A novel small compound that promotes nuclear translocation of YB-1 ameliorates experimental hepatic fibrosis in mice |
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Authors: | Higashi Kiyoshi Tomigahara Yoshitaka Shiraki Hiroaki Miyata Kaori Mikami Toshiyuki Kimura Toru Moro Tadashi Inagaki Yutaka Kaneko Hideo |
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Institution: | Environmental Health Science Laboratory, Sumitomo Chemical Company Limited, Osaka 554-8558, Japan. |
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Abstract: | Transforming growth factor-β (TGF-β) is considered to be a major factor contributing to liver fibrosis. We have previously shown that nuclear translocation of YB-1 antagonizes the TGF-β/Smad3 signaling in regulating collagen gene expression. More recently, we have demonstrated that the novel small compound HSc025 promotes nuclear translocation of YB-1, resulting in the improvement of skin and pulmonary fibrosis. Here, we presented evidence as to the mechanism by which HSc025 stimulates nuclear translocation of YB-1 and the pharmacological effects of HSc025 on a murine model of hepatic fibrosis. A proteomics approach and binding assays using HSc025-immobilized resin showed that HSc025 binds to the amino acid sequence within the C-tail region of YB-1. In addition, immunoprecipitation experiments and glutathione S-transferase pulldown assays identified poly(A)-binding protein (PABP) as one of the cytoplasmic anchor proteins of YB-1. HSc025 directly binds to YB-1 and interrupts its interaction with PABP, resulting in accelerated nuclear translocation of YB-1. Transfection of cells with PABP siRNA promoted nuclear translocation of YB-1 and subsequently inhibited basal and TGF-β-stimulated collagen gene expression. Moreover, HSc025 significantly suppressed collagen gene expression in cultured activated hepatic stellate cells. Oral administration of HSc025 to mice with carbon tetrachloride-induced hepatic fibrosis improved liver injury as well as the degree of hepatic fibrosis. Altogether, the results provide a novel insight into therapy for organ fibrosis using YB-1 modulators. |
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Keywords: | Collagen Extracellular Matrix Nuclear Translocation Proteomics Transforming Growth Factor beta (TGFbeta) YB-1 Small Compound Tissue Fibrosis |
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