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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Line
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Cell Line, Tumor
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Cullin Proteins / genetics
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Cullin Proteins / metabolism
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DNA Copy Number Variations / genetics
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Female
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Gene Expression / drug effects
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Gene Expression / genetics
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Humans
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I-kappa B Kinase / genetics
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I-kappa B Kinase / metabolism*
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Interleukin-8 / genetics
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Intracellular Signaling Peptides and Proteins / physiology*
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Kaplan-Meier Estimate
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Kelch-Like ECH-Associated Protein 1
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Mice
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Mutation / physiology
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NF-kappa B / metabolism*
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Neoplasms / genetics
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Neoplasms / metabolism
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Neovascularization, Physiologic / genetics
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Protein Binding / physiology
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Protein Interaction Domains and Motifs / physiology
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RNA, Small Interfering / genetics
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Transcription Factor RelA / metabolism
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Transfection
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Tumor Necrosis Factor-alpha / pharmacology
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Ubiquitination / physiology
Substances
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CUL3 protein, human
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Carrier Proteins
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Cullin Proteins
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Interleukin-8
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Intracellular Signaling Peptides and Proteins
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KEAP1 protein, human
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Kelch-Like ECH-Associated Protein 1
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NF-kappa B
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RBX1 protein, human
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RELA protein, human
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RNA, Small Interfering
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha
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I-kappa B Kinase