KEAP1 E3 Ligase-Mediated Downregulation of NF-κB Signaling by Targeting IKKβ
Open accessAbstract
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.
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By integrating differences in translocation over time, they identified known key negative regulators with effects on p65 relaxation that did not score in the initial static screen, including TNFAIP3, KEAP1, and USP7.
“By integrating differences in translocation over time, we were able to identify known key negative regulators of the pathway with effects on p65 relaxation that did not score in the initial static screen, including TNFAIP3 (an NF-κB target gene that provides negative feedback by deubiquitinating multiple upstream signaling components) (Chen, 2005), KEAP1 (a ubiquitin ligase involved in degradation”
From Optical Pooled Screens in Human Cells (2019) · cites this paper as Lee et al., 2009
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The Role of NRF2/KEAP1 Signaling Pathway in Cancer Metabolism
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Self-citationDimethyl fumarate, a two‐edged drug: Current status and future directions
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Phytochemicals as Anti-Inflammatory Agents in Animal Models of Prevalent Inflammatory Diseases
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- Authors
- Lee, D.-F., Kuo, H.-P., Liu, M., Chou, C.-K., Xia, W., Du, Y., Shen, J., Chen, C.-T., Huo, L., Hsu, M.-C., Li, C.-W., Ding, Q., Liao, T.-L., Lai, C.-C., Lin, A.-C., Chang, Y.-H., Tsai, S.-F., Li, L.-Y., & Hung, M.-C.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- National Health Research Institutes (TW)
- National Chung Hsing University (TW)
- Asia University (TW)
- Corresponding author
- Hung, Mien-Chie
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 36
- Issue
- 1
- Pages
- 131-140
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC2770835
- OpenAlex
- W2101540252
- Cited by
- 399
- References
- 20
- Citations by year
- 2026: 10 · 2025: 24 · 2024: 24 · 2023: 27 · 2022: 41 · 2021: 27 · 2020: 37 · 2019: 32 · 2018: 22 · 2017: 23 · 2016: 22 · 2015: 20 · 2014: 24 · 2013: 14 · 2012: 18
- FWCI
- 5.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- Breast Cancer Research Foundation (CA16672)
- National Breast Cancer Foundation
- National Health Research Institutes
- National Institutes of Health (CA-16 672, 5p20ca101936-05, CA109311, CCSG CA16672, CA101936, CA099031)
- National Cancer Institute (P50CA116199, CA-16672, P50-CA83639, R01CA109311, P01CA099031, P50CA083639, P20-CA101936, P30CA016672)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Keywords
- Keap1, IKKβ, NF-κB signaling, ubiquitination, protein degradation, tumor angiogenesis, tumor progression, RBX1, carcinogenesis
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Animals, Breast Neoplasms, Carrier Proteins, Cell Line, Female, Humans, Mutation, Neoplasms, Protein Binding, Transfection, Tumor Necrosis Factor-alpha, Signal Transduction, Gene Expression, Interleukin-8, NF-kappa B, Neovascularization, Physiologic, RNA, Small Interfering, Cullin Proteins, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Mice, I-kappa B Kinase, Transcription Factor RelA, Kaplan-Meier Estimate, Protein Interaction Domains and Motifs, Ubiquitination, DNA Copy Number Variations
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