Nair A P, Hahn S, Banholzer R, Hirsch H H, Moroni C
Institute for Medical Microbiology, University of Basel, Switzerland.
Nature. 1994 May 19;369(6477):239-42. doi: 10.1038/369239a0.
In T cells, cyclosporin A (CsA) exerts its immunosuppressive effect by preventing transcriptional induction of the expression of interleukin(IL)-2. This is achieved by a mechanism that involves binding of a CsA-cyclophilin complex to calcineurin, which in turn inhibits the phosphatase-controlled translocation of transcription factor NFAT to the nucleus. We have previously identified IL-3 as an autocrine oncogenic regulator in tumour cell lines generated by introducing the v-H-ras oncogene into IL-3-dependent mast cells. Here we report that CsA specifically blocks autocrine tumour cell growth. The mechanism involves down-regulation of IL-3 expression by destabilization of the messenger RNA and requires ongoing transcription. Transcripts from exogenous IL-3 genes lacking the (A+U)-rich element (ARE) in the 3' untranslated terminal repeat could not be destabilized, suggesting that at least part of this sequence, which is known to mediate decay of short-lived mRNA, participates in a CsA-sensitive regulatory mechanism.
在T细胞中，环孢素A（CsA）通过阻止白细胞介素（IL）-2表达的转录诱导发挥其免疫抑制作用。这是通过一种机制实现的，该机制涉及CsA-亲环蛋白复合物与钙调神经磷酸酶的结合，进而抑制转录因子NFAT在磷酸酶控制下向细胞核的转运。我们之前已将IL-3鉴定为通过将v-H-ras癌基因导入IL-3依赖性肥大细胞而产生的肿瘤细胞系中的自分泌致癌调节因子。在此我们报告，CsA特异性地阻断自分泌肿瘤细胞生长。其机制涉及通过信使核糖核酸的去稳定作用下调IL-3表达，并且需要持续转录。来自在3'非翻译末端重复序列中缺乏富含（A+U）元件（ARE）的外源性IL-3基因的转录本无法被去稳定，这表明已知介导短命信使核糖核酸衰变的该序列的至少一部分参与了CsA敏感的调节机制。
