Neu differentiation factor/heregulin induction by hepatocyte and keratinocyte growth factors
Neu differentiation factor/heregulin induction by hepatocyte and keratinocyte growth factors
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DOI：
10.1038/sj.onc.1203357
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发表时间：
2000-02-03
期刊：
影响因子：
8
通讯作者：
Bottaro, DP
中科院分区：
文献类型：
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作者：
Castagnino, P;Lorenzi, MV;Bottaro, DP
肝细胞生长因子（HGF）是一种广泛产生的间质-上皮相互作用的多效性介质。在Balb/MK角质形成细胞中由HGF启动的基因表达变化的研究中，我们观察到Neu-differentiation factor（NDF）mRNA（也称为heregulin或HRG）的诱导。进一步表征Balb/MK角质形成细胞中NDF表达的调节揭示了角质形成细胞生长因子（KGF）和表皮生长因子（EGF）的有效诱导，但不是由HGF/NK 2，一种替代的HGF同种型，具有促运动但不具有促有丝分裂或形态发生活性。持续治疗（8小时）的Balb/MK细胞与KGF刺激分泌成熟的NDF蛋白到培养基中，和Balb/MK细胞与纯化的重组NDF蛋白处理显示出增加的DNA合成。我们还发现在小鼠的两种组织修复模型中NDF诱导的证据：在全层皮肤伤口中，局部增加KGF产生，以及在部分肝切除术后的肾脏中，循环HGF水平升高。这些结果表明，间充质来源的HGF和KGF可以激活自分泌的NDF信号在其上皮的目标，并表明，这种机制有助于协调伤口修复的阶段，并可能发展，这些生长因子在演唱会直接上皮细胞增殖，形态发生和分化。
Hepatocyte growth-factor (HGF) is a potent, widely produced, pleiotropic mediator of mesenchymal-epithelial interaction. In a study of changes in gene expression initiated by HGF in Balb/MK keratinocytes, we observed the induction of Neu-differentiation factor (NDF) mRNA (also known as heregulin, or HRG). Further characterization of the regulation of NDF expression in Balb/MK keratinocytes revealed potent induction by keratinocyte growth factor (KGF) and epidermal growth factor (EGF), but not by HGF/NK2, an alternative HGF isoform with motogenic but not mitogenic or morphogenic activities. Sustained treatment (8 h) of Balb/MK cells with KGF stimulated secretion of mature NDF protein into the culture medium, and Balb/MK cells treated with purified recombinant NDF protein showed increased DNA synthesis. We also found evidence of NDF induction in two models of tissue repair in mice: in full-thickness skin wounds, following locally increased KGF production, and in kidney after partial hepatectomy, following elevation of circulating HGF levels. These results reveal that mesenchymally-derived HGF and KGF can activate autocrine NDF signaling in their epithelial targets, and suggest that this mechanism contributes to the coordination of stages of wound repair, and possibly development, where these growth factors act in concert to direct epithelial proliferation, morphogenesis and differentiation.