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Molecular Pharmacology

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Research ArticleArticle

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

Gero Siemann, Roland Blume, Daniela Grapentin, Elke Oetjen, Markus Schwaninger and Willhart Knepel
Molecular Pharmacology June 1999, 55 (6) 1094-1100; DOI: https://doi.org/10.1124/mol.55.6.1094
Gero Siemann
Department of Molecular Pharmacology, University of Göttingen, Göttingen, Germany
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Roland Blume
Department of Molecular Pharmacology, University of Göttingen, Göttingen, Germany
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Daniela Grapentin
Department of Molecular Pharmacology, University of Göttingen, Göttingen, Germany
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Elke Oetjen
Department of Molecular Pharmacology, University of Göttingen, Göttingen, Germany
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Markus Schwaninger
Department of Molecular Pharmacology, University of Göttingen, Göttingen, Germany
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Willhart Knepel
Department of Molecular Pharmacology, University of Göttingen, Göttingen, Germany
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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.

Footnotes

    • Received October 26, 1998.
    • Accepted February 22, 1999.
  • Send reprint requests to: Willhart Knepel, Ph.D., Department of Molecular Pharmacology, University of Göttingen, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany. E-mail:wknepel{at}med.uni-goettingen.de

  • ↵1 Present address: Department of Neurology, University of Heidelberg, Heidelberg, Germany.

  • This work was supported by Deutsche Forschungsgemeinschaft Grant SFB402/A3.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (6)
Molecular Pharmacology
Vol. 55, Issue 6
1 Jun 1999
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Research ArticleArticle

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

Gero Siemann, Roland Blume, Daniela Grapentin, Elke Oetjen, Markus Schwaninger and Willhart Knepel
Molecular Pharmacology June 1, 1999, 55 (6) 1094-1100; DOI: https://doi.org/10.1124/mol.55.6.1094

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Research ArticleArticle

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

Gero Siemann, Roland Blume, Daniela Grapentin, Elke Oetjen, Markus Schwaninger and Willhart Knepel
Molecular Pharmacology June 1, 1999, 55 (6) 1094-1100; DOI: https://doi.org/10.1124/mol.55.6.1094
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