A Role for CCAAT/Enhancer-binding Protein in Hepatic Expression of Thrombin-activable Fibrinolysis Inhibitor

• Published in: The Journal of biological chemistry 2002-07, Vol.277 (28), p.25329-25336
• Main Authors: Boffa, Michael B., Hamill, Jeffrey D., Bastajian, Nazareth, Dillon, Rebecca, Nesheim, Michael E., Koschinsky, Marlys L.
• Format: Article
• Language: English
• Subjects: Animals; Carboxypeptidase B2 - metabolism; CCAAT-Enhancer-Binding Proteins - metabolism; CCAAT-Enhancer-Binding Proteins - physiology; Cricetinae; Humans; Liver - metabolism; Promoter Regions, Genetic; Protein Binding; Rats; Tumor Cells, Cultured
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M203688200

Thrombin-activable fibrinolysis inhibitor (TAFI) is a procarboxypeptidase B-like zymogen that upon activation by thrombin, thrombin-thrombomodulin, or plasmin attenuates fibrin clot lysis by inhibiting positive feedback in the fibrinolytic cascade. The concentration of TAFI in plasma varies in the human population and thus may constitute a risk factor for thrombotic disorders. In addition, TAFI has been reported to be a positive acute phase reactant in mice. We have initiated molecular analysis of the human TAFI promoter to understand the mechanisms underlying regulation of TAFI gene expression. We identified a putative C/EBP-binding site between −53 and −40 of the promoter. Mutations in this site that abolish C/EBP binding decrease TAFI promoter activity in human hepatoma (HepG2) cells by ∼80%. Gel mobility shift analyses indicated that C/EBP-β present in HepG2 nuclear extracts and C/EBP-α and -β present in adult rat liver nuclear extracts bind to the C/EBP site. C/EBP-α, -β, and -δ isoforms are all capable of binding to the C/EBP site and activating the TAFI promoter. The identification of a functional C/EBP-binding site in the human TAFI promoter may have important implications for the regulation of expression of this gene during development and in response to inflammatory stimuli.