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