tailieunhanh - Báo cáo khoa học: 15-Deoxy D12,14-prostaglandin J2 suppresses transcription by promoter 3 of the human thromboxane A2 receptor gene through peroxisome proliferator-activated receptor c in human erythroleukemia cells

In humans, thromboxane (TX) A2 signals through two receptor isoforms, thromboxane receptor (TP)aand TPb, which are transcriptionally regula-ted by distinct promoters, Prm1 and Prm3, respectively, within the single TP gene. The aim of the current study was to investigate the ability of the endogenous peroxisome proliferator-activated receptor (PPAR)c ligand 15-deoxy-D 12,14 -prostaglandin J2 (15d-PGJ2) to regulate expression of the human TP gene and to ascertain its potential effects on the individual TPa and TPbisoforms | iFEBS Journal 15-Deoxy D12 14-prostaglandin J2 suppresses transcription by promoter 3 of the human thromboxane A2 receptor gene through peroxisome proliferator-activated receptor c in human erythroleukemia cells Adrian T. Coyle Martina B. O Keeffe and B. Therese Kinsella Department of Biochemistry Conway Institute of Biomolecular and BiomedicalResearch University College Dublin Ireland Keywords thromboxane receptor promoter peroxisome proliferator-activated receptor c 15-deoxy A12 14-prostaglandin J2 isoforms Correspondence B. T. Kinsella Department of Biochemistry Conway Institute of Biomolecular and BiomedicalResearch University College Dublin Belfield Dublin 4 Ireland Fax 353 1 2837211 Tel 353 1 7166727 E-mail Received 15 June 2005 revised 28 July 2005 accepted 29 July 2005 doi In humans thromboxane TX A2 signals through two receptor isoforms thromboxane receptor TP a and TPp. which are transcriptionally regulated by distinct promoters Prm1 and Prm3 respectively within the single TP gene. The aim of the current study was to investigate the ability of the endogenous peroxisome proliferator-activated receptor PPAR c ligand 15-deoxy-D12 14-prostaglandin J2 15d-PGJ2 to regulate expression of the human TP gene and to ascertain its potential effects on the individual TPa and TPb isoforms. 15d-PGJ2 suppressed Prm3 transcriptional activity and TPb mRNA expression in the platelet progenitor megakaryocytic human erythroleukemia HEL cell line but had no effect on Prm1 or Prm2 activity or on TPa mRNA expression. 15d-PGJ2 also resulted in reductions in the overall level of TP protein expression and TP-mediated intracellular calcium mobilization in HEL cells. 15d-PGJ2 suppression of Prm3 transcriptional activity and TPb mRNA expression was found to occur through a novel mechanism involving direct binding of PPARy-retinoic acid X receptor RXR heterodimers to a PPARc response element PPRE composed of two imperfect