GENES: STRUCTURE AND REGULATION
A Role for CCAAT/Enhancer-binding Protein in Hepatic Expression of Thrombin-activable Fibrinolysis Inhibitor*

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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.

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Published, JBC Papers in Press, May 8, 2002, DOI 10.1074/jbc.M203688200

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This work was supported by Canadian Institutes for Health Research Grant MOP-36491.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.