Transcriptional activation of human mu-opioid receptor gene by insulin-like growth factor-I in neuronal cells is modulated by the transcription factor REST
Transcriptional activation of human mu-opioid receptor gene by insulin-like growth factor-I in neuronal cells is modulated by the transcription factor REST
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DOI：
10.1111/j.1471-4159.2008.05303.x
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发表时间：
2008-06-01
影响因子：
4.7
通讯作者：
Spampinato, Santi
中科院分区：
文献类型：
--
作者：
Bedini, Andrea;Baiula, Monica;Spampinato, Santi
人μ-阿片受体基因（OPRM 1）启动子含有一个DNA序列，该序列与转录抑制中涉及的阻遏元件1沉默转录因子（REST）结合。我们研究了是否胰岛素样生长因子I（IGF-I），影响神经元诱导和成熟的各个方面，在REST的潜在影响的背景下，调节OPRM 1在神经元细胞中的转录。将一系列OPRM 1-荧光素酶启动子/报告基因构建体转染到两种神经元细胞模型中，神经母细胞瘤衍生的SH-SY 5 Y细胞和PC 12细胞。在前者中，人μ阿片受体（hMOPr）mRNA的内源性水平进行了评估，通过实时PCR。IGF-I在以下细胞中上调OPRM 1转录：缺乏REST的PC 12细胞、用缺乏REST DNA结合元件的构建体转染的SH-SY 5 Y细胞，或当REST在视黄酸分化细胞中下调时。IGF-I激活信号转导子和转录激活子-3信号通路，并且该转录因子结合位于启动子中的信号转导子和转录激活子-1/3 DNA元件，增加OPRM 1转录。我们认为，减少休息是一个关键的开关，使IGF-I上调hMOPr。这些发现有助于阐明hMOPr表达是如何在神经元细胞中调节的。
The human mu-opioid receptor gene (OPRM1) promoter contains a DNA sequence binding the repressor element 1 silencing transcription factor (REST) that is implicated in transcriptional repression. We investigated whether insulin-like growth factor I (IGF-I), which affects various aspects of neuronal induction and maturation, regulates OPRM1 transcription in neuronal cells in the context of the potential influence of REST. A series of OPRM1-luciferase promoter/reporter constructs were transfected into two neuronal cell models, neuroblastoma-derived SH-SY5Y cells and PC12 cells. In the former, endogenous levels of human mu-opioid receptor (hMOPr) mRNA were evaluated by real-time PCR. IGF-I up-regulated OPRM1 transcription in: PC12 cells lacking REST, in SH-SY5Y cells transfected with constructs deficient in the REST DNA binding element, or when REST was down-regulated in retinoic acid-differentiated cells. IGF-I activates the signal transducer and activator of transcription-3 signaling pathway and this transcription factor, binding to the signal transducer and activator of transcription-1/3 DNA element located in the promoter, increases OPRM1 transcription. We propose that a reduction in REST is a critical switch enabling IGF-I to up-regulate hMOPr. These findings help clarify how hMOPr expression is regulated in neuronal cells.