INHIBITION OF CAMP-RESPONSIVE ELEMENT-MEDIATED GENE-TRANSCRIPTION BY CYCLOSPORINE-A AND FK506 AFTER MEMBRANE DEPOLARIZATION

The cAMP-responsive element (CRE) and its cognate transcription factor CREB can mediate induction of gene transcription in response to membr ane depolarization and calcium influx. In this study, the effect of cy closporin A (CsA) and FK506 on depolarization-induced glucagon gene tr anscription was investigated in a pancreatic islet cell line by transf ection of reporter fusion genes. CsA and FK506 inhibited depolarizatio n-induced glucagon gene transcription, FK506 being more potent than Cs A. CsA/FK506 responsiveness was mediated by the glucagon CRE and also by well characterized CREs of the choriogonadotropin and somatostatin genes. Rapamycin antagonized the inhibitory effect of FK506 but not Cs A, suggesting that FK506 and CsA may act through complex formation wit h distinct intracellular immunophilins. Overexpression of calcineurin, which is known to be inhibited by drug-immunophilin complexes, render ed pancreatic islet cells more resistant to the inhibitory effects of CsA and FK506. These results demonstrate an inhibition by CsA and FK50 6 of CRE-mediated, calcium-induced transcription and suggest that memb rane depolarization relies on calcineurin phosphatase activity for act ivation of CREB/CRE-mediated gene transcription. The interference with CRE-mediated gene transcription represents a novel mechanism of CsA/F K506 action, which may underlie pharmacological effects and toxic mani festations of these potent immunosuppressive drugs.