{"doi":"10.1152/physiolgenomics.00160.2012","title":"Elevated cJUN expression and an ATF/CRE site within the ATF3 promoter contribute to activation of ATF3 transcription by the amino acid response","abstract":"<jats:p>Mammalian cells respond to amino acid deprivation through multiple signaling pathways referred to as the amino acid response (AAR). Transcription factors mediate the AAR after their activation by several mechanisms; examples include translational control (activating transcription factor 4, ATF4), phosphorylation (p-cJUN), and transcriptional control (ATF3). ATF4 induces ATF3 transcription through a promoter-localized C/EBP-ATF response element (CARE). The present report characterizes an ATF/CRE site upstream of the CARE that also contributes to AAR-induced ATF3 transcription. ATF4 binds to the ATF/CRE and CARE sequences and both are required for a maximal response to ATF4 induction. ATF3, which antagonizes ATF4 and represses its own gene, also exhibited binding activity to the ATF/CRE and CARE sequences. The AAR resulted in elevated total cJUN and p-cJUN protein levels and both forms exhibited binding activity to the ATF/CRE and CARE ATF3 sequences. Knockdown of AAR-enhanced cJUN expression blocked induction of the ATF3 gene and mutation of either the ATF/CRE or the CARE site prevented the cJUN-dependent increase in ATF3-driven luciferase activity. The results indicate that both increased cJUN and the cis-acting ATF/CRE sequence within the ATF3 promoter contribute to the transcriptional activation of the gene during the AAR.</jats:p>","journal":"Physiological Genomics","year":2013,"id":601520,"datarank":0.48283137373023016,"base_score":3.2188758248682006,"endowment":3.2188758248682006,"self_citation_contribution":0.48283137373023016,"citation_network_contribution":0.0,"self_endowment_contribution":0.48283137373023016,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"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":254431,"name":"Michael S. Kilberg","orcid":"0000-0002-6009-3822","position":1,"is_corresponding":false},{"id":1542383,"name":"Lingchen Fu","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Elevated cJUN expression and an ATF/CRE site within the ATF3 promoter contribute to activation of ATF3 transcription by the amino acid response","abstract":"<jats:p>Mammalian cells respond to amino acid deprivation through multiple signaling pathways referred to as the amino acid response (AAR). Transcription factors mediate the AAR after their activation by several mechanisms; examples include translational control (activating transcription factor 4, ATF4), phosphorylation (p-cJUN), and transcriptional control (ATF3). ATF4 induces ATF3 transcription through a promoter-localized C/EBP-ATF response element (CARE). The present report characterizes an ATF/CRE site upstream of the CARE that also contributes to AAR-induced ATF3 transcription. ATF4 binds to the ATF/CRE and CARE sequences and both are required for a maximal response to ATF4 induction. ATF3, which antagonizes ATF4 and represses its own gene, also exhibited binding activity to the ATF/CRE and CARE sequences. The AAR resulted in elevated total cJUN and p-cJUN protein levels and both forms exhibited binding activity to the ATF/CRE and CARE ATF3 sequences. Knockdown of AAR-enhanced cJUN expression blocked induction of the ATF3 gene and mutation of either the ATF/CRE or the CARE site prevented the cJUN-dependent increase in ATF3-driven luciferase activity. The results indicate that both increased cJUN and the cis-acting ATF/CRE sequence within the ATF3 promoter contribute to the transcriptional activation of the gene during the AAR.</jats:p>","is_dataset_classified":null,"base_score":3.2188758248682006,"endowment":3.2188758248682006,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"23269699","pmcid":"PMC3568878","openalex_id":"https://openalex.org/W2063338364","authors":[],"funders":[{"funder_name":"NIDDK NIH HHS","grant_id":"DK-94729","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"R01 DK094729","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"R01 DK092062","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"DK-92062","title":null}],"total_grants":4,"fwci":1.1079,"citation_percentile":0.74612932,"influential_citations":0,"citation_trend":[{"year":2013,"count":2},{"year":2014,"count":3},{"year":2015,"count":3},{"year":2016,"count":2},{"year":2017,"count":1},{"year":2018,"count":3},{"year":2019,"count":2},{"year":2021,"count":3},{"year":2022,"count":1},{"year":2023,"count":3},{"year":2024,"count":1}],"oa_status":"closed","license":null,"oa_locations":[{"url":"https://www.physiology.org/doi/pdf/10.1152/physiolgenomics.00160.2012","host_type":"publisher"},{"url":"https://doi.org/10.1152/physiolgenomics.00160.2012","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/23269699","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/3568878","host_type":"repository"}],"fields_of_study":["Endoplasmic Reticulum Stress and Disease","CRISPR and Genetic Engineering","RNA regulation and disease","Activating Transcription Factor 3","Activating Transcription Factor 4","Amino Acids","Base Sequence","Binding Sites","CCAAT-Enhancer-Binding Protein-beta","Gene Expression Regulation, Neoplastic","Hep G2 Cells","Histidinol","Humans","Immunoblotting","Molecular Sequence Data","Promoter Regions, Genetic","Protein Binding","Proto-Oncogene Proteins c-jun","RNA Interference","Response Elements","Reverse Transcriptase Polymerase Chain Reaction","Transcription, Genetic"],"mesh_terms":["Amino Acids","Base Sequence","Binding Sites","Histidinol","Humans","Molecular Sequence Data","Promoter Regions, Genetic","Protein Binding","Transcription, Genetic","Immunoblotting","Gene Expression Regulation, Neoplastic","Proto-Oncogene Proteins c-jun","Reverse Transcriptase Polymerase Chain Reaction","Response Elements","CCAAT-Enhancer-Binding Protein-beta","RNA Interference","Activating Transcription Factor 3","Activating Transcription Factor 4","Hep G2 Cells"],"keywords":["Activating transcription factor","ATF3","ATF4","Transcription factor","Gene knockdown","Promoter","Activating transcription factor 2","Response element","Biology","Molecular biology","Transcription (linguistics)","Gene","Gene expression","Genetics"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-29T16:35:57.004849Z","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":[]}