Distamycin A inhibits HMGA1-binding to the P-selectin promoter and attenuates lung and liver inflammation during murine endotoxemia

Background The architectural transcription factor High Mobility Group-A1 (HMGA1) binds to the minor groove of AT-rich DNA and forms transcription factor complexes (“enhanceosomes”) that upregulate expression of select genes within the inflammatory cascade during critical illness syndromes such as ac...

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Fecha de publicación:
2010
Institución:
Universidad del Rosario
Repositorio:
Repositorio EdocUR - U. Rosario
Idioma:
eng
OAI Identifier:
oai:repository.urosario.edu.co:10336/27530
Acceso en línea:
https://doi.org/10.1371/journal.pone.0010656
https://repository.urosario.edu.co/handle/10336/27530
Palabra clave:
Inflammation
Transcription factors
Endothelial cells
Transfection
Radiolabeling
Endotoxemia
Neutrophils
Gene regulation
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Abierto (Texto Completo)
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dc.title.spa.fl_str_mv Distamycin A inhibits HMGA1-binding to the P-selectin promoter and attenuates lung and liver inflammation during murine endotoxemia
dc.title.TranslatedTitle.spa.fl_str_mv La distamicina A inhibe la unión de HMGA1 al promotor de la selectina P y atenúa la inflamación pulmonar y hepática durante la endotoxemia murina
title Distamycin A inhibits HMGA1-binding to the P-selectin promoter and attenuates lung and liver inflammation during murine endotoxemia
spellingShingle Distamycin A inhibits HMGA1-binding to the P-selectin promoter and attenuates lung and liver inflammation during murine endotoxemia
Inflammation
Transcription factors
Endothelial cells
Transfection
Radiolabeling
Endotoxemia
Neutrophils
Gene regulation
title_short Distamycin A inhibits HMGA1-binding to the P-selectin promoter and attenuates lung and liver inflammation during murine endotoxemia
title_full Distamycin A inhibits HMGA1-binding to the P-selectin promoter and attenuates lung and liver inflammation during murine endotoxemia
title_fullStr Distamycin A inhibits HMGA1-binding to the P-selectin promoter and attenuates lung and liver inflammation during murine endotoxemia
title_full_unstemmed Distamycin A inhibits HMGA1-binding to the P-selectin promoter and attenuates lung and liver inflammation during murine endotoxemia
title_sort Distamycin A inhibits HMGA1-binding to the P-selectin promoter and attenuates lung and liver inflammation during murine endotoxemia
dc.subject.keyword.spa.fl_str_mv Inflammation
Transcription factors
Endothelial cells
Transfection
Radiolabeling
Endotoxemia
Neutrophils
Gene regulation
topic Inflammation
Transcription factors
Endothelial cells
Transfection
Radiolabeling
Endotoxemia
Neutrophils
Gene regulation
description Background The architectural transcription factor High Mobility Group-A1 (HMGA1) binds to the minor groove of AT-rich DNA and forms transcription factor complexes (“enhanceosomes”) that upregulate expression of select genes within the inflammatory cascade during critical illness syndromes such as acute lung injury (ALI). AT-rich regions of DNA surround transcription factor binding sites in genes critical for the inflammatory response. Minor groove binding drugs (MGBs), such as Distamycin A (Dist A), interfere with AT-rich region DNA binding in a sequence and conformation-specific manner, and HMGA1 is one of the few transcription factors whose binding is inhibited by MGBs. Objectives To determine whether MGBs exert beneficial effects during endotoxemia through attenuating tissue inflammation via interfering with HMGA1-DNA binding and modulating expression of adhesion molecules. Methodology/Principal Findings Administration of Dist A significantly decreased lung and liver inflammation during murine endotoxemia. In intravital microscopy studies, Dist A attenuated neutrophil-endothelial interactions in vivo following an inflammatory stimulus. Endotoxin induction of P-selectin expression in lung and liver tissue and promoter activity in endothelial cells was significantly reduced by Dist A, while E-selectin induction was not significantly affected. Moreover, Dist A disrupted formation of an inducible complex containing NF-?B that binds an AT-rich region of the P-selectin promoter. Transfection studies demonstrated a critical role for HMGA1 in facilitating cytokine and NF-?B induction of P-selectin promoter activity, and Dist A inhibited binding of HMGA1 to this AT-rich region of the P-selectin promoter in vivo. Conclusions/Significance We describe a novel targeted approach in modulating lung and liver inflammation in vivo during murine endotoxemia through decreasing binding of HMGA1 to a distinct AT-rich region of the P-selectin promoter. These studies highlight the ability of MGBs to function as molecular tools for dissecting transcriptional mechanisms in vivo and suggest alternative treatment approaches for critical illness.
publishDate 2010
dc.date.created.spa.fl_str_mv 2010-05-14
dc.date.accessioned.none.fl_str_mv 2020-08-19T14:42:35Z
dc.date.available.none.fl_str_mv 2020-08-19T14:42:35Z
dc.type.eng.fl_str_mv article
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dc.type.spa.spa.fl_str_mv Artículo
dc.identifier.doi.none.fl_str_mv https://doi.org/10.1371/journal.pone.0010656
dc.identifier.issn.none.fl_str_mv EISSN: 1932-6203
dc.identifier.uri.none.fl_str_mv https://repository.urosario.edu.co/handle/10336/27530
url https://doi.org/10.1371/journal.pone.0010656
https://repository.urosario.edu.co/handle/10336/27530
identifier_str_mv EISSN: 1932-6203
dc.language.iso.spa.fl_str_mv eng
language eng
dc.relation.citationIssue.none.fl_str_mv No. 5
dc.relation.citationStartPage.none.fl_str_mv E10656
dc.relation.citationTitle.none.fl_str_mv PLoS One
dc.relation.citationVolume.none.fl_str_mv Vol. 5
dc.relation.ispartof.spa.fl_str_mv PLoS One, EISSN: 1932-6203, Vol.5, No.5 (May 2010); pp. E10656
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spelling c2131491-6815-4839-8ae8-8b272a198cb7-1a26eae31-8f96-4b38-9c2c-19fa78acdb6a-168d53803-b256-4538-98dc-b2f5de9ad3e7-1bec5b926-834b-45b0-b283-19a8c5f8da18-1399db9db-1557-4dcc-9fcf-6b3d221ed212-159e5c102-3208-4008-9a8e-378889ee1298-1179b03d8-2de8-4212-bf18-cb3093f4d935-152f477e7-0aa8-4263-8ed5-89998fb51aeb-1eb58a8d0-acd8-40e9-8312-9893f0650da8-1cee71152-71bf-42f5-8175-022e7bf245b0-1528667196002020-08-19T14:42:35Z2020-08-19T14:42:35Z2010-05-14Background The architectural transcription factor High Mobility Group-A1 (HMGA1) binds to the minor groove of AT-rich DNA and forms transcription factor complexes (“enhanceosomes”) that upregulate expression of select genes within the inflammatory cascade during critical illness syndromes such as acute lung injury (ALI). AT-rich regions of DNA surround transcription factor binding sites in genes critical for the inflammatory response. Minor groove binding drugs (MGBs), such as Distamycin A (Dist A), interfere with AT-rich region DNA binding in a sequence and conformation-specific manner, and HMGA1 is one of the few transcription factors whose binding is inhibited by MGBs. Objectives To determine whether MGBs exert beneficial effects during endotoxemia through attenuating tissue inflammation via interfering with HMGA1-DNA binding and modulating expression of adhesion molecules. Methodology/Principal Findings Administration of Dist A significantly decreased lung and liver inflammation during murine endotoxemia. In intravital microscopy studies, Dist A attenuated neutrophil-endothelial interactions in vivo following an inflammatory stimulus. Endotoxin induction of P-selectin expression in lung and liver tissue and promoter activity in endothelial cells was significantly reduced by Dist A, while E-selectin induction was not significantly affected. Moreover, Dist A disrupted formation of an inducible complex containing NF-?B that binds an AT-rich region of the P-selectin promoter. Transfection studies demonstrated a critical role for HMGA1 in facilitating cytokine and NF-?B induction of P-selectin promoter activity, and Dist A inhibited binding of HMGA1 to this AT-rich region of the P-selectin promoter in vivo. Conclusions/Significance We describe a novel targeted approach in modulating lung and liver inflammation in vivo during murine endotoxemia through decreasing binding of HMGA1 to a distinct AT-rich region of the P-selectin promoter. These studies highlight the ability of MGBs to function as molecular tools for dissecting transcriptional mechanisms in vivo and suggest alternative treatment approaches for critical illness.application/pdfhttps://doi.org/10.1371/journal.pone.0010656EISSN: 1932-6203https://repository.urosario.edu.co/handle/10336/27530engPLOS Public Library of ScienceNo. 5E10656PLoS OneVol. 5PLoS One, EISSN: 1932-6203, Vol.5, No.5 (May 2010); pp. E10656https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0010656&type=printableAbierto (Texto Completo)http://purl.org/coar/access_right/c_abf2PLoS Oneinstname:Universidad del Rosarioreponame:Repositorio Institucional EdocURInflammationTranscription factorsEndothelial cellsTransfectionRadiolabelingEndotoxemiaNeutrophilsGene regulationDistamycin A inhibits HMGA1-binding to the P-selectin promoter and attenuates lung and liver inflammation during murine endotoxemiaLa distamicina A inhibe la unión de HMGA1 al promotor de la selectina P y atenúa la inflamación pulmonar y hepática durante la endotoxemia murinaarticleArtículohttp://purl.org/coar/version/c_970fb48d4fbd8a85http://purl.org/coar/resource_type/c_6501Baron, Rebecca M.Riascos, Dario F.Macias, Alvaro A.Layne, Matthew D.Cheng, GuiyingHarris, CailinChung, Su WolReeves, Raymondvon Andrian, Ulrich H.Perrella, Mark A.López Guzmán, SilviaORIGINALjournal-pone-0010656.pdfapplication/pdf4099056https://repository.urosario.edu.co/bitstreams/9796f9a2-abd0-4a8d-ae2b-b4c7fd956184/download2d324f5e4ea27034f263cad2bfae4ae0MD51TEXTjournal-pone-0010656.pdf.txtjournal-pone-0010656.pdf.txtExtracted texttext/plain73275https://repository.urosario.edu.co/bitstreams/5169ad98-41f1-41cf-a6b2-26e284b4b10c/downloadd6388d8b8531232303f9e2bf1ae3dd25MD52THUMBNAILjournal-pone-0010656.pdf.jpgjournal-pone-0010656.pdf.jpgGenerated Thumbnailimage/jpeg5025https://repository.urosario.edu.co/bitstreams/36f73ba1-88a5-4fe7-bd49-b828b38c0175/download92bef788bda2bc554146feaf992ea8ceMD5310336/27530oai:repository.urosario.edu.co:10336/275302021-06-03 00:50:14.494https://repository.urosario.edu.coRepositorio institucional EdocURedocur@urosario.edu.co