Mattila P S, Ullman K S, Fiering S, Emmel E A, McCutcheon M, Crabtree G R, Herzenberg L A
Department of Genetics, Stanford University School of Medicine, CA 94305.
EMBO J. 1990 Dec;9(13):4425-33. doi: 10.1002/j.1460-2075.1990.tb07893.x.
Cyclosporin A and FK506 are immunosuppressive compounds that have similar inhibitory effects on the expression of several lymphokines produced by T lymphocytes. Despite their similar effects the drugs bind to two different cytosolic protein, cyclophilin and FKBP respectively, which raises the possibility that they have different modes of action. Using constructs in which mRNA production controlled by a specific transcription factor could be readily measured we found that both cyclosporin A and FK506 completely inhibited transcription activated by NF-AT, NFIL2 A, NFIL2 B and partially inhibited transcription activated by NF kappa B. Cyclosporin A and FK506 inhibited only transcriptional activation that was dependent on Ca2+ mobilization. However, cyclosporin A and FK506 did not inhibit Ca2+ mobilization dependent expression of c-fos mRNA indicating that only a subset of signalling pathways regulated by Ca2+ is sensitive to these drugs. Furthermore, we did not observe any qualitative differences between the effect of cyclosporin A and FK506 on six different transcription factors which suggests that these drugs may interfere with the activity of a novel Ca2+ dependent step that regulates several transcription factors.
环孢菌素A和FK506是免疫抑制化合物，它们对T淋巴细胞产生的几种淋巴因子的表达具有相似的抑制作用。尽管它们的作用相似，但这两种药物分别与两种不同的胞质蛋白——亲环蛋白和FKBP结合，这增加了它们具有不同作用模式的可能性。使用能够轻松测量由特定转录因子控制的mRNA产生的构建体，我们发现环孢菌素A和FK506都完全抑制了由NF-AT、NFIL2 A、NFIL2 B激活的转录，并部分抑制了由NF-κB激活的转录。环孢菌素A和FK506仅抑制依赖于Ca2+动员的转录激活。然而，环孢菌素A和FK506并不抑制c-fos mRNA的Ca2+动员依赖性表达，这表明只有一部分由Ca2+调节的信号通路对这些药物敏感。此外，我们没有观察到环孢菌素A和FK506对六种不同转录因子的作用存在任何质的差异，这表明这些药物可能会干扰调节几种转录因子的一个新的Ca2+依赖性步骤的活性。
