Platelet-derived growth factor is a principal inductive factormodulating mannose 6-phosphate/insulin-like growth factor-II receptorgene expression via a distal E-box in activated hepatic stellate cells.
Hepatic stellate cells (HSCs) become activated during the earlystages of hepatic injury associated with fibrogenesis. The mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGFIIR) plays animportant role in early fibrogenesis by participating in the activationof latent transforming growth factor-beta, a potent inducer of thematrix proteins in activated stellate cells that produce the hepaticnodule. Platelet-derived growth factor (PDGF), a potent HSC mitogen, isreleased early in hepatic injury and activates several signallingpathways in HSCs. In this study we examined the role of PDGF-BB in HSCregulation of M6P/IGFIIR gene expression. Several promoter elementswere found and characterized that modulate M6P/IGFIIR expression inactivated stellate cells. The presence of a distal CACGTG E-box at-2695 was required for M6P/IGFIIR expression in transfectedstellate cells. When the distal E-box was removed there was no significant M6P/IGFIIR promoter activity. The distal E-box-binding protein responded specifically to PDGF-BB with increased binding. This coincided with PDGF-BB up-regulation of M6P/IGFIIR mRNA transcript levels. Downstream elements include two proximal (-2 to-48) CACGTG E-boxes that bind a different protein to the distal(-2695) E-box. The proximal E-boxes respond moderately to PDGF-BB. The promoter segment encompassing -144 to +109 is able to respond dramatically to serum but is refractory to PDGF-BB. However, a constitutively bound protein binding to the -611/-716 fragment appears to be a repressor that suppresses inductive changes in protein binding occurring downstream of -611. These results indicate that the M6P/IGFIIR promoter responds primarily and specifically to PDGF-BB through a distal E-box element and possibly through two proximal E-box elements.
Weiner
J A
JA
Gastroenterology Section, Dept. of Medicine, University of Chicago Medical Center, MC 4076, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
Chen
A
A
Davis
B H
BH
D000818:Animals; D000077214:Becaplermin; D001665:Binding Sites; D005786:Gene Expression Regulation; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008103:Liver Cirrhosis / Q000209:etiology; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011485:Protein Binding; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017527:Receptor, IGF Type 2 / Q000096:biosynthesis / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid
D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D017527:Receptor, IGF Type 2; D000077214:Becaplermin