title: Regulation of the gene encoding human thrombin-activatable fibrinolysis inhibitor by estrogen and progesterone.
abstract: Thrombin-activatable fibrinolysis inhibitor (TAFI) is a pro-carboxypeptidase B-like pro-enzyme that upon activation attenuates fibrinolysis and inflammatory processes. There is a large inter-individual variability in plasma TAFI levels within the population which is primarily due to epigenetic factors. Novel associations between plasma TAFI levels and sex steroids have triggered interest in determining the role of TAFI as a mediator of the cardioprotective effects of estrogens and progestins, or as a mediator of the increased thrombotic risk that accompanies use of oral contraceptives or hormone replacement therapy (HRT). In this study, we measured the effect of sex steroids on hepatic expression of CPB2, the human gene encoding TAFI. Using human hepatocellular carcinoma cells cultured in the presence of progesterone and 17β-estradiol, we demonstrated that the level of TAFI protein is decreased by those sex steroids. These changes in protein expression were paralleled by decreases in CPB2 mRNA abundance and promoter activity. We did not find evidence of estrogen or progesterone receptor binding sites in the CPB2 promoter region, suggesting that the genomic effects of progesterone and 17β-estradiol are mediated indirectly, without receptor binding to the CPB2 promoter. Indeed, we found that the effect of estrogen was independent of the estrogen receptor and was mediated through a novel signaling pathway dependent on phosphatidylinositol 3-kinase and Akt that did not involve GPR30. Our findings provide the molecular explanation for the ability of female sex steroids to decrease plasma TAFI concentrations.
authors: Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
authors: Mathieu
authors: M
authors: Garand
authors: Joellen H H
authors: JH
authors: Lin
authors: Branislava
authors: B
authors: Zagorac
authors: Marlys L
authors: ML
authors: Koschinsky
authors: Michael B
authors: MB
authors: Boffa
mesh_terms: D025901:Carboxypeptidase B2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C109584:GPER1 protein, human; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D011374:Progesterone; D004958:Estradiol; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D025901:Carboxypeptidase B2