Suppression of stellate cell type I collagen gene expression involves AP-2 transmodulation of nuclear factor-1-dependent gene transcription.
The regulation of collagen gene expression was studied in culture-activated rat hepatic stellate cells, the fibrogenic effector cell involved in hepatic fibrogenesis. Treatment of cells with a 5-lipoxygenase-specific inhibitor caused a reduction in alphaI(I) collagen mRNA transcript abundance, which suggested that leukotriene production was involved in maintaining the activated cell's high level of collagen mRNA production. The underlying mechanism involved a decrease in collagen gene transcription. Suppression of gene transcription was localized to an nuclear factor-1 (NF-1) binding domain in the proximal promoter and an AP-2 binding domain adjacent to it. Gel retardation assays demonstrated that an increase in AP-2 binding adjacent to the NF-1 site was likely to be the transmodulator responsible for the suppression of the NF-1-dependent gene expression. The data suggest that post-translational alterations in AP-2 activity are responsible for this unappreciated mechanism of regulating the collagen gene.
Chen
A
A
Gastroenterology Section, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Beno
D W
DW
Davis
B H
BH
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D003094:Collagen / Q000235:genetics* / Q000378:metabolism; D018983:DNA Footprinting; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors; D008099:Liver / Q000378:metabolism*; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D011033:Podophyllin / Q000031:analogs & derivatives / Q000378:metabolism; D011034:Podophyllotoxin / Q000031:analogs & derivatives; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D051840:Y-Box-Binding Protein 1
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D016859:Lipoxygenase Inhibitors; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; C003170:mitopodozide; D011033:Podophyllin; D003094:Collagen; D011034:Podophyllotoxin