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首页> 外文期刊>Molecular and Cellular Biology >Differential Utilization of Ras Signaling Pathways by Macrophage Colony-Stimulating Factor (CSF) and Granulocyte-Macrophage CSF Receptors during Macrophage Differentiation
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Differential Utilization of Ras Signaling Pathways by Macrophage Colony-Stimulating Factor (CSF) and Granulocyte-Macrophage CSF Receptors during Macrophage Differentiation

机译：巨噬细胞分化过程中巨噬细胞集落刺激因子（CSF）和粒细胞-巨噬细胞CSF受体对Ras信号通路的差异利用。

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) independently stimulate the proliferation and differentiation of macrophages from bone marrow progenitor cells. Although the GM-CSF and M-CSF receptors are unrelated, both couple to Ras-dependent signal transduction pathways, suggesting that these pathways might account for common actions of GM-CSF and M-CSF on the expression of macrophage-specific genes. To test this hypothesis, we have investigated the mechanisms by which GM-CSF and M-CSF regulate the expression of the macrophage scavenger receptor A (SR-A) gene. We demonstrate that induction of the SR-A gene by M-CSF is dependent on AP-1 and cooperating Ets domain transcription factors that bind to sites in an M-CSF-dependent enhancer located 4.1 to 4.5 kb upstream of the transcriptional start site. In contrast, regulation by GM-CSF requires a separate enhancer located 4.5 to 4.8 kb upstream of the transcriptional start site that confers both immediate-early and sustained transcriptional responses. Results of a combination of DNA binding experiments and functional assays suggest that immediate transcriptional responses are mediated by DNA binding proteins that are constitutively bound to the GM-CSF enhancer and are activated by Ras. At 12 to 24 h after GM-CSF treatment, the GM-CSF enhancer becomes further occupied by additional DNA binding proteins that may contribute to sustained transcriptional responses. In concert, these studies indicate that GM-CSF and M-CSF differentially utilize Ras-dependent signal transduction pathways to regulate scavenger receptor gene expression, consistent with the distinct functional properties of M-CSF- and GM-CSF-derived macrophages.
机译：粒细胞巨噬细胞集落刺激因子（GM-CSF）和巨噬细胞集落刺激因子（M-CSF）独立地刺激巨噬细胞从骨髓祖细胞的增殖和分化。尽管GM-CSF和M-CSF受体无关，但都与Ras依赖的信号转导途径偶联，表明这些途径可能解释了GM-CSF和M-CSF对巨噬细胞特异性基因表达的共同作用。为了验证这一假设，我们研究了GM-CSF和M-CSF调节巨噬细胞清除剂受体A（SR-A）基因表达的机制。我们证明了由M-CSF诱导SR-A基因依赖于AP-1和与位于转录起始位点上游4.1至4.5 kb的M-CSF依赖性增强子中的站点结合的Ets域转录因子。相反，通过GM-CSF进行调节则需要一个位于转录起始位点上游4.5至4.8 kb的单独增强子，该增强子可同时赋予早期和持续的转录反应。 DNA结合实验和功能测定的组合结果表明，即时转录反应由与GM-CSF增强子组成性结合并被Ras激活的DNA结合蛋白介导。 GM-CSF处理后12至24小时，GM-CSF增强子进一步被可能有助于持续转录反应的其他DNA结合蛋白所占据。一致地，这些研究表明GM-CSF和M-CSF差异地利用Ras依赖性信号转导途径来调节清道夫受体基因的表达，这与M-CSF和GM-CSF衍生的巨噬细胞的独特功能特性相一致。

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