PT  - JOURNAL ARTICLE
AU  - Gero Siemann
AU  - Roland Blume
AU  - Daniela Grapentin
AU  - Elke Oetjen
AU  - Markus Schwaninger
AU  - Willhart Knepel
TI  - Inhibition of Cyclic AMP Response Element-Binding Protein/Cyclic AMP Response Element-Mediated Transcription by the Immunosuppressive Drugs Cyclosporin A and FK506 Depends on the Promoter Context
AID  - 10.1124/mol.55.6.1094
DP  - 1999 Jun 01
TA  - Molecular Pharmacology
PG  - 1094--1100
VI  - 55
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/55/6/1094.short
4100  - http://molpharm.aspetjournals.org/content/55/6/1094.full
SO  - Mol Pharmacol1999 Jun 01; 55
AB  - The immunosuppressants cyclosporin A and FK506 (tacrolimus) can block the phosphatase calcineurin, thereby inhibiting gene transcription directed by the cyclic AMP (cAMP)- and calcium-responsive transcription factor, cAMP response element (CRE)-binding protein, and its binding site, CRE, in various cell lines. This action is a novel molecular mechanism of cyclosporin A and FK506 action. Because inhibition of CREB/CRE-directed transcription by cyclosporin A and FK506 has previously been observed by using synthetic minienhancers, reporter fusion genes were constructed to examine the effect of cyclosporin A and FK506 on the transcriptional activity of CRE-containing natural promoters. In transient transfection experiments, cyclosporin A and FK506 inhibited the transcriptional activation by cAMP and the membrane depolarization of three CRE-containing promoters. However, cyclosporin A and FK506 failed to inhibit the activation by cAMP of another promoter, the rat insulin I gene promoter. The lack of cyclosporin A/FK506 sensitivity is not intrinsic to the insulin CRE because cyclosporin A and FK506 inhibited the activation by cAMP of the insulin CRE when isolated and used as a synthetic minienhancer. Rather, cyclosporin A/FK506 resistance may be conferred by specific promoter interactions because a mutational analysis of the insulin promoter revealed that inside this promoter, CRE activity depends on an adjacent control element. These data show that cyclosporin A and FK506 can inhibit CRE activity when the CRE resides in its natural promoter. However, the cyclosporin A/FK506 sensitivity depends on the specific promoter context. The results suggest that cyclosporin A and FK506 may alter target tissue function through the regulation of a subset of CRE-containing genes.