Oncotarget

Research Papers:

Mutation of cysteine 46 in IKK-beta increases inflammatory responses

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 and Liang Liu _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2015; 6:31805-31819. https://doi.org/10.18632/oncotarget.5567

Metrics: PDF 903 views  |   HTML 1476 views  |   ?  


Abstract

Ting Li1,*, Vincent Kam Wai Wong1,*, Zhi Hong Jiang1, Shui Ping Jiang1, Yan Liu2, Ting Yu Wang2, Xiao Jun Yao1, Xiao Hui Su1, Feng Gen Yan1, Juan Liu1, Elaine Lai-Han Leung1, Xiao Qin Yi2, Yuen Fan Wong2, Hua Zhou1 and Liang Liu1

1 State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China

2 Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China

* These authors contributed equally to this work

Correspondence to:

Liang Liu, email:

Hua Zhou, email:

Keywords: cysteine mutation, dihydromyricetin, IKK-β inhibitor, inflammation, NF-κB

Received: April 15, 2015 Accepted: August 13, 2015 Published: September 10, 2015

Abstract

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 5567