Ono Koichiro, Ohtomo Toshihiko, Ninomiya-Tsuji Jun, Tsuchiya Masayuki
Chugai Pharmaceutical Co., Ltd., Fuji-Gotemba Research Laboratories, Gotemba-shi, Shizuoka-ken, Japan.
Biochem Biophys Res Commun. 2003 Jul 25;307(2):332-7. doi: 10.1016/s0006-291x(03)01207-5.
Transforming growth factor-beta (TGF-beta) is crucially virulent in the progression of fibrotic disorders. TAK1 (TGF-beta activated kinase 1) is one of the mitogen-activated kinase kinase kinase (MAPKKK) that is involved in TGF-beta signal transduction. To elucidate the importance of TAK1 in TGF-beta-induced fibrotic marker expression, we investigated whether dominant negative TAK1 could suppress TGF-beta signaling. Based on the finding that TAB1 (TAK1 binding protein 1) binding to TAK1 is required for TAK1 activation, a minimal portion of TAK1 lacking kinase activity that binds to TAB1 was designed as a TAK1 dominant negative inhibitor (TAK1-DN). The effect of TAK1-DN was assessed in the cells that respond to TGF-beta stimulation and that lead to the increase in production of extracellular matrix (ECM) proteins. TAK1-DN, indeed, decreased the ECM protein production, indicating that TAK1-DN retains the ability to intercept the TGF-beta signaling effectively.
转化生长因子-β（TGF-β）在纤维化疾病进展中具有关键毒性。TAK1（TGF-β激活激酶1）是参与TGF-β信号转导的丝裂原活化蛋白激酶激酶激酶（MAPKKK）之一。为阐明TAK1在TGF-β诱导的纤维化标志物表达中的重要性，我们研究了显性负性TAK1是否能抑制TGF-β信号传导。基于TAK1激活需要TAB1（TAK1结合蛋白1）与TAK1结合这一发现，设计了一个与TAB1结合但缺乏激酶活性的TAK1最小片段作为TAK1显性负性抑制剂（TAK1-DN）。在对TGF-β刺激有反应并导致细胞外基质（ECM）蛋白产生增加的细胞中评估TAK1-DN的作用。事实上，TAK1-DN降低了ECM蛋白的产生，表明TAK1-DN保留了有效阻断TGF-β信号传导的能力。
