ArticleProceedings of the National Academy of Sciences of the United States of America2005
Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 218 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
218 citing papers in PubMed, 1 synthesis or guideline pooled it, 448 citations in OpenAlex.
- Combination therapy in combating cancer.Oncotarget · 2017Pooled it
- γ-Glutamylcysteine alleviates hypertension and vascular remodeling in SHR by suppressing oxidative stress through Keap1 S-glutathionylation.Redox report : communications in free radical research · 2026Article
- Compensation for impaired sensing of selenoprotein deficiency by alternative cysteine residues in KEAP1.Redox biology · 2026Article
- Interplay between NRF2 post-translational modifications and protein-protein interactions: Perspectives from emerging structural and functional evidence.Archives of biochemistry and biophysics · 2026Review
- Covalent Modification of Keap1 by the Key Metabolic Cofactor Coenzyme A Under Oxidative and Metabolic Stress.Antioxidants (Basel, Switzerland) · 2026Article
- Graph-Based Deep Learning Models for Predicting pJournal of chemical information and modeling · 2026Article
- Drosophila Keap1 Proteins Assemble Nuclear Condensates in Response to Oxidative Stress.Antioxidants (Basel, Switzerland) · 2026Article
- Altered transposon element-derived genes distort oxygen-free radical scavenger systems in FXD.NAR molecular medicine · 2026Article
- Plant polyphenols as context-dependent modulators of cellular signalling networks.Frontiers in nutrition · 2026Review
- IRG1-itaconate axis in immunometabolism: mechanistic roles and therapeutic potential in inflammatory diseases.Frontiers in immunology · 2026Review
- Effects of the Pharmacological Modulation of NRF2 in Cancer Progression.Medicina (Kaunas, Lithuania) · 2025Review
- Molecular defense strategy of volatile organic compound-emitting plants (order Piperales) against herbivorous mammals.Communications biology · 2025Article
- Deciphering the determinants of recombinant protein expression across the human secretome.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Dynamic regulation of the oxidative stress response by the E3 ligase TRIP12.Cell reports · 2025Article
- [Research progress in the regulation of allergic rhinitis pathogenesis by the NRF2 pathway].Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology head and neck surgery · 2025Review
- Role of oxeiptosis in disease mechanisms and therapeutic opportunities.Apoptosis : an international journal on programmed cell death · 2025Review
- HFE-Related Hemochromatosis May Be a Primary Kupffer Cell Disease.Biomedicines · 2025Review
- Pharmacodynamics (PD), Pharmacokinetics (PK) and PK-PD Modeling of NRF2 Activating Dietary Phytochemicals in Cancer Prevention and in Health.Current pharmacology reports · 2025Review
- Potential Signal Pathways and Therapeutic Effects of Mesenchymal Stem Cell on Oxidative Stress in Diseases.Current pharmaceutical design · 2025Review
- Emerging Therapeutic Targets in Rheumatoid Arthritis: Focusing on HIF-1α, Nrf2, STATs, and RORγt.Current drug targets · 2025Review
158 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
The risks of cancer and other degenerative diseases caused by reactive oxygen species and electrophiles can be reduced by the up-regulation of detoxifying enzymes. A major mechanism whereby these protective enzymes are induced occurs through activation of the antioxidant response element (ARE) by the oxidative-stress sensor protein Kelch-like ECH-associated protein 1 (Keap1) and the transcription factor NF-E2-related factor 2 (Nrf2). Under basal conditions, Keap1 sequesters Nrf2 in the cytoplasm by binding to its Neh2 domain. Chemical inducers such as sulforaphane are known to react with Keap1 cysteine residues, thereby promoting Nrf2 nuclear accumulation and hence ARE activation. A widely accepted model for Nrf2 nuclear accumulation is that modification of Keap1 cysteines leads directly to dissociation of the Keap1-Nrf2 complex. This model is based on studies with mouse proteins and has served as the experimental basis and hypothesis for numerous investigations. Through a combination of chemical, mass spectrometry, and isothermal titration calorimetry methods, we have tested the direct-dissociation model using a series of ARE inducers: sulforaphane, isoliquiritigenin, 15-deoxy-Delta12,14-prostaglandin-J2, menadione, 1-Cl-2,4-dinitrobenzene, and biotinylated iodoacetamide. Surprisingly, these data suggest that the direct disruption model for Keap1-Nrf2 is incorrect. The relative reactivity of human Keap1 cysteines was determined. In addition to the same five cysteines identified for mouse Keap1, two highly reactive and previously unobserved cysteines were identified. Based on these results, a model is proposed that should aid in the understanding of Keap1-Nrf2 signaling mechanisms.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.