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

Files in This Item:
File Description SizeFormat 
Turner & Kinsella hIP Reg by Chol inc Supp Data JLipidRes 11thOct12.pdfManuscript including Supplemental Data1.61 MBAdobe PDFDownload
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
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
Other funder
Type of material: Journal Article
Publisher: American Society for Biochemistry and Molecular Biology, Inc.
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
Gene expression
Transcription factors
Cholesterol
DOI: 10.1194/jlr.M029314
Language: en
Status of Item: Peer reviewed
Appears in Collections:Biomolecular and Biomedical Science Research Collection

Show full item record

SCOPUSTM   
Citations 50

7
Last Week
0
Last month
checked on Jun 22, 2018

Google ScholarTM

Check

Altmetric


This item is available under the Attribution-NonCommercial-NoDerivs 3.0 Ireland. No item may be reproduced for commercial purposes. For other possible restrictions on use please refer to the publisher's URL where this is made available, or to notes contained in the item itself. Other terms may apply.