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The Wilms’ tumor suppressor protein WT1 acts as a key transcriptional repressor of the human thromboxane A2 receptor gene in megakaryocytes
Alternative Title
Thromboxane A2 receptor gene regulation
Author(s)
Date Issued
2009-11
Date Available
2011-09-22T15:30:00Z
Abstract
In humans, TPα and TPβ isoforms of the thromboxane A2 receptor are transcriptionally regulated by distinct promoters, designated Prm1 and Prm3. Previous investigations identified two upstream repressor regions (URR) 1 and URR2 within Prm1. Herein, it was sought to characterize Prm1, identifying the factor(s) regulating URR1 and URR2 in human erythroleukemia (HEL) 92.1.7 cells. Genetic reporter assays and 5’ deletions confirmed the presence of URR1 and URR2 but also identified a third repressor, designated RR3, within the proximal “core” promoter. Bioinformatic analysis revealed several GC elements representing putative sites for Egr1/Sp1/Wilms tumor (WT)1 within URR1, URR2 and RR3. While mutation of three GC elements within URR1 and of an adjacent GC element suggested that repressor binding occurs through a cooperative mechanism, repressors binding to the single GC elements within URR2 and RR3 act independently to regulate Prm1. While EMSAs and supershift assays demonstrated that each of the GC elements can bind Egr1 and WT1 in vitro, chromatin immunoprecipitations established that WT1 is the factor predominantly bound to each of the repressor regions in vivo. Additionally, ectopic expression of -KTS isoforms of WT1 decreased Prm1-directed gene expression and TPα mRNA expression. Collectively, these data establish WT1 as a critical repressor of Prm1, suppressing TPα expression in the platelet progenitor megakaryoblastic HEL cells.
Sponsorship
Health Research Board
Other Sponsorship
Wellcome Trust
Type of Material
Journal Article
Publisher
Wiley-Blackwell
Journal
Journal of Cellular Molecular Medicine
Volume
13
Issue
11-12
Start Page
4571
End Page
4586
Copyright (Published Version)
2008 The Authors
Subject – LCSH
Thromboxanes
Cell receptors
Nephroblastoma
Transcription factors
Language
English
Status of Item
Peer reviewed
ISSN
1582-4934
This item is made available under a Creative Commons License
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