Regulation of the Human Prostacyclin Receptor Gene by the Cholesterol-responsive Sterol Response Element Binding Protein (SREBP) 1.

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dc.contributor.author Turner, Elizebeth C.
dc.contributor.author Kinsella, B. Therese
dc.date.accessioned 2012-10-16T13:55:57Z
dc.date.available 2013-11-01T04:00:08Z
dc.date.copyright 2012 by the American Society for Biochemistry and Molecular Biology, Inc. en
dc.date.issued 2012-09-11
dc.identifier.citation Journal of Lipid Research en
dc.identifier.uri http://hdl.handle.net/10197/3870
dc.description.abstract Prostacyclin and its prostacyclin receptor, the IP, play essential roles in regulating haemostasis and vascular tone and have also been implicated in a range cardio-protective effects, but through largely unknown mechanisms. In this study, the influence of cholesterol on human (h)IP gene expression was investigated in cultured vascular endothelial and platelet-progenitor megakaryocytic cells. Cholesterol-depletion increased hIP mRNA, hIP promoter-directed reporter gene expression and hIP-induced cAMP generation in all cell types. Furthermore, the constitutively active SREBP1a, but not SREBP2, increased hIP mRNA and promoter-directed gene expression while deletional and mutational analysis uncovered an evolutionary conserved sterol-response element (SRE), adjacent to a known functional Sp1 element, within the core hIP promoter. Moreover, chromatin immunoprecipitation assays confirmed direct cholesterol-regulated binding of SREBP1a to this hIP promoter region in vivo, while immunofluorescence microscopy corroborated that cholesterol-depletion significantly increases hIP expression levels. In conclusion, the hIP gene is directly regulated by cholesterol-depletion that occurs through binding of SREBP1a to a functional SRE within its core promoter. Mechanistically, these data establish that cholesterol can regulate hIP expression which may, at least in part, account for the combined cardio-protective actions of low serum cholesterol through its regulation of prostacyclin receptor (IP) expression within the human vasculature. en
dc.description.sponsorship Science Foundation Ireland en
dc.description.sponsorship Other funder en
dc.language.iso en en
dc.publisher American Society for Biochemistry and Molecular Biology, Inc. en
dc.rights This research was originally published in Journal of Lipid Research. Elizebeth C. Turner and B. Therese Kinsella. Regulation of the human prostacyclin receptor gene by the cholesterol-responsive SREBP1, November 2012 The Journal of Lipid Research, 53, 2390-2404. © the American Society for Biochemistry and Molecular Biology. en
dc.subject Prostacyclin Receptor en
dc.subject Prostacyclin en
dc.subject Gene expression en
dc.subject Sterol-response element (SRE) en
dc.subject Promoter en
dc.subject Transcription en
dc.subject Sterol-response element binding protein (SREBP) en
dc.subject.lcsh Prostacyclin--Receptors en
dc.subject.lcsh Gene expression en
dc.subject.lcsh Transcription factors en
dc.subject.lcsh Cholesterol en
dc.title Regulation of the Human Prostacyclin Receptor Gene by the Cholesterol-responsive Sterol Response Element Binding Protein (SREBP) 1. en
dc.type Journal Article en
dc.internal.availability Full text available en
dc.status Peer reviewed en
dc.identifier.volume 53 en
dc.identifier.issue November 2012 en
dc.identifier.startpage 2390
dc.identifier.endpage 2404
dc.identifier.doi 10.1194/jlr.M029314
dc.neeo.contributor Turner|Elizebeth C.|aut|
dc.neeo.contributor Kinsella|B. Therese|aut|
dc.description.othersponsorship Programme for Research in Third Level Institutions (PRTLI) 1 en
dc.description.admin DG - 15/10/2012 en
dc.description.admin Update rights statement with correct citation when available en


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