Published online before print February 10, 2005, doi: 10.1161/01.RES.0000158967.96231.88
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Submitted on October 17, 2004
Revised on January 3, 2005
Accepted on January 27, 2005
Molecular Basis of Estrogen-Induced Cyclooxygenase Type 1 Upregulation in Endothelial Cells
Linda L. Gibson ;
From the Department of Pediatrics (L.L.G., L.H., S.O.-L., Z.G., K.L.C., P.W.S.), University of Texas Southwestern Medical Center at Dallas and the Vascular Biology Research Center (K.K.W.), University of Texas-Houston Health Science Center, Dallas, Tex.
* To whom correspondence should be addressed. E-mail: philip.shaul{at}utsouthwestern.edu.
Estrogen upregulates cyclooxygenase-1 (COX-1) expression in endothelial cells. To determine the basis of this process, studies were performed in ovine endothelial cells transfected with the human COX-1 promoter fused to luciferase. Estradiol (E2) caused activation of the COX-1 promoter with maximal stimulation at 10-8 mol/L E2, and the response was mediated by either ER
or ER
. Mutagenesis revealed a primary role for a putative Sp1 binding motif at -89 (relative to the ATG codon) and lesser involvement of a consensus Sp1 site at -111. Electrophoretic mobility shift assays yielded a single complex with the site at -89, and supershift analyses implicated AP-2 and ER, and not Sp1, in protein-DNA complex formation. In endothelial cells with minimal endogenous ER, the transfection of ER mutants lacking the DNA binding domain or primary nuclear localization signals caused 4-fold greater stimulation of promoter activity with E2 than wild-type ER. In contrast, mutant ER lacking the A-B domains was inactive. Thus, estrogen-mediated upregulation of COX-1 in endothelium is uniquely independent of direct ER-DNA binding and instead entails protein-DNA interaction involving AP-2 and ER at a proximal regulatory element. In addition, the process may be initiated by cytoplasmic ER, and critical receptor elements reside within the amino terminus.
Key words: cyclooxygenase • endothelium • estrogen • estrogen receptor
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