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首页> 外文期刊>Molecular and Cellular Biology >Utilization of an NF-ATp Binding Promoter Element for EGR3 Expression in T Cells but Not Fibroblasts Provides a Molecular Model for the Lymphoid Cell-Specific Effect of Cyclosporin A
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Utilization of an NF-ATp Binding Promoter Element for EGR3 Expression in T Cells but Not Fibroblasts Provides a Molecular Model for the Lymphoid Cell-Specific Effect of Cyclosporin A

机译：利用NF-ATp结合启动子元件在T细胞而非成纤维细胞中表达EGR3提供了针对环孢菌素A淋巴样细胞特异性作用的分子模型

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Cyclosporin A (CsA) mainly exerts its immunosuppressive action by selectively inhibiting Ca2+/calcineurin-dependent gene transcription in lymphoid cells. A model explaining the tissue-specific effect of this drug on gene expression has not been established to date, since none of the known intracellular targets of CsA (e.g., cyclophilins, calcineurin, and NF-AT) is lymphoid cell specific. To investigate this issue, we performed a detailed comparative analysis of the promoter regulating the two-signal-dependent (Ca2+ionophore plus phorbol myristate acetate [PMA]), CsA-sensitive expression of EGR3 in T cells and the one-signal-dependent (PMA), CsA-insensitive expression of EGR3 in fibroblasts. As a result, we identified a 27-bp promoter element functionally interacting with transcription factors NF-ATp and NF-ATc that is crucial for the CsA-sensitive expression of the EGR3 gene in T cells. In contrast, the same element was without function in fibroblasts, and other, CsA-insensitive promoter regions were found to be responsible for EGR3 gene expression in these cells. The inactivity of the 27-bp element in fibroblasts was apparently due to insufficient expression levels of NF-ATp, since overexpression of NF-ATp, but not NF-ATc, restored the two-signal phenotype and CsA sensitivity of EGR3 promoter induction in these cells. The differential usage of an NF-AT binding site explains the selective effect of CsA on EGR3 gene expression in T cells versus fibroblasts and may represent one of the basic mechanisms underlying the tissue specificity of CsA.
机译：环孢菌素A（CsA）主要通过选择性抑制淋巴样细胞中Ca 2 + /钙调神经磷酸酶的基因转录来发挥其免疫抑制作用。迄今为止，尚未建立解释该药物对基因表达的组织特异性作用的模型，因为已知的CsA细胞内靶标（例如，亲环蛋白，钙调神经磷酸酶和NF-AT）都没有淋巴样细胞特异性。为了研究此问题，我们对调节两个信号依赖性启动子（Ca 2 + ionophore加上佛波醇肉豆蔻酸酯乙酸盐[PMA]），CsA敏感的EGR3在T中的表达进行了详细的比较分析。细胞和成纤维细胞中EGR3的单信号依赖性（PMA），CsA不敏感表达。结果，我们鉴定了与转录因子NF-ATp和NF-ATc功能性相互作用的27 bp启动子元件，这对于T细胞中EGR3基因的CsA敏感表达至关重要。相反，同一元素在成纤维细胞中没有功能，并且发现其他CsA不敏感启动子区域负责这些细胞中EGR3基因的表达。成纤维细胞中27 bp元件的失活显然是由于NF-ATp的表达水平不足，因为NF-ATp而非NF-ATc的过表达恢复了EGR3启动子诱导的两个信号表型和CsA敏感性。细胞。 NF-AT结合位点的不同用法解释了CsA对T细胞与成纤维细胞中EGR3基因表达的选择性作用，并且可能代表了CsA组织特异性的基本机制之一。

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