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The t-PA -7351C>T enhancer polymorphism decreases Sp1 and Sp3 protein binding affinity and transcriptional responsiveness to retinoic acid.

Wolf AT, Medcalf RL, Jern C

Institute of Clinical Neuroscience, Sahlgrenska University Hospital/Sahlgrenska, Göteborg University, S-413 45 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.

Published 20 January 2005 in Blood, 105(3): 1060-7.
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