Transcriptional regulation of human MAP2 gene in melanoma: role of neuronal bHLH factors and Notch1 signaling.
Transcriptional regulation of human MAP2 gene in melanoma: role of neuronal bHLH factors and Notch1 signaling.
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人类 MAP2 基因在黑色素瘤中的转录调控：神经元 bHLH 因子和 Notch1 信号传导的作用。
DOI：
10.1093/nar/gkl476
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发表时间：
2006
影响因子：
14.9
通讯作者：
Setaluri, Vijayasaradhi
中科院分区：
文献类型：
--
作者：
Bhat, Kumar M. R.;Maddodi, Nityanand;Shashikant, Cooduvalli;Setaluri, Vijayasaradhi
微管相关蛋白2（MAP 2）是一种神经元特异性蛋白，稳定微管，对神经突生长和树突发育至关重要。尽管MAP 2被广泛用作神经元分化的标志物，但其转录调控尚未被研究。我们发现MAP 2在人皮肤黑色素瘤中经常被激活。在这里，我们确定了一个2.2 kb的区域，这是足够的神经元特异性表达在体外和体内。小鼠、大鼠和人MAP 2启动子序列的比较分析显示存在保守的bHLH因子结合位点。电泳迁移率变化分析、启动子突变和共转染实验表明，NeuroD（一种促神经元分化因子）和Hairy和分裂增强子（HES 1）（一种转录抑制因子）参与MAP 2启动子活性的调节。黑色素瘤细胞同时表达NeuroD和HES 1。染色质免疫沉淀显示，在转移性黑色素瘤细胞中，MAP 2启动子的N-box区域被内源性HES 1占据。我们发现，Notch信号的抑制，调节HES 1基因的表达，和/或shRNA敲低HES 1的结果在MAP 2启动子活性的上调。因此，我们的数据表明，Notch信号，这是在黑色素瘤的进展，和HES 1发挥作用，在黑色素瘤的进展过程中的MAP 2基因调控。
Microtubule-associated protein 2 (MAP2), a neuron-specific protein, stabilizes microtubules and is critical for neurite outgrowth and dendrite development. Although MAP2 is widely used as a marker of neuronal differentiation, regulation of its transcription has not been investigated. We showed that MAP2 is frequently activated in human cutaneous melanoma. Here, we identified a 2.2 kb region that is sufficient for neuronal-specific expression in vitro and in vivo. Comparative analysis of the mouse, rat and human MAP2 promoter sequences showed the presence of a conserved bHLH factor binding sites. Electrophoretic mobility shift analysis, promoter mutagenesis and co-transfection experiments showed that NeuroD, a pro-neuronal differentiation factor, and Hairy and Enhancer of Split (HES1), a transcription repressor, are involved in the regulation of MAP2 promoter activity. Melanoma cells express both NeuroD and HES1. Chromatin immunoprecipitation showed that in metastatic melanoma cells N-box region of the MAP2 promoter is occupied by endogenous HES1. We show that the inhibition of Notch signaling, a regulator of HES1 gene expression, and/or shRNA knockdown of HES1 results in the upregulation of MAP2 promoter activity. Thus, our data suggest that Notch signaling, which is implicated in melanoma progression, and HES1 play a role in MAP2 gene regulation during melanoma progression.
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