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首页> 外文期刊>The Journal of Biochemistry >Role of down-regulated neutral ceramidase during all-trans retinoic acid-induced neuronal differentiation in SH-SY5Y neuroblastoma cells
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Role of down-regulated neutral ceramidase during all-trans retinoic acid-induced neuronal differentiation in SH-SY5Y neuroblastoma cells

机译：下调中性神经酰胺酶在SH-SY5Y成神经细胞瘤细胞全反式维甲酸诱导的神经元分化中的作用

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Neutral ceramidase (NCDase) is considered to be a critical enzyme for controlling the turnover of ceramide, an important bioactive lipid, which determines cell's fate. All-trans retinoic acid (ATRA) has been reported to induce neuronal differentiation and cell-cycle arrest [Lopez-Carballo, Moreno, Masia, Perez, and Barettino (Activation of the phosphatidylinositol 3-kinase/Akt signalling pathway by retinoic acid is required for neural differentiation of SH-SY5Y human neuroblastoma cells. J Biol Chem 2002:277:25297-304.)]. In this study, we observed that ATRA-induced cellular ceramide accumulation, cell-growth arrest and differentiation accompanied with down-regulation of NCDase in SH-SY5Y cells, without a decrease in sphingosine or sphingosine 1-phosphate. We examined whether the down-regulation of NCDase was involved in the increase in ceramide and cell differentiation. ATRA was found to down-regulate mRNA, protein and the enzyme activity of NCDase. Interestingly, GATA-2 was also decreased with ATRA treatment, and experiments using its expression vector and siRNA and chromatin immunoprecipitation assay demonstrated GATA-2 acted as transcription-factor of NCDase gene expression. By establishing stable transfectants with decreased NCDase expression and activity, we clarified the significance of NCDase down-regulation for ATRA-induced neuronal differentiation. Those sub-clones showed both increased cellular ceramide and reduced cell growth as well as neuronal differentiation phenotypes. These results demonstrate that down-regulation of NCDase through ATRA-induced GATA-2 decrease plays an important role in induction of ceramide accumulation and neuronal differentiation in SH-SY5Y cells.
机译：中性神经酰胺酶（NCDase）被认为是控制神经酰胺（一种决定生物命运的重要生物活性脂质）的周转的关键酶。已报道全反式维甲酸（ATRA）诱导神经元分化和细胞周期停滞[Lopez-Carballo，Moreno，Masia，Perez和Barettino（需要通过维甲酸激活磷脂酰肌醇3-激酶/ Akt信号通路） （SH Biol Chem 2002：277：25297-304。）。在这项研究中，我们观察到ATRA诱导的细胞神经酰胺蓄积，细胞生长停滞和分化伴随着SH-SY5Y细胞中NCDase的下调，而鞘氨醇或鞘氨醇1-磷酸却没有降低。我们检查了NCDase的下调是否与神经酰胺和细胞分化的增加有关。发现ATRA下调NCDase的mRNA，蛋白质和酶活性。有趣的是，ATRA处理也降低了GATA-2的表达，使用其表达载体和siRNA进行的实验以及染色质免疫沉淀实验表明，GATA-2是NCDase基因表达的转录因子。通过建立具有降低的NCDase表达和活性的稳定转染子，我们阐明了NCDase下调对于ATRA诱导的神经元分化的意义。这些亚克隆显示出增加的神经酰胺和减少的细胞生长以及神经元分化表型。这些结果表明，通过ATRA诱导的GATA-2降低，NCDase的下调在诱导SH-SY5Y细胞神经酰胺蓄积和神经元分化中起重要作用。

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