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Cancer-Derived Mutations in KEAP1 Impair NRF2 Degradation but not Ubiquitination
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Abstract
NRF2 is a transcription factor that mediates stress responses. Oncogenic mutations in NRF2 localize to one of its two binding interfaces with KEAP1, an E3 ubiquitin ligase that promotes proteasome-dependent degradation of NRF2. Somatic mutations in KEAP1 occur commonly in human cancer, where KEAP1 may function as a tumor suppressor. These mutations distribute throughout the KEAP1 protein but little is known about their functional impact. In this study, we characterized 18 KEAP1 mutations defined in a lung squamous cell carcinoma tumor set. Four mutations behaved as wild-type KEAP1, thus are likely passenger events. R554Q, W544C, N469fs, P318fs, and G333C mutations attenuated binding and suppression of NRF2 activity. The remaining mutations exhibited hypomorphic suppression of NRF2, binding both NRF2 and CUL3. Proteomic analysis revealed that the R320Q, R470C, G423V, D422N, G186R, S243C, and V155F mutations augmented the binding of KEAP1 and NRF2. Intriguingly, these “super-binder” mutants exhibited reduced degradation of NRF2. Cell-based and in vitro biochemical analyses demonstrated that despite its inability to suppress NRF2 activity, the R320Q “superbinder” mutant maintained the ability to ubiquitinate NRF2. These data strengthen the genetic interactions between KEAP1 and NRF2 in cancer and provide new insight into KEAP1 mechanics. Cancer Res; 74(3); 808–17. ©2013 AACR.
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“Specifically, we discover that the kelch-like protein KEAP1 and the transcriptional activator NRF2, mediate levels of PD-L1 upregulation after IFN γ stimulation.”
From Characterizing the molecular regulation of inhibitory immune checkpoints with multimodal single-cell screens (2021) · cites this paper as [23]
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Metadata
- Authors
- Hast, B. E., Cloer, E. W., Goldfarb, D., Li, H., Siesser, P. F., Yan, F., Walter, V., Zheng, N., Hayes, D. N., & Major, M. B.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Major, Michael B.
- ORCID
- Venue
- Cancer Research
- Published
- 2014-02-01
- Volume
- 74
- Issue
- 3
- Pages
- 808-817
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3932503
- OpenAlex
- W2164442171
- Cited by
- 138
- References
- 45
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 10 · 2023: 16 · 2022: 7 · 2021: 7 · 2020: 18 · 2019: 15 · 2018: 13 · 2017: 12 · 2016: 12 · 2015: 11 · 2014: 5
- FWCI
- 4.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion, public-domain)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion, public-domain)
- UNC Libraries
- Funders
- Howard Hughes Medical Institute
- Golfers Against Cancer
- National Institutes of Health (1dp2od007149-01)
- National Cancer Institute (U24CA143848, T32-CA09475, T32CA009475, T32CA071341)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- Keap1, Nrf2, somatic mutations, lung squamous cell carcinoma, E3 ubiquitin ligase, proteasomal degradation, ubiquitination, protein-protein binding, CUL3, tumor suppressor, passenger mutations
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Humans, Models, Molecular, Mutation, Neoplasms, Protein Binding, Protein Conformation, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2, Ubiquitination, Protein Multimerization, Proteolysis
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