Masuda Yutaka, Yazawa Jun, Makino Yuuka, Takada Kimihiko
Laboratory of Clinical Pharmacy, Showa Pharmaceutical University.
Biol Pharm Bull. 2015;38(10):1529-35. doi: 10.1248/bpb.b15-00295.
Thrombin-activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase B-like proenzyme biosynthesized in the liver and released into the blood circulation. Activated TAFI (TAFIa) has been implicated as an important player in maintaining the balance between blood coagulation and fibrinolysis. In the present study, regulation of TAFI (CPB2) gene expression was investigated using cultured human hepatoma HepG2 cells. HepG2 cells were treated with the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, and the levels of TAFI antigen and CPB2 mRNA were measured. HepG2 cells treated with LY29400 decreased their release of TAFI antigen into the conditioned medium (CM). In parallel, there were decreased levels of CPB2 mRNA and TAFI antigen in the cells. However, CPB2 gene promoter activity was not influenced by treatment of the cells with LY294002. The half-life of the CPB2 transcript was shortened by treatment with LY294002 compared with control. The present results suggest that the PI3K inhibitor LY294002 suppresses expression of TAFI, a prothrombotic factor, by decreasing the stability of CPB2 transcripts.
凝血酶激活的纤维蛋白溶解抑制剂（TAFI）是一种在肝脏中生物合成并释放到血液循环中的羧肽酶B样前酶。活化的TAFI（TAFIa）被认为是维持凝血和纤维蛋白溶解平衡的重要因素。在本研究中，使用培养的人肝癌HepG2细胞研究了TAFI（CPB2）基因表达的调控。用磷酸肌醇3激酶（PI3K）抑制剂LY294002处理HepG2细胞，并测量TAFI抗原和CPB2 mRNA的水平。用LY29400处理的HepG2细胞减少了TAFI抗原向条件培养基（CM）中的释放。同时，细胞中CPB2 mRNA和TAFI抗原的水平降低。然而，CPB2基因启动子活性不受LY294002处理细胞的影响。与对照相比，用LY294002处理缩短了CPB2转录本的半衰期。目前的结果表明，PI3K抑制剂LY294002通过降低CPB2转录本的稳定性来抑制促血栓形成因子TAFI的表达。
