A novel small compound that promotes nuclear translocation of YB-1 ameliorates experimental hepatic fibrosis in mice.
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.
Environmental Health Science Laboratory, Sumitomo Chemical Company Limited, Osaka 554-8558, Japan.
Kiyoshi
K
Higashi
Yoshitaka
Y
Tomigahara
Hiroaki
H
Shiraki
Kaori
K
Miyata
Toshiyuki
T
Mikami
Toru
T
Kimura
Tadashi
T
Moro
Yutaka
Y
Inagaki
Hideo
H
Kaneko
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000466:Alkadienes / Q000494:pharmacology*; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002252:Carbon Tetrachloride Poisoning / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D039102:Poly(A)-Binding Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D017434:Protein Structure, Tertiary; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051840:Y-Box-Binding Protein 1
D000466:Alkadienes; D002251:Carbon Tetrachloride; D003094:Collagen; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D039102:Poly(A)-Binding Proteins; D051900:Smad3 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051840:Y-Box-Binding Protein 1; C546007:HSc025; C497790:SMAD3 protein, human; C497791:Smad3 protein, mouse; C497787:Smad3 protein, rat; C541744:Ybx1 protein, mouse; C070856:YBX1 protein, human