SMAD公司
细胞生物学
肝星状细胞
MAPK/ERK通路
蛋白激酶B
信号转导
细胞外基质
PI3K/AKT/mTOR通路
生长因子
转化生长因子
蛋白激酶A
生物
激酶
癌症研究
内分泌学
生物化学
受体
作者
Christopher J. Parsons,Motoki Takashima,Richard A. Rippe
标识
DOI:10.1111/j.1440-1746.2006.04659.x
摘要
Abstract Liver fibrosis, a wound‐healing response to a variety of chronic stimuli, is characterized by excessive deposition of extracellular matrix (ECM) proteins, of which type I collagen predominates. This alters the structure of the liver leading to organ dysfunction. The activated hepatic stellate cell (HSC) is primarily responsible for excess collagen deposition during liver fibrosis. Two important aspects are involved in mediating the fibrogenic response: first the HSC becomes directly fibrogenic by synthesizing ECM proteins; second, the activated HSC proliferates, effectively amplifying the fibrogenic response. Although the precise mechanisms responsible for HSC activation remain elusive, substantial insight is being gained into the molecular mechanisms responsible for ECM production and cell proliferation in the HSC. The activated HSC becomes responsive to both proliferative (platelet‐derived growth factor) and fibrogenic (transforming growth factor‐β[TGF‐β]) cytokines. It is becoming clear that these cytokines activate both mitogen‐activated protein kinase (MAPK) signaling, involving p38, and focal adhesion kinase–phosphatidylinositol 3‐kinase–Akt–p70 S6 kinase (FAK‐PI3K‐Akt‐p70 S6K ) signaling cascades. Together, these regulate the proliferative response, activating cell cycle progression as well as collagen gene expression. In addition, signaling by both TGF‐β, mediated by Smad proteins, and p38 MAPK influence collagen gene expression. Smad and p38 MAPK signaling have been found to independently and additively regulate α1(I) collagen gene expression by transcriptional activation while p38 MAPK, but not Smad signaling, increases α1(I) collagen mRNA stability, leading to increased synthesis and deposition of type I collagen. It is anticipated that by understanding the molecular mechanisms responsible for HSC proliferation and excess ECM production new therapeutic targets will be identified for the treatment of liver fibrosis.
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