KEAP1 E3 ligase-mediated downregulation of NF-kappaB signaling by targeting IKKbeta

Authors

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-Hui Chang
Shih-Feng Tsai
Long-Yuan Li
Mien-Chie Hung

Publication Date

10-9-2009

Journal

Molecular Cell

Abstract

IkappaB kinase beta (IKKbeta) is involved in tumor development and progression through activation of the nuclear factor (NF)-kappaB pathway. However, the molecular mechanism that regulates IKKbeta 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 IKKbeta ubiquitination. Depletion of KEAP1 led to the accumulation and stabilization of IKKbeta and to upregulation of NF-kappaB-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 IKKbeta degradation. Our results suggest that the dysregulation of KEAP1-mediated IKKbeta ubiquitination may contribute to tumorigenesis.

Keywords

Animals, Breast Neoplasms, Carrier Proteins, Cell Line, Cell Line, Tumor, Cullin Proteins, DNA Copy Number Variations, Female, Gene Expression, Humans, I-kappa B Kinase, Interleukin-8, Intracellular Signaling Peptides and Proteins, Kaplan-Meier Estimate, Mice, Mutation, NF-kappa B, Neoplasms, Neovascularization, Physiologic, Protein Binding, Protein Interaction Domains and Motifs, RNA, Small Interfering, Signal Transduction, Transcription Factor RelA, Transfection, Tumor Necrosis Factor-alpha, Ubiquitination