{"doi":"10.1128/mcb.24.24.10941-10953.2004","title":"Keap1 Is a Redox-Regulated Substrate Adaptor Protein for a Cul3-Dependent Ubiquitin Ligase Complex","abstract":null,"journal":"Molecular and Cellular Biology","year":2004,"id":669811,"datarank":14.514325912245628,"base_score":7.126890808898808,"endowment":7.126890808898808,"self_citation_contribution":1.0690336213348213,"citation_network_contribution":13.445292290910807,"self_endowment_contribution":1.0690336213348213,"citer_contribution":13.445292290910807,"corpus_percentile":null,"corpus_rank":null,"citation_count":1244,"citer_count":200,"citers_with_citation_signal":200,"citers_with_endowment":200,"datacite_reuse_total":2,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1749386,"name":"Shih-Ching Lo","orcid":null,"position":1,"is_corresponding":false},{"id":594971,"name":"Janet V. Cross","orcid":"0000-0002-9528-0812","position":2,"is_corresponding":false},{"id":837043,"name":"Dennis J. Templeton","orcid":null,"position":3,"is_corresponding":false},{"id":447520,"name":"Mark Hannink","orcid":"0000-0002-7319-6572","position":4,"is_corresponding":false},{"id":228195,"name":"Donna D. Zhang","orcid":"0000-0002-8972-697X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex.","abstract":"The bZIP transcription factor Nrf2 controls a genetic program that protects cells from oxidative damage and maintains cellular redox homeostasis. Keap1, a BTB-Kelch protein, is the major upstream regulator of Nrf2 and controls both the subcellular localization and steady-state levels of Nrf2. In this report, we demonstrate that Keap1 functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex. Keap1 assembles into a functional E3 ubiquitin ligase complex with Cul3 and Rbx1 that targets multiple lysine residues located in the N-terminal Neh2 domain of Nrf2 for ubiquitin conjugation both in vivo and in vitro. Keap1-dependent ubiquitination of Nrf2 is inhibited following exposure of cells to quinone-induced oxidative stress and sulforaphane, a cancer-preventive isothiocyanate. A mutant Keap1 protein containing a single cysteine-to-serine substitution at residue 151 within the BTB domain of Keap1 is markedly resistant to inhibition by either quinone-induced oxidative stress or sulforaphane. Inhibition of Keap1-dependent ubiquitination of Nrf2 correlates with decreased association of Keap1 with Cul3. Neither quinone-induced oxidative stress nor sulforaphane disrupts association between Keap1 and Nrf2. Our results suggest that the ability of Keap1 to assemble into a functional E3 ubiquitin ligase complex is the critical determinant that controls steady-state levels of Nrf2 in response to cancer-preventive compounds and oxidative stress.","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":2,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"15572695","pmcid":"PMC533977","openalex_id":null,"authors":[],"funders":[{"funder_name":"NCI NIH HHS","grant_id":"P50 CA 103130","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"1R01 GM 59213","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM059213","title":null},{"funder_name":"NCI NIH HHS","grant_id":"CA 66134","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA066134","title":null}],"total_grants":5,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":null,"license":null,"oa_locations":[],"fields_of_study":[],"mesh_terms":["COS Cells","Cell Line, Tumor","Animals","Humans","Breast Neoplasms","Thiocyanates","Isothiocyanates","Hydroquinones","Sulfoxides","Ubiquitin-Protein Ligases","Cullin Proteins","Luciferases","Lysine","Serine","Intracellular Signaling Peptides and Proteins","Adaptor Proteins, Signal Transducing","Proteins","Cell Cycle Proteins","DNA-Binding Proteins","Trans-Activators","Ubiquitins","Anticarcinogenic Agents","Antioxidants","Immunoblotting","Precipitin Tests","Amino Acid Substitution","Amino Acid Sequence","Protein Structure, Tertiary","Substrate Specificity","Oxidation-Reduction","Oxidative Stress","Genes, Reporter","NF-E2-Related Factor 2","Kelch-Like ECH-Associated Protein 1","Chlorocebus aethiops"],"keywords":[],"sdg_mappings":[],"linked_datasets":[{"doi":"10.6084/m9.figshare.14299501.v1","title":"Additional file 2 of NRF2 is required for structural and metabolic maturation of human induced pluripotent stem cell-derived ardiomyocytes","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.14299501","title":"Additional file 2 of NRF2 is required for structural and metabolic maturation of human induced pluripotent stem cell-derived ardiomyocytes","publisher":"figshare","resource_type":"JournalArticle"}],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-15T04:57:12.012348Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}