Molecular basis of estrogen-induced cyclooxygenase type 1 upregulation in endothelial cells

Linda L. Gibson, Lisa Hahner, Sherri Osborne-Lawrence, Zohre German, Kenneth K. Wu, Ken L. Chambliss, Philip W. Shaul

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

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 ERα or ERβ. 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-2α and ERα, and not Sp1, in protein-DNA complex formation. In endothelial cells with minimal endogenous ER, the transfection of ERα mutants lacking the DNA binding domain or primary nuclear localization signals caused 4-fold greater stimulation of promoter activity with E 2 than wild-type ERα. In contrast, mutant ERα lacking the A-B domains was inactive. Thus, estrogen-mediated upregulation of COX-1 in endothelium is uniquely independent of direct ERα-DNA binding and instead entails protein-DNA interaction involving AP-2α and ERα at a proximal regulatory element. In addition, the process may be initiated by cytoplasmic ERα, and critical receptor elements reside within the amino terminus.

Original languageEnglish (US)
Pages (from-to)518-525
Number of pages8
JournalCirculation research
Volume96
Issue number5
DOIs
StatePublished - Mar 18 2005

Keywords

  • Cyclooxygenase
  • Endothelium
  • Estrogen
  • Estrogen receptor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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