IDENTIFICATION OF CALCINEURIN AS A KEY SIGNALING ENZYME IN LYMPHOCYTE-T ACTIVATION
IDENTIFICATION OF CALCINEURIN AS A KEY SIGNALING ENZYME IN LYMPHOCYTE-T ACTIVATION
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DOI：
10.1038/357695a0
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发表时间：
1992-06-25
期刊：
影响因子：
64.8
通讯作者：
CRABTREE, GR
中科院分区：
文献类型：
--
作者：
CLIPSTONE, NA;CRABTREE, GR
免疫抑制药物环孢菌素A（CsA）和FK 506都干扰Ca 2+敏感性T细胞信号转导途径1-4，从而阻止参与淋巴因子基因表达的特异性转录因子（如NF-AT和NF-IL 2A）的激活1，5 -7。CsA和FK 506似乎分别通过与同源细胞内受体8-10亲环素和FKBP相互作用发挥作用（综述见参考文献11）。Ca 2 +/钙调蛋白调节的磷酸酶钙调磷酸酶是体外药物异构酶复合物的主要靶标12。因此，我们已经测试的假设，这种相互作用是负责CsA/FK 506的体内效应。我们在这里报告，钙调磷酸酶在Jurkat细胞的过度表达，使他们更耐CsA和FK 506的影响，并增强NFAT和NFIL 2A依赖的转录。这些结果确定钙调神经磷酸酶作为一个关键酶的T细胞信号转导级联反应，并提供生物学证据支持的概念，药物异构酶复合物与钙调神经磷酸酶的相互作用的基础CsA/FK 506介导的免疫抑制的分子基础。
THE immunosuppressive drugs cyclosporin A (CsA) and FK506 both interfere with a Ca2+-sensitive T-cell signal transduction pathway 1-4, thereby preventing the activation of specific transcription factors (such as NF-AT and NF-IL2A) 1,5-7 involved in lymphokine gene expression. CsA and FK506 seem to act by interaction with their cognate intracellular receptors 8-10, cyclophilin and FKBP, respectively (see ref. 11 for review). The Ca2+/calmodulin-regulated phosphatase calcineurin is a major target of drug-isomerase complexes in vitro 12. We have therefore tested the hypothesis that this interaction is responsible for the in vivo effects of CsA/FK506. We report here that overexpression of calcineurin in Jurkat cells renders them more resistant to the effects of CsA and FK506 and augments both NFAT- and NFIL2A-dependent transcription. These results identify calcineurin as a key enzyme in the T-cell signal transduction cascade and provide biological evidence to support the notion that the interaction of drug-isomerase complexes with calcineurin underlies the molecular basis of CsA/FK506-mediated immunosuppression.