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Blood, 1 February 2005, Vol. 105, No. 3, pp. 1060-1067. Prepublished online as a Blood First Edition Paper on October 5, 2004; DOI 10.1182/blood-2003-12-4383. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-12-4383v1 105/3/1060    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Wolf, A. T. Articles by Jern, C. Search for Related Content PubMed PubMed Citation Articles by Wolf, A. T. Articles by Jern, C. Related Collections Hemostasis, Thrombosis, and Vascular Biology Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY The t-PA –7351C>T enhancer polymorphism decreases Sp1 and Sp3 protein binding affinity and transcriptional responsiveness to retinoic acid Anna Tjärnlund Wolf, Robert L. Medcalf, and Christina Jern From the Institute of Clinical Neuroscience, Sahlgrenska University Hospital/Sahlgrenska, Sahlgrenska Academy, Göteborg University, Sweden; the Cardiovascular Institute, Clinical Experimental Research Laboratory, Sahlgrenska University Hospital/Östra, Sahlgrenska Academy, Göteborg University, Sweden; the Department of Medicine, Alfred Medical Research and Education Precinct (AMREP), Monash University, Prahran, Victoria, Australia; and the Department of Clinical Genetics, Sahlgrenska University Hospital/Östra, Göteborg, Sweden. We have previously identified a common polymorphism at the tissue-type plasminogen activator (t-PA) locus (–7351C>T), located within a GC-box in the retinoic acid (RA) and steroid hormone responsive t-PA enhancer. The aim of the present study was to functionally characterize this t-PA variant. Electrophoretic mobility shift assays (EMSAs) using crude nuclear extracts from human endothelial, HeLa, and NT2 neuronal cells revealed a 10-fold greater protein binding affinity to the wild-type C allele compared with the mutant T allele variant. Sp1 and Sp3 were identified as the GC-box binding proteins. Luciferase reporter assays showed that the C allele generated higher transcriptional activity after induction by RA, compared with the T allele variant. Further EMSAs showed that RA treatment enhanced Sp1/Sp3 binding to the GC-box. Formation of the Sp1/Sp3 containing complex was inhibited by anti–RA receptor (RAR) antibodies, suggesting that Sp1/Sp3 and RAR interact. The t-PA –7351C>T polymorphism is therefore functional at the level of transcription. The reduced binding affinity of Sp1/Sp3 to the T allele could explain our earlier observations of a reduced t-PA release and an increased risk of myocardial infarction in individuals carrying this allele. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Kathiresan, Q. Yang, M. G. Larson, A. L. Camargo, G. H. Tofler, J. N. Hirschhorn, S. B. Gabriel, and C. J. O'Donnell Common Genetic Variation in Five Thrombosis Genes and Relations to Plasma Hemostatic Protein Level and Cardiovascular Disease Risk Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1405 - 1412. [Abstract] [Full Text] [PDF] K. Jood, P. Ladenvall, A. Tjarnlund-Wolf, C. Ladenvall, M. Andersson, S. Nilsson, C. Blomstrand, and C. Jern Fibrinolytic Gene Polymorphism and Ischemic Stroke Stroke, October 1, 2005; 36(10): 2077 - 2081. [Abstract] [Full Text] [PDF]

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