Depolarization of neural cells induces transcription of the down syndrome critical region 1 isoform 4 via a calcineurin/nuclear factor of activated T cells-dependent pathway
Depolarization of neural cells induces transcription of the down syndrome critical region 1 isoform 4 via a calcineurin/nuclear factor of activated T cells-dependent pathway
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DOI：
10.1074/jbc.m506205200
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发表时间：
2005-08-19
影响因子：
4.8
通讯作者：
Redondo, JM
中科院分区：
文献类型：
--
作者：
Cano, E;Canellada, A;Redondo, JM
在这项研究中，我们表明唐氏综合症关键区域异构体 4 (DSCR1.4) 的转录调控是由神经细胞中的钙调神经磷酸酶/活化 T 细胞核因子 (NFAT) 通路介导的。引起细胞内钙浓度增加的刺激（例如膜去极化）诱导 DSCR1.4 从头转录，mRNA 表达在 4 小时后达到峰值，然后下降。通过硝苯地平和维拉帕米的阻断证实了通过生理相关的 L 型钙通道的作用。 DSCR1.4 的这种钙依赖性转录受到钙调神经磷酸酶抑制剂环孢菌素 A 和 FK506 的抑制。缺失分析表明，钙和钙调神经磷酸酶依赖性激活是由核苷酸-350和-166之间的启动子区域介导的，该区域包含推定的NFAT结合基序。外源性 NFATc2 有效增强了 DSCR1.4 启动子转录活性，并且通过 NFAT 抑制剂肽 VIVIT 抑制去极化诱导型启动子活性，证实了内源性 NFAT 信号通路参与 DSCR1.4 转录。 DSCR1 蛋白（钙加压素 1）的外源过度表达导致 DSCR1.4 转录和 NFAT 依赖性信号传导受到抑制。这些发现表明 DSCR1.4 产物的钙调磷酸酶依赖性诱导可能代表神经细胞中 NFAT 信号稳态控制的重要自动调节机制。
In this study we showed that the transcriptional regulation of Down syndrome critical region isoform 4 (DSCR1.4) is mediated by the calcineurin/nuclear factor of activated T cells (NFAT) pathway in neural cells. Stimuli that elicit an increase in the intracellular concentrations of calcium, such as membrane depolarization, induced de novo transcription of DSCR1.4, with mRNA expression peaking after 4 h and then declining. Action via the physiologically relevant L-type calcium channel was confirmed by blockade with nifedipine and verapamil. This calcium-dependent transcription of DSCR1.4 was inhibited by the calcineurin inhibitors cyclosporin A and FK506. Deletional analysis showed that the calcium- and calcineurin-dependent activation is mediated by the promoter region between nucleotides -350 and -166, a region that contains putative NFAT-binding motifs. Exogenous NFATc2 potently augmented the DSCR1.4 promoter transcriptional activity, and the involvement of endogenous NFAT signaling pathway in DSCR1.4 transcription was confirmed by the suppression of depolarization-inducible promoter activity with the NFAT inhibitor peptide VIVIT. Exogenous overexpression of DSCR1 protein (calcipressin 1) resulted in the inhibition of the transcription of DSCR1.4 and NFAT-dependent signaling. These findings suggest that calcineurin-dependent induction of DSCR1.4 product may represent an important auto-regulatory mechanism for the homeostatic control of NFAT signaling in neural cells.