Cyclosporin A enhances the calcium-dependent induction of AP-1 complex and c-fos mRNA in a T cell lymphoma

Biochemical and Biophysical Research Communications
Q SuF J Dumont

Abstract

The immunosuppressant cyclosporin A (CsA) exerts its pharmacologic actions by inhibiting calcineurin function. Here, we investigated the effect of CsA on the DNA-binding activity of the transcription factor, AP-1, in YAC-1 cells. We found that elevation of intracellular Ca2+ by ionomycin increased AP-1 DNA-binding activity in these cells. CsA treatment upregulated the ionomycin-induced, but not the basal AP-1 DNA-binding activity. In contrast, a CsA analog, MeVal4CsA, that does not inhibit calcineurin, failed to enhance ionomycin-induced AP-1 DNA-binding activity. This activity was shown to involve c-Fos, c-Jun and JunB. CsA consistently augmented ionomycin-induced c-fos mRNA expression and more variably that of JunB. Therefore, calcineurin negatively regulates Ca(2+)-stimulated AP-1 activity principally at the c-fos induction level. By inhibiting calcineurin, CsA shifts the balance between positive and negative AP-1 regulation. Since AP-1 controls the transcription of many genes, this finding may have implications for both the immunosuppressive and toxic effects of CsA.

Citations

Oct 21, 2003·The Journal of Physiology·Pasi TaviHeikki Ruskoaho
Feb 1, 2000·The Journal of Biological Chemistry·J Navarro-AntolínS Lamas
Aug 21, 2013·In Vitro Cellular & Developmental Biology. Animal·Mirim JinMyoung Yun Pyo
May 31, 2019·Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]·Ming LeiFang Xu
Jul 9, 1999·Immunology Letters·M MagócsiA Kolonics
May 2, 2001·The International Journal of Biochemistry & Cell Biology·C SolàJ Serratosa

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