NUCLEAR-ASSOCIATION OF A T-CELL TRANSCRIPTION FACTOR BLOCKED BY FK-506 AND CYCLOSPORINE-A
NUCLEAR-ASSOCIATION OF A T-CELL TRANSCRIPTION FACTOR BLOCKED BY FK-506 AND CYCLOSPORINE-A
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DOI：
10.1038/352803a0
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发表时间：
1991-08-29
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：
FLANAGAN, WM;CORTHESY, B;CRABTREE, GR
环孢菌素A和FK 506抑制T细胞和B细胞活化以及有效免疫应答所必需的其他过程1-3。 在T淋巴细胞中，这些药物破坏从T细胞抗原受体到协调免疫应答的细胞因子基因的信号传递中的未知步骤4-6。 FK 506和环孢菌素的假定细胞内受体是顺-反脯氨酰异构酶7-11。 药物的结合可抑制异构酶活性8、10、11，但对其他脯氨酰异构酶抑制剂的研究12和对酵母中环孢菌素耐药突变体的分析表明，药物的作用是由于药物与异构酶之间形成抑制复合物13、14，而不是抑制异构酶活性。 对于早期T细胞基因活化至关重要的转录因子NF-AT似乎是环孢菌素A和FK 506作用的特异性靶点，因为在用这些药物处理的T细胞中，由该蛋白指导的转录被阻断，对其他转录因子如AP-1和NF-κ-B几乎没有影响（参考文献15-17）。 在这里，我们证明，当来自抗原受体的信号诱导一个预先存在的胞质亚基易位到细胞核和联合收割机与一个新合成的核亚基的NF-AT形成。 FK 506和环孢菌素A阻断胞质组分的易位，而不影响核亚基的合成。
CYCLOSPORIN A and FK506 inhibit T- and B-cell activation and other processes essential to an effective immune response 1-3. In T lymphocytes these drugs disrupt an unknown step in the transmission of signals from the T-cell antigen receptor to cytokine genes that coordinate the immune response 4-6. The putative intracellular receptors for FK506 and cyclosporin are cis-trans prolyl isomerases 7-11. Binding of the drug inhibits isomerase activity 8,10,11, but studies with other prolyl isomerase inhibitors 12 and analysis of cyclosporin-resistant mutants in yeast suggest that the effects of the drug result from the formation of an inhibitory complex between the drug and isomerase 13,14, and not from inhibition of isomerase activity. A transcription factor, NF-AT, which is essential for early T-cell gene activation, seems to be a specific target of cyclosporin A and FK506 action because transcription directed by this protein is blocked in T cells treated with these drugs, with little or no effect on other transcription factors such as AP-1 and NF-kappa-B (refs 15-17). Here we demonstrate that NF-AT is formed when a signal from the antigen receptor induces a pre-existing cytoplasmic subunit to translocate to the nucleus and combine with a newly synthesized nuclear subunit of NF-AT. FK506 and cyclosporin A block translocation of the cytoplasmic component without affecting synthesis of the nuclear subunit.