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- Title
The immunosuppressive drugs cyclosporin A and tacrolimus inhibit membrane depolarization-induced CREB transcriptional activity at the coactivator level.
- Authors
Oetjen, Elke; Thoms, Kai-Martin; Laufer, Yvonne; Pape, Daniela; Blume, Roland; Pingfeng Li; Knepel, Willhart
- Abstract
Cyclosporin A and tacrolimus are clinically important immunosuppressive drugs directly targeting the transcription factor nuclear factor of activated T cells (NFAT). Through inhibition of calcineurin phosphatase activity they block the dephosphorylation and thus activation of NFAT. Cyclosporin A and tacrolimus also inhibit other calcineurin-dependent transcription factors including the ubiquitously expressed cAMP response element-binding protein (CREB). Membrane depolarization by phosphorylating CREB on Ser119 leads to the recruitment of its coactivator CREB-binding protein (CBP) that stimulates initiation of transcription.It was unknown at what step in CREB-mediated transcription cyclosporin A and tacrolimus interfere.In transient transfection experiments, using GAL4-CREB fusion proteins and a pancreatic isletß-cell line, cyclosporin A inhibited depolarization-induced activation of CREB proteins which carried various deletions or mutations throughout their sequence providing no evidence for the existence of a distinct CREB domain conferring cyclosporin A sensitivity. In a mammalian two-hybrid assay, cyclosporin A did not inhibit Ser119-dependent interaction of CREB with its coactivator CBP.Using GAL4-CBP fusion proteins, cyclosporin A inhibited depolarization-induced CBP activity, with cyclosporin A-sensitive domains mapped to both the N- (aa 1-451) and C-terminal (aa 2040-2305) ends of CBP. The depolarization-induced transcriptional activity of the CBP C-terminus was enhanced by overexpression of calcineurin and was inhibited by cyclosporin A and tacrolimus in a concentration-dependent manner with IC50 values (10 and 1?nM, respectively) consistent with their known IC50 values for inhibition of calcineurin.These data suggest that, in contrast to NFAT, cyclosporin A and tacrolimus inhibit CREB transcriptional activity at the coactivator level.British Journal of Pharmacology (2005) 144, 982-993. doi:10.1038/sj.bjp.0706127
- Subjects
CYCLOSPORINE; IMMUNOSUPPRESSIVE agents; CYCLIC peptides; TACROLIMUS; TRANSCRIPTION factors; CYCLIC adenylic acid
- Publication
British Journal of Pharmacology, 2005, Vol 144, Issue 7, p982
- ISSN
0007-1188
- Publication type
Article
- DOI
10.1038/sj.bjp.0706127