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

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dc.creatorBaron, Rebecca M.spa
dc.creatorLópez Guzmán, Silvia
dc.creatorRiascos, Dario F.spa
dc.creatorMacias, Alvaro A.spa
dc.creatorLayne, Matthew D.spa
dc.creatorCheng, Guiyingspa
dc.creatorHarris, Cailinspa
dc.creatorChung, Su Wolspa
dc.creatorReeves, Raymondspa
dc.creatorvon Andrian, Ulrich H.spa
dc.creatorPerrella, Mark A.spa
dc.date.accessioned2020-08-19T14:42:35Z
dc.date.available2020-08-19T14:42:35Z
dc.date.created2010-05-14spa
dc.description.abstractBackground 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.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0010656
dc.identifier.issnEISSN: 1932-6203
dc.identifier.urihttps://repository.urosario.edu.co/handle/10336/27530
dc.language.isoengspa
dc.publisherPLOS Public Library of Sciencespa
dc.relation.citationIssueNo. 5
dc.relation.citationStartPageE10656
dc.relation.citationTitlePLoS One
dc.relation.citationVolumeVol. 5
dc.relation.ispartofPLoS One, EISSN: 1932-6203, Vol.5, No.5 (May 2010); pp. E10656spa
dc.relation.urihttps://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0010656&type=printablespa
dc.rights.accesRightsinfo:eu-repo/semantics/openAccess
dc.rights.accesoAbierto (Texto Completo)spa
dc.sourcePLoS Onespa
dc.source.instnameinstname:Universidad del Rosario
dc.source.reponamereponame:Repositorio Institucional EdocUR
dc.subject.keywordInflammationspa
dc.subject.keywordTranscription factorsspa
dc.subject.keywordEndothelial cellsspa
dc.subject.keywordTransfectionspa
dc.subject.keywordRadiolabelingspa
dc.subject.keywordEndotoxemiaspa
dc.subject.keywordNeutrophilsspa
dc.subject.keywordGene regulationspa
dc.titleDistamycin A inhibits HMGA1-binding to the P-selectin promoter and attenuates lung and liver inflammation during murine endotoxemiaspa
dc.title.TranslatedTitleLa distamicina A inhibe la unión de HMGA1 al promotor de la selectina P y atenúa la inflamación pulmonar y hepática durante la endotoxemia murinaspa
dc.typearticleeng
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersion
dc.type.spaArtículospa
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