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首页> 外文期刊>The FEBS journal >All-trans-retinoic acid inhibits collapsin response mediator protein-2 transcriptional activity during SH-SY5Y neuroblastoma cell differentiation
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All-trans-retinoic acid inhibits collapsin response mediator protein-2 transcriptional activity during SH-SY5Y neuroblastoma cell differentiation

机译：全反式维甲酸抑制SH-SY5Y神经母细胞瘤细胞分化过程中的胶原蛋白介导蛋白2转录活性

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摘要

Neurons are highly polarized cells composed of two structurally and functionally distinct parts, the axon and the dendrite. The establishment of this asymmetric structure is a tightly regulated process. In fact, alterations in the proteins involved in the configuration of the microtubule lattice are frequent in neuro-oncologic diseases. One of these cytoplasmic mediators is the protein known as collapsin response mediator protein-2, which interacts with and promotes tubulin polymerization. In this study, we investigated collapsin response mediator protein-2 transcriptional regulation during all-trans-retinoic acid-induced differentiation of SH-SY5Y neuroblastoma cells. All-trans-retinoic acid is considered to be a potential preventive and therapeutic agent, and has been extensively used to differentiate neuroblastoma cells in vitro. Therefore, we first demonstrated that collapsin response mediator protein-2 mRNA levels are downregulated during the differentiation process. After completion of deletion construct analysis and mutagenesis and mobility shift assays, we concluded that collapsin response mediator protein-2 basal promoter activity is regulated by the transcription factors AP-2 and Pax-3, whereas E2F, Sp1 and NeuroD1 seem not to participate in its regulation. Furthermore, we finally established that reduced expression of collapsin response mediator protein-2 after all-trans-retinoic acid exposure is associated with impaired Pax-3 and AP-2 binding to their consensus sequences in the collapsin response mediator protein-2 promoter. Decreased attachment of AP-2 is a consequence of its accumulation in the cytoplasm. On the other hand, Pax-3 shows lower binding due to all-trans-retinoic acid-mediated transcriptional repression. Unraveling the molecular mechanisms behind the action of all-trans-retinoic acid on neuroblastoma cells may well offer new perspectives for its clinical application.
机译：神经元是高度极化的细胞，由轴突和树突这两个在结构和功能上不同的部分组成。这种不对称结构的建立是一个严格监管的过程。实际上，在神经肿瘤疾病中，与微管格构型有关的蛋白质的改变是常见的。这些细胞质介体之一是被称为胶原蛋白反应介体蛋白2的蛋白质，其与微管蛋白聚合相互作用并促进微管蛋白聚合。在这项研究中，我们调查了全反式维甲酸诱导的SH-SY5Y神经母细胞瘤细胞分化过程中collapsin反应介质蛋白2的转录调控。全反式视黄酸被认为是一种潜在的预防和治疗剂，已被广泛用于体外分化成神经母细胞瘤细胞。因此，我们首先证明了在分化过程中，胶原蛋白介导蛋白2 mRNA的表达水平被下调。在完成缺失构建体分析以及诱变和迁移率迁移分析后，我们得出结论，胶原蛋白介导蛋白2基础启动子活性受转录因子AP-2和Pax-3调控，而E2F，Sp1和NeuroD1似乎不参与它的规定。此外，我们最终确定，在全反式维甲酸暴露后，胶原蛋白应答介导蛋白-2表达的降低与受损的Pax-3和AP-2与其在胶原蛋白介导蛋白-2启动子中的共有序列的结合有关。 AP-2附着减少是其在细胞质中积累的结果。另一方面，Pax-3由于全反式维甲酸介导的转录抑制而显示出较低的结合。揭示全反式维甲酸对神经母细胞瘤细胞作用的分子机制可能为其临床应用提供新的观点。

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