E-box-binding repressor is down-regulated in hepatic stellate cells during up-regulation of mannose 6-phosphate/insulin-like growth factor-II receptor expression in early hepatic fibrogenesis.
Hepatic stellate cells become activated during the early stages of hepatic injury associated with fibrogenesis. The mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGFIIR) plays an important role in early fibrogenesis by participating in the activation of latent transforming growth factor-beta, a potent inducer of the matrix proteins in activated stellate cells that define the fibrotic phenotype. In this study we examined hepatic stellate cell regulation of M6P/IGFIIR expression and found that M6P/IGFIIR mRNA transcript levels increased in stellate cells from rats exposed to carbon tetrachloride (CCl4), a potent fibrogenic stimulant. Two E-boxes residing in the proximal promoter of M6P/IGFIIR were found to each bind a novel 75-kDa transcription factor (P75) in quiescent stellate cells of normal livers. This E-box binding was down-regulated as an early response in stellate cells exposed to CCl4, coinciding with increased M6P/IGFIIR transcript levels. Mutagenized E-boxes in M6P/IGFIIR promoter-chloramphenicol acetyltransferase (CAT) reporter constructs produced a substantial increase in reporter expression when compared with the corresponding native promoter-CAT construct when transfected in culture-activated stellate cells, suggesting P75's role as a repressor. The results indicate P75's participation in the regulation of M6P/IGFIIR transcription in hepatic stellate cells during fibrogenesis.
Weiner
J A
JA
Gastroenterology Section, Department of Medicine, University of Chicago Medical Center, Chicago, Illinois 60637, USA.
Chen
A
A
Davis
B H
BH
D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism / Q000473:pathology; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008970:Molecular Weight; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017527:Receptor, IGF Type 2 / Q000096:biosynthesis*; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
D012333:RNA, Messenger; D017527:Receptor, IGF Type 2; D012097:Repressor Proteins; D004247:DNA