Abstract
Hepatic stellate cells become activated into myofibroblast-like cells during the early stages of hepatic injury associated with fibrogenesis. The subsequent dysregulation of hepatic stellate cell collagen gene expression is a central pathogenetic step during the development of cirrhosis. The cytoplasmic Raf and mitogen-activated protein (MAPK) kinases were found to differentially regulate alpha I(I) collagen gene expression in activated stellate cells. This suggests an unappreciated branch point exists between Raf and MAPK. A MAPK-stimulatory signal was mapped to the most proximal NF-1 and Sp-1 binding domains of the 5'-untranslated region of the collagen gene. A Raf-inhibitory signal was mapped to a further upstream binding domain involving a novel 60-kDa DNA-binding protein (p60). The cell-specific expression and induction of p60 in stellate cells during the early stages of hepatic fibrogenesis in vivo suggest a central role for this pathway during liver injury and stellate cell activation.
Highlights
The detailed cytoplasmic signaling involved in the regulation of key structural and/or disease-related genes is poorly understood
We evaluated the role of the Ras-Raf-MAPK cascade during collagen gene expression using cultured hepatic stellate cells (HSC), the major collagen-producing effector cell responsible for hepatic fibrogenesis (16 –21)
This system utilizes activated early passage cells, which recapitulate many features of the diseased stellate cell in vivo. (16 –21). This model can serve as a paradigm of the enhanced collagen gene expression, which occurs in vivo during liver injury and fibrogenesis (16 –21)
Summary
The detailed cytoplasmic signaling involved in the regulation of key structural and/or disease-related genes is poorly understood. We evaluated the role of the Ras-Raf-MAPK cascade during collagen gene expression using cultured hepatic stellate cells (HSC), the major collagen-producing effector cell responsible for hepatic fibrogenesis (16 –21). It was found that blockage of Ras or Raf activity led to an increase in collagen gene expression.
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