Regulation of the Human Prostacyclin Receptor Gene by the Cholesterol-responsive Sterol Response Element Binding Protein (SREBP) 1.
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|Title:||Regulation of the Human Prostacyclin Receptor Gene by the Cholesterol-responsive Sterol Response Element Binding Protein (SREBP) 1.||Authors:||Turner, Elizebeth C.
Kinsella, B. Therese
|Permanent link:||http://hdl.handle.net/10197/3870||Date:||11-Sep-2012||Online since:||2013-11-01T04:00:08Z||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.||Funding Details:||Science Foundation Ireland
|Type of material:||Journal Article||Publisher:||American Society for Biochemistry and Molecular Biology, Inc.||Journal:||Journal of Lipid Research||Volume:||53||Issue:||November 2012||Start page:||2390||End page:||2404||Copyright (published version):||2012 by the American Society for Biochemistry and Molecular Biology, Inc.||Keywords:||Prostacyclin Receptor; Prostacyclin; Gene expression; Sterol-response element (SRE); Promoter; Transcription; Sterol-response element binding protein (SREBP)||Subject LCSH:||Prostacyclin--Receptors
|DOI:||10.1194/jlr.M029314||Language:||en||Status of Item:||Peer reviewed|
|Appears in Collections:||Biomolecular and Biomedical Science Research Collection|
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