Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A

W. Michael Flanagan, Blaise Corthésy, Richard J. Bram, Gerald R. Crabtree

Research output: Contribution to journalArticlepeer-review

918 Scopus citations


CYCLOSPORINA and FK506 inhibit T- and B-cell activation and other processes essential to an effective immune response1-3. In T lymphocytes these drugs disrupt an unknown step in the trans-mission of signals from the T-cell antigen receptor to cytokine genes that coordinate the immune response4-6. The putative intracellular receptors for FK506 and cyclosporin arecis-trans prolyl isomerases7-11. Binding of the drug inhibits isomerase activity8,10,11, but studies with other prolyl isomerase inhibitors12 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 isomerase13,14, and not from inhibi-tion 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-κB (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.

Original languageEnglish (US)
Pages (from-to)803-807
Number of pages5
Issue number6338
StatePublished - Jan 1 1991

ASJC Scopus subject areas

  • General


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