Decreased expression of insulin-like growth factor binding protein-5 during N-(4-hydroxyphenyl)retinamide-induced neuronal differentiation of ARPE-19 human retinal pigment epithelial cells: regulation by CCAAT/enhancer-binding protein.
Decreased expression of insulin-like growth factor binding protein-5 during N-(4-hydroxyphenyl)retinamide-induced neuronal differentiation of ARPE-19 human retinal pigment epithelial cells: regulation by CCAAT/enhancer-binding protein.
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DOI：
10.1002/jcp.22191
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发表时间：
2010-09
影响因子：
5.6
通讯作者：
Redmond, T. Michael
中科院分区：
文献类型：
--
作者：
Samuel, William;Kutty, R. Krishnan;Vijayasarathy, Camasamudram;Pascual, Iranzu;Duncan, Todd;Redmond, T. Michael
胰岛素样生长因子（IGF）结合蛋白-5（IGFBP 5）是IGF轴的重要成员，参与调节细胞生长和分化，通过调节IGF信号传导以及IGF非依赖性机制起作用。我们通过微阵列分析确定IGFBP 5为在N-（4-羟基苯基）-视黄酰胺（4 HPR）诱导的人视网膜色素上皮（RPE）细胞的神经元分化过程中差异调节的基因。IGFBP 5在人RPE细胞中表达，并且在4 HPR诱导的神经元分化过程中，其表达、mRNA以及蛋白质都大大降低。外源性IGFBP 5不阻断神经元分化，表明IGFBP 5下调可能不是神经元分化的先决条件。MEK 1/2抑制剂U 0126可有效阻断MAPK信号通路，抑制4 HPR诱导的RPE细胞IGFBP 5表达下调，抑制4 HPR诱导的RPE细胞IGFBP 5表达下调，抑制RPE细胞向神经元分化。IGFBP 5启动子中C/EBP反应元件的缺失显著降低了启动子的基础活性，并在报告基因分析中消除了其对4 HPR处理的反应性，表明IGFBP 5的表达受C/EBP的调控。因此，我们的结果清楚地表明，IGFBP 5的表达下调在4 HPR诱导的人RPE细胞的神经元分化通过MAPK信号转导途径涉及C/EBPβ。
Insulin-like growth factor (IGF)-binding protein -5 (IGFBP5), an important member of the IGF axis involved in regulating cell growth and differentiation, acts by modulating IGF signaling and also by IGF-independent mechanisms. We identified IGFBP5 by microarray analysis as a gene differentially regulated during N-(4-Hydroxyphenyl)-retinamide (4HPR)-induced neuronal differentiation of human retinal pigment epithelial (RPE) cells. IGFBP5 is expressed in human RPE cells, and its expression, mRNA as well as protein, is greatly decreased during the 4HPR-induced neuronal differentiation. Exogenous IGFBP5 does not block the neuronal differentiation indicating that IGFBP5 down-regulation may not be a prerequisite for the neuronal differentiation. IGFBP5 down-regulation, similar to neuronal differentiation, is mediated by the MAPK pathway since U0126, an inhibitor of MEK1/2, effectively blocked it. The overexpression of transcription factor CCAAT/enhancer binding protein-β (C/EBPβ) inhibited the 4HPR-induced down-regulation of IGFBP5 expression and the neuronal differentiation of RPE cells. The deletion of C/EBP response element from IGFBP5 promoter markedly decreased the basal promoter activity and abolished its responsiveness to 4HPR treatment in reporter assays, suggesting that the expression of IGFBP5 is regulated by C/EBP. Thus, our results clearly demonstrate that the IGFBP5 expression is down-regulated during 4HPR-induced neuronal differentiation of human RPE cells through a MAPK signal transduction pathway involving C/EBPβ.
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