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Prepublished online as a Blood First Edition Paper on June 28, 2002; DOI 10.1182/blood-2002-02-0415. This Article Full Text (PDF) All Versions of this Article: 2002-02-0415v1 100/13/4454    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wu, S.-q. Articles by Aird, W. C Search for Related Content PubMed PubMed Citation Articles by Wu, S.-q. Articles by Aird, W. C Social Bookmarking                   What's this? Submitted February 8, 2002 Accepted June 18, 2002 The Proximal Serum Response Element in the Egr-1 Promoter Mediates Response to Thrombin in Primary Human Endothelial Cells Sheng-qian Wu, Takashi Minami, Diana Donovan, and William C Aird* Molecular Medicine, RW-663, Beth Israel Deaconess Medical Center, Boston, MA, USA * Corresponding author; email: waird{at}caregroup.harvard.edu. Thrombin signaling in endothelial cells provides an important link between coagulation and inflammation. We report here that thrombin induces endogenous Egr-1 mRNA and Egr-1 promoter activity in primary human endothelial cells, by approximately 6-fold and 3-fold, respectively. In transient transfection assays, deletion of the 3' cluster of serum response elements (SREs), but not the 5' cluster of SREs, resulted in a loss of thrombin response. When coupled to a heterologous core promoter, a region spanning the 3' SRE cluster contained information for thrombin response, whereas a region spanning the 5' SRE cluster had no such effect. A point mutation of the most proximal SRE (SRE-1), but not of the proximal Ets motif or upstream SREs, abrogated the response to thrombin. In electrophoretic mobility shift assays, nuclear extracts from thrombin-treated cells displayed increased binding of total and phosphorylated serum response factor (SRF) to SRE-1. Thrombin-mediated induction of Egr-1 was blocked by inhibitors of MEK1/2, but not by inhibitors of protein kinase C, phosphatidylinositol 3-kinase or p38 mitogen-activated protein kinase (MAPK). Taken together, these data suggest that thrombin induces Egr-1 expression in endothelial cells by a MAPK-dependent mechanism that involves an interaction between SRF and SRE-1. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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