activated NF-κB in cell and in vitro and preferentially prevented p50-mediated DNA-binding activity of NF-κB rather than that of ReIA as measured using in vitro translated p50 and ReIA proteins. Moreover, a p50 mutant with a Cys-62 → Ser mutation was not inhibited with kamebakaurin, indicating that the effect of kamebakaurin was probably due to its interaction with cysteine 62 in p50. The covalent modification of p50 by kamebakaurin was further demonstrated by mass spectrometry analysis that showed an increase in the molecular mass of kamebakaurin-treated p50, and this modification was not reverted by addition of dithiothreitol. These results suggested that kamebakaurin exhibited its inhibitory activity by a direct covalent modification of cysteine 62 in the p50. Also, treatment of cells with kamebakaurin prevented the tumor necrosis factor-α (TNF-α) expression of antiapoptotic NF-κB target genes encoding c-IAP1 (hiap-2) and c-IAP2 (hiap-1), members of the inhibitor of apoptosis family, and Bfl-1/A1 a prosurvival Bcl-2 homologue, and augmented the TNF-α-induced caspase 8 activity, thereby resulting in sensitizing MCF-7 cells to TNF-α-induced apoptosis. Taken together, kamebakaurin is a valuable candidate for the intervention of NF-κB-dependent pathological conditions such as inflammation and cancer.
- Amer Soc Biochemistry Molecular Biology Inc
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