{"doi":"10.17615/g1fy-ae71","title":"Positive and negative regulation of EAAT2 by NF-κB: a role for N-myc in TNFα-controlled repression","abstract":"The glutamate transporter gene, EAAT2/GLT-1, is induced by epidermal growth factor (EGF) and downregulated by tumor necrosis factor α (TNFα). While TNFα is generally recognized as a positive regulator of NF-κB-dependent gene expression, its ability to control transcriptional repression is not well characterized. Additionally, the regulation of NF-κB by EGF is poorly understood. Herein, we demonstrate that both TNFα-mediated repression and EGF-mediated activation of EAAT2 expression require NF-κB. We show that EGF activates NF-κB independently of signaling to IκB. Furthermore, TNFα can abrogate IKKβ- and p65-mediated activation of EAAT2. Our results suggest that NF-κB can intrinsically activate EAAT2 and that TNFα mediates repression through a distinct pathway also requiring NF-κB. Consistently, we find that N-myc is recruited to the EAAT2 promoter with TNFα and that N-myc-binding sites are required for TNFα-mediated repression. Moreover, N-myc overexpression inhibits both basal and p65-induced activation of EAAT2. Our data highlight the remarkable specificity of NF-κB activity to regulate gene expression in response to diverse cellular signals and have implications for glutamate homeostasis and neurodegenerative disease.","journal":"UNC Libraries","year":2020,"id":137810,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9527,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":256476,"name":"Raquel Sitcheran","orcid":"0000-0001-8916-9707","position":1,"is_corresponding":false},{"id":598467,"name":"Pankaj Gupta","orcid":"0000-0001-7573-7945","position":2,"is_corresponding":false},{"id":282004,"name":"Paul B. Fisher","orcid":"0000-0002-0085-4546","position":3,"is_corresponding":false},{"id":544112,"name":"Albert S. Baldwin","orcid":"0000-0003-1246-1333","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:16:59.449905Z","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":[]}