scholarly journals Platelet-derived growth factor is a principal inductive factor modulating mannose 6-phosphate/insulin-like growth factor-II receptor gene expression via a distal E-box in activated hepatic stellate cells

2000 ◽  
Vol 345 (2) ◽  
pp. 225 ◽  
Author(s):  
Joel A. WEINER ◽  
Anping CHEN ◽  
Bernard H. DAVIS
2000 ◽  
Vol 345 (2) ◽  
pp. 225-231 ◽  
Author(s):  
Joel A. WEINER ◽  
Anping CHEN ◽  
Bernard H. DAVIS

Hepatic stellate cells (HSCs) 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-β, a potent inducer of the matrix proteins in activated stellate cells that produce the hepatic nodule. Platelet-derived growth factor (PDGF), a potent HSC mitogen, is released early in hepatic injury and activates several signalling pathways in HSCs. In this study we examined the role of PDGF-BB in HSC regulation of M6P/IGFIIR gene expression. Several promoter elements were found and characterized that modulate M6P/IGFIIR expression in activated stellate cells. The presence of a distal CACGTG E-box at -2695 was required for M6P/IGFIIR expression in transfected stellate 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.


1992 ◽  
Vol 262 (2) ◽  
pp. L140-L146 ◽  
Author(s):  
R. N. Han ◽  
S. Buch ◽  
B. A. Freeman ◽  
M. Post ◽  
A. K. Tanswell

The expression of platelet-derived growth factor (PDGF), its receptor, and related genes was studied in the lung tissue of rats exposed to air or 85% O2. PDGF-B chain mRNA was increased by 6 days and PDGF B-type receptor mRNA was increased by 4 and 6 days of exposure to 85% O2. Despite a continued increase of cell division, both PDGF-B chain and B-type receptor mRNAs had returned to control values by 14 days of exposure to 85% O2. PDGF-A chain mRNA was unaffected by exposure to 85% O2. Nuclear runoff transcription analysis confirmed increased transcription of PDGF-B chain mRNA, whereas Western blot analysis of lung homogenates suggested consequent increased translation of PDGF-B chain mRNA to PDGF-BB at 7 days of exposure to 85% O2. Combined immunocytochemistry and autoradiography localized PDGF-BB to the major site of cell division, the pulmonary interstitium. We speculate that the early pulmonary fibroblast hyperplasia observed following exposure to 85% O2 is mediated by increased PDGF-B chain gene expression and may also be mediated by changes in PDGF B-type receptor gene expression.


1997 ◽  
Vol 249 (2) ◽  
pp. 187-195 ◽  
Author(s):  
José L. Ojeda ◽  
M. Teresa Berciano ◽  
José I. Polanco ◽  
Miguel Lafarga ◽  
José C. Rodríguez-Rey

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