KEAP1 E3 Ligase-Mediated Downregulation of NF-κB Signaling by Targeting IKKβ

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• 作者：Dung-Fang Lee ; Hsu-Ping Kuo ; Mo Liu ; Chao-Kai Chou ; Weiya Xia ; Yi Du ; Jia Shen ; Chun-Te Chen ; Longfei Huo ; Ming-Chuan Hsu ; Chia-Wei Li ; Qingqing Ding ; Tsai-Lien Liao ; Chien-Chen Lai ; Ann-Chi Lin ; Ya-H
• 刊名：Molecular Cell
• 出版年：2009
• 期刊代码：111_10972765
• 类别：bio
• 出版时间：9 October 2009
• 卷：36
• 期：1
• 页码：131-140
• 文件大小：1427 K

摘要

Summary

IκB kinase β (IKKβ) is involved in tumor development and progression through activation of the nuclear factor (NF)-κB pathway. However, the molecular mechanism that regulates IKKβ degradation remains largely unknown. Here, we show that a Cullin 3 (CUL3)-based ubiquitin ligase, Kelch-like ECH-associated protein 1 (KEAP1), is responsible for IKKβ ubiquitination. Depletion of KEAP1 led to the accumulation and stabilization of IKKβ and to upregulation of NF-κB-derived tumor angiogenic factors. A systematic analysis of the CUL3, KEAP1, and RBX1 genomic loci revealed a high percentage of genome loss and missense mutations in human cancers that failed to facilitate IKKβ degradation. Our results suggest that the dysregulation of KEAP1-mediated IKKβ ubiquitination may contribute to tumorigenesis.