A dominant negative TAK1 inhibits cellular fibrotic responses induced by TGF-beta |
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Authors: | Ono Koichiro Ohtomo Toshihiko Ninomiya-Tsuji Jun Tsuchiya Masayuki |
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Institution: | Chugai Pharmaceutical Co., Ltd., Fuji-Gotemba Research Laboratories, Gotemba-shi, Shizuoka-ken, Japan. onokui@chugai-pharm.co.jp |
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Abstract: | 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. |
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Keywords: | Transforming growth factor-β TGF-β activated kinase 1 Dominant negative inhibitor Fibrotic marker proteins |
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