Antagonism of transforming growth factor-Beta signaling inhibits fibrosis-related genes.
In the fibrotic process, the transforming growth factor-beta1 (TGF-beta1)/Smad3 (Sma- and Mad-related protein 3) signaling plays a central role. To screen for antagonists of TGF-beta1/Smad3 signaling and to investigate their effects on the genes related to fibrosis, we construct a molecular model with a luciferase reporter gene. Results showed that both SB-431542 [4-(5-benzo[1,3]dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)-benzamide] and small interference RNA (siRNA) against Smad3 could dose-dependently suppress the reporter gene. More importantly, they both significantly inhibited the expression of plasminogen activator inhibitor-type 1 (PAI-1) and type I collagenalpha1 (Col Ialpha1) genes in rat hepatic stellate cells. Thus, SB-431542 and Smad3/siRNA may be potential therapeutics for fibrosis.
Liu
Xing-Jun
XJ
Protein & Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
Ruan
Cheng-Mai
CM
Gong
Xian-Feng
XF
Li
Xing-Zhou
XZ
Wang
Huai-Liang
HL
Wang
Min-Wei
MW
Yin
James Q
JQ
D000818:Animals; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004149:Dioxoles / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D005355:Fibrosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008907:Mink; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; D034741:RNA, Small Interfering; D051900:Smad3 Protein; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1