Raf and mitogen-activated protein kinase regulate stellate cell collagen gene expression
Raf and mitogen-activated protein kinase regulate stellate cell collagen gene expression
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DOI：
10.1074/jbc.271.19.11039
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发表时间：
1996-05-10
影响因子：
4.8
通讯作者：
Beno, DWA
中科院分区：
文献类型：
--
作者：
Davis, BH;Chen, AP;Beno, DWA
在与纤维发生相关的肝损伤的早期阶段，肝星状细胞被激活为肌成纤维细胞样细胞。随后的肝星状细胞胶原蛋白基因表达失调是肝硬化发展过程中的核心发病步骤。研究发现细胞质 Raf 和丝裂原激活蛋白 (MAPK) 激酶可差异调节活化星状细胞中的 α I(I) 胶原蛋白基因表达。这表明 Raf 和 MAPK 之间存在一个未被意识到的分支点。 MAPK 刺激信号被映射到胶原蛋白基因 5'-非翻译区域的最近端 NF-1 和 Sp-1 结合域。 Raf 抑制信号被映射到涉及新型 60 kDa DNA 结合蛋白 (p60) 的更上游结合域。在体内肝纤维化的早期阶段，星状细胞中 p60 的细胞特异性表达和诱导表明该途径在肝损伤和星状细胞激活过程中发挥着核心作用。
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.