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

Artikel i vetenskaplig tidskrift
Författare Anna Tjärnlund-Wolf
Robert L Medcalf
Christina Jern
Publicerad i Blood
Volym 105
Nummer/häfte 3
Sidor 1060-7
ISSN 0006-4971
Publiceringsår 2005
Publicerad vid Institutionen för klinisk neurovetenskap
Sidor 1060-7
Språk en
Länkar dx.doi.org/10.1182/blood-2003-12-43...
Ämnesord Cytosine, DNA-Binding Proteins, metabolism, Enhancer Elements (Genetics), genetics, Fetal Blood, Humans, Immunoglobulins, metabolism, Infant, Newborn, Kinetics, Polymorphism, Genetic, Protein Binding, Reverse Transcriptase Polymerase Chain Reaction, Sequence Deletion, Sp3 Transcription Factor, Thymine, Tissue Plasminogen Activator, genetics, metabolism, Transcription Factors, metabolism, Transcription, Genetic, drug effects, Tretinoin, pharmacology
Ämneskategorier Cell- och molekylärbiologi

Sammanfattning

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.

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