{"corpus_id":14887528,"paper_sha":"246913c2ddfaa2eec68159f78eb5015c8a8e0468","doi":"10.1155/2016/7928681","arxiv_id":null,"pmid":26966581,"pmcid":"4761389","mag_id":2271927923,"dblp_id":null,"acl_id":null,"title":"Dependence of Proximal GC Boxes and Binding Transcription Factors in the Regulation of Basal and Valproic Acid-Induced Expression of t-PA","year":2016,"publication_date":"2016-02-07","venue":"International Journal of Vascular Medicine","journal":{"name":"International Journal of Vascular Medicine","pages":null,"volume":"2016"},"journal_issn":null,"journal_title":null,"publication_types":["JournalArticle"],"pubmed_pub_types":["Journal Article"],"s2_fields_of_study":["Biology","Medicine"],"reference_count":32,"citation_count":3,"influential_citation_count":0,"is_open_access":true,"arxiv_categories":null,"arxiv_license":null,"arxiv_journal_ref":null,"mesh_headings":null,"chemicals":null,"comments_corrections":null,"source_flags":5,"s2_open_access_pdf_url":"http://downloads.hindawi.com/journals/ijvm/2016/7928681.pdf","s2_open_access_landing_url":"https://www.semanticscholar.org/paper/246913c2ddfaa2eec68159f78eb5015c8a8e0468","s2_open_access_license":"CCBY","s2_open_access_status":"GOLD","pmc_open_access_pdf_url":null,"pmc_open_access_landing_url":null,"pmc_open_access_license":null,"pmc_open_access_status":null,"unpaywall_open_access_pdf_url":null,"unpaywall_open_access_landing_url":null,"unpaywall_open_access_license":null,"unpaywall_open_access_status":null,"abstract":"Objective. Endothelial tissue-type plasminogen activator (t-PA) release is a pivotal response to protect the circulation from occluding thrombosis. We have shown that the t-PA gene is epigenetically regulated and greatly induced by the histone deacetylase (HDAC) inhibitor valproic acid (VPA). We now investigated involvement of known t-PA promoter regulatory elements and evaluated dependence of potential interacting transcription factors/cofactors. Methods. A reporter vector with an insert, separately mutated at either the t-PA promoter CRE or GC box II or GC box III elements, was transfected into HT-1080 and HUVECs and challenged with VPA. HUVECs were targeted with siRNA against histone acetyl transferases (HAT) and selected transcription factors from the Sp/KLF family. Results. An intact VPA-response was observed with CRE mutated constructs, whereas mutation of GC boxes II and III reduced the magnitude of the induction by 54 and 79% in HT-1080 and 49 and 50% in HUVECs, respectively. An attenuated induction of t-PA mRNA was observed after Sp2, Sp4, and KLF5 depletion. KLF2 and p300 (HAT) were identified as positive regulators of basal t-PA expression and Sp4 and KLF9 as repressors. Conclusion. VPA-induced t-PA expression is dependent on the proximal GC boxes in the t-PA promoter and may involve interactions with Sp2, Sp4, and KLF5.","claims":[{"public_id":"cl_61795cb071a7666ea7acf0a8dd5c49d3","status":"active","text":"Depletion of Sp2, Sp4, and KLF5 attenuates the VPA-induced increase in t-PA mRNA.","confidence":0.96,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_61795cb071a7666ea7acf0a8dd5c49d3"},{"public_id":"cl_5a694b04798ab61eaf6734981c0339e2","status":"active","text":"KLF2 and p300 act as positive regulators of basal t-PA expression, whereas Sp4 and KLF9 act as repressors.","confidence":0.95,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_5a694b04798ab61eaf6734981c0339e2"},{"public_id":"cl_d4b1074919a9dd37346032714638998c","status":"active","text":"Mutation of GC boxes II and III reduced the magnitude of VPA-induced transcriptional activation by 54% and 79% in HT-1080 cells and by 49% and 50% in HUVECs, respectively.","confidence":0.97,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_d4b1074919a9dd37346032714638998c"},{"public_id":"cl_efb8b878600800a57d31359d25d11e3a","status":"active","text":"VPA-induced t-PA expression depends on the proximal GC boxes in the t-PA promoter rather than on the CRE element.","confidence":0.98,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_efb8b878600800a57d31359d25d11e3a"}],"concepts":[{"public_id":"co_1be540a59aa50151a7dcb8b9a5302114","status":"active","name":"t-PA promoter","description":"The promoter region controlling transcription of the t-PA gene.","types":["genetic element"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_1be540a59aa50151a7dcb8b9a5302114"},{"public_id":"co_20907ad59584708312fbeedfa4951567","status":"active","name":"Sp2","description":"A member of the Sp/KLF transcription factor family targeted by siRNA.","types":["transcription factor"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_20907ad59584708312fbeedfa4951567"},{"public_id":"co_33362f347fa20df3fc0b677e5316f80a","status":"active","name":"KLF2","description":"A Krüppel-like transcription factor identified as a positive regulator of basal t-PA expression.","types":["transcription factor"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_33362f347fa20df3fc0b677e5316f80a"},{"public_id":"co_3e1302a0f9dcb3de1a13a7bd8dcfdeba","status":"active","name":"GC box III","description":"The third GC-box promoter element analyzed by mutation in the t-PA promoter.","types":["regulatory element"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_3e1302a0f9dcb3de1a13a7bd8dcfdeba"},{"public_id":"co_411c8c19682f00ca250f487dfd5e6061","status":"active","name":"CRE element","description":"A cAMP response element within the t-PA promoter tested for its role in VPA responsiveness.","types":["regulatory element"],"aliases":["CRE"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_411c8c19682f00ca250f487dfd5e6061"},{"public_id":"co_4b6d5010f0f98d5ab637d31993a9f579","status":"active","name":"HT-1080","description":"A human fibrosarcoma cell line used for reporter assays in this study.","types":["cell line"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_4b6d5010f0f98d5ab637d31993a9f579"},{"public_id":"co_593b2de011206fbe5985ae460ec8910e","status":"active","name":"t-PA mRNA","description":"Messenger RNA encoding t-PA, used as a readout of gene expression.","types":["mRNA"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_593b2de011206fbe5985ae460ec8910e"},{"public_id":"co_7f9f606cfa4d2d5e3599f1764f881aea","status":"active","name":"valproic acid","description":"An HDAC inhibitor used here to stimulate t-PA expression.","types":["compound"],"aliases":["VPA"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_7f9f606cfa4d2d5e3599f1764f881aea"},{"public_id":"co_84cc9eb976e8c01fe8fab1527bbe44ee","status":"active","name":"p300","description":"A histone acetyltransferase cofactor assessed for its role in basal t-PA expression.","types":["cofactor","histone acetyltransferase"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_84cc9eb976e8c01fe8fab1527bbe44ee"},{"public_id":"co_884349aea5a0b7e6f701d6d3dcec1843","status":"active","name":"proximal GC boxes","description":"GC-rich promoter elements located close to the transcription start region of the t-PA promoter.","types":["regulatory element"],"aliases":["GC boxes II and III"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_884349aea5a0b7e6f701d6d3dcec1843"},{"public_id":"co_a81b4670d48fde3c8d4e1b740530cd60","status":"active","name":"KLF5","description":"A Krüppel-like transcription factor targeted in the siRNA experiments.","types":["transcription factor"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_a81b4670d48fde3c8d4e1b740530cd60"},{"public_id":"co_ac4d916a56d60245f9bf117d68c6e350","status":"active","name":"Sp4","description":"A member of the Sp/KLF transcription factor family examined as a regulatory factor of t-PA expression.","types":["transcription factor"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_ac4d916a56d60245f9bf117d68c6e350"},{"public_id":"co_bae8196685240f35db7ae3b3e8a086db","status":"active","name":"HUVECs","description":"Human umbilical vein endothelial cells used for promoter and siRNA experiments.","types":["cell type"],"aliases":["human umbilical vein endothelial cells"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_bae8196685240f35db7ae3b3e8a086db"},{"public_id":"co_bf53411f5f0704d71234919b3b249740","status":"active","name":"KLF9","description":"A Krüppel-like transcription factor identified as a repressor of basal t-PA expression.","types":["transcription factor"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_bf53411f5f0704d71234919b3b249740"},{"public_id":"co_c0a47b43624178118944a171ce201e2b","status":"active","name":"t-PA","description":"Tissue-type plasminogen activator, an endothelial protein involved in fibrinolysis.","types":["protein"],"aliases":["tissue-type plasminogen activator"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_c0a47b43624178118944a171ce201e2b"},{"public_id":"co_caa20db58bdb6ced545dfc9df133662b","status":"active","name":"GC box II","description":"The second GC-box promoter element analyzed by mutation in the t-PA promoter.","types":["regulatory element"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_caa20db58bdb6ced545dfc9df133662b"}],"external_ids":{"DOI":"10.1155/2016/7928681","ArXiv":null,"PubMed":26966581,"PubMedCentral":"4761389","MAG":2271927923,"DBLP":null,"ACL":null},"open_access":{"is_open_access":true,"pdf_url":"http://downloads.hindawi.com/journals/ijvm/2016/7928681.pdf","landing_url":"https://www.semanticscholar.org/paper/246913c2ddfaa2eec68159f78eb5015c8a8e0468","source":"semantic_scholar","pdf_url_source":"semantic_scholar_open_access_pdf","license":"CCBY","status":"GOLD","reason":null},"reference_availability":{"status":"available","references_indexed":true,"full_text_available":false,"full_text_source":null,"count_basis":"semantic_scholar_metadata","extraction_status":"not_applicable","reason":null},"source":{"provider":"episteme2","base_corpus":"semantic_scholar_dump","freshness_mode":"unknown","basis":["semantic_scholar_metadata","postgres_metadata"],"limits":["paper metadata is based on indexed upstream scholarly datasets","claims and concepts are available only for extracted papers","absence of claims or concepts means no extracted graph data is available in this response"],"status":"available","degraded":false,"degraded_reasons":[],"diagnostics":{"status":"available","degraded":false,"degraded_reasons":[],"metadata_status":"available","graph_status":"available","abstract_status":"available"},"source_flags":5},"paper_id":636438,"paper_uid":"33f9f4e4-3aa3-4a7c-b0ae-66898e1f3345","canonical_identity":{"paper_id":636438,"paper_uid":"33f9f4e4-3aa3-4a7c-b0ae-66898e1f3345","identity_status":"available","lookup_basis":"semantic_scholar_external_id","compatibility_path":"corpus_id"},"url":"https://sah.borca.ai/papers/14887528"}