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Merck

Mutation of cysteine 46 in IKK-beta increases inflammatory responses.

Oncotarget (2015-09-18)
Ting Li, Vincent Kam Wai Wong, Zhi Hong Jiang, Shui Ping Jiang, Yan Liu, Ting Yu Wang, Xiao Jun Yao, Xiao Hui Su, Feng Gen Yan, Juan Liu, Elaine Lai-Han Leung, Xiao Qin Yi, Yuen Fan Wong, Hua Zhou, Liang Liu
RESUMEN

Activation of IκB kinase β (IKK-β) and nuclear factor (NF)-κB signaling contributes to cancer pathogenesis and inflammatory disease; therefore, the IKK-β-NF-κB signaling pathway is a potential therapeutic target. Current drug design strategies focus on blocking NF-κB signaling by binding to specific cysteine residues on IKK-β. However, mutations in IKK-β have been found in patients who may eventually develop drug resistance. For these patients, a new generation of IKK-β inhibitors are required to provide novel treatment options. We demonstrate in vitro that cysteine-46 (Cys-46) is an essential residue for IKK-β kinase activity. We then validate the role of Cys-46 in the pathogenesis of inflammation using delayed-type hypersensitivity (DTH) and an IKK-β C46A transgenic mouse model. We show that a novel IKK-β inhibitor, dihydromyricetin (DMY), has anti-inflammatory effects on WT DTH mice but not IKK-β C46A transgenic mice. These findings reveal the role of Cys-46 in the promotion of inflammatory responses, and suggest that Cys-46 is a novel drug-binding site for the inhibition of IKK-β.