TY - JOUR T1 - Activation of the Dual-Leucine-Zipper-Bearing Kinase and Induction of β-Cell Apoptosis by the Immunosuppressive Drug Cyclosporin A JF - Molecular Pharmacology JO - Mol Pharmacol SP - 652 LP - 659 DO - 10.1124/mol.107.040782 VL - 73 IS - 3 AU - Silke Plaumann AU - Roland Blume AU - Svenja Börchers AU - Hans Jürgen Steinfelder AU - Willhart Knepel AU - Elke Oetjen Y1 - 2008/03/01 UR - http://molpharm.aspetjournals.org/content/73/3/652.abstract N2 - Post-transplant diabetes is an untoward effect often observed under immunosuppressive therapy with cyclosporin A. Besides the development of peripheral insulin resistance and a decrease in insulin gene transcription, a β-cell toxic effect has been described. However, its molecular mechanism remains unknown. In the present study, the effect of cyclosporin A and the dual leucine-zipper-bearing kinase (DLK) on β-cell survival was investigated. Cyclosporin A decreased the viability of the insulin-producing pancreatic islet cell line HIT in a time- and concentration-dependent manner. Upon exposure to the immunosuppressant fragmentation of DNA, the activation of the effector caspase-3 and a decrease of full-length caspase-3 and BclXL were observed in HIT cells and in primary mature murine islets, respectively. Cyclosporin A and tacrolimus, both potent inhibitors of the calcium/calmodulin-dependent phosphatase calcineurin, stimulated the enzymatic activity of cellular DLK in an in vitro kinase assay. Immunocytochemistry revealed that the overexpression of DLK but not its kinase-dead mutant induced apoptosis and enhanced cyclosporin A-induced apoptosis to a higher extent than the drug alone. Moreover, in the presence of DLK, the effective concentration for cyclosporin A-caused apoptosis was similar to its known IC50 value for the inhibition of calcineurin activity in β cells. These data suggest that cyclosporin A through inhibition of calcineurin activates DLK, thereby leading to β-cell apoptosis. This action may thus be a novel mechanism through which cyclosporin A precipitates post-transplant diabetes. The American Society for Pharmacology and Experimental Therapeutics ER -