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  • Title: 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.
    Author: Siemann G, Blume R, Grapentin D, Oetjen E, Schwaninger M, Knepel W.
    Journal: Mol Pharmacol; 1999 Jun; 55(6):1094-100. PubMed ID: 10347253.
    Abstract:
    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.
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