Inhibition of transforming growth factor-beta-induced liver fibrosis by a retinoic acid derivative via the suppression of Col 1A2 promoter activity.
Transforming growth factor-beta1 (TGF-beta1) mediates expression of collagen 1A2 (Col 1A2) gene via a synergistic cooperation between Smad2/Smad3 and Sp1, both act on the Col 1A2 gene promoter. In our previous study, we reported that a retinoic acid derivative obtained from Phellinus linteus (designated PL) antagonizes TGF-beta-induced liver fibrosis through regulation of ROS and calcium influx. In this continuing study we seek further the effect of PL on the Smad signaling pathway. We used a Col 1A2 promoter-luciferase construct to study the action of PL on Smad through TGF-beta. We found that PL decreases the promoter activity of Col 1A2, hinders the translocalization of phosphorylated Smad2/3-Smad 4 complex from cytosol into nucleus and inhibits Sp1 binding activity. These results suggest that PL inhibits TGF-beta1-induced Col 1A2 promoter activity through blocking ROS and calcium influx as well as impeding Sp1 binding and translocalization of pSmad 2/3-Smad4 complex into nucleus.
Yang
Kun-Lin
KL
Institute of Basic Medical Sciences, Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
Chang
Wen-Teng
WT
Hung
Kuo-Chen
KC
Li
Eric I C
EI
Chuang
Chia-Chang
CC
D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000037:antagonists & inhibitors* / Q000235:genetics; D024042:Collagen Type I; D003510:Cyclohexanes / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010421:Pentanoic Acids / Q000494:pharmacology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology*
C525866:5-(2,2-dimethyl-6-methylenecyclohexyl)-3-methyl-2,4-pentadienoic acid; D024042:Collagen Type I; D003510:Cyclohexanes; D010421:Pentanoic Acids; D017382:Reactive Oxygen Species; D051785:Smad Proteins; D016329:Sp1 Transcription Factor; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D003094:Collagen