CYCLOSPORINE-A ENHANCES THE CALCIUM-DEPENDENT INDUCTION OF AP-1 COMPLEX AND C-FOS MESSENGER-RNA IN A T-CELL LYMPHOMA

The immunosuppressant cyclosporin A (CsA) exerts its pharmacologic act ions by inhibiting calcineurin function. Here, we investigated the eff ect of CsA on the DNA-binding activity of the transcription factor, AP -I, in YAC-1 cells. We found that elevation of intracellular Ca2+ by i onomycin increased AP-I DNA-binding activity in these cells. CsA treat ment upregulated the ionomycin-induced, but not the basal AP-1 DNA-bin ding activity. In contrast, a CsA analog, MeVal(4)CsA, that does not i nhibit calcineurin, failed to enhance ionomycin-induced AP-I DNA-bindi ng activity. This activity was shown to involve c-Fos, c-Jun and JunB. CsA consistently augmented ionomycin-induced c-fos mRNA expression an d more variably that of JunB. Therefore, calcineurin negatively regula tes Ca2+-stimulated AP-1 activity principally at the c-fos induction l evel. By inhibiting calcineurin, CsA shifts the balance between positi ve and negative AP-I regulation. Since AP-1 controls the transcription of many genes, this finding may have implications for both the immuno suppressive and toxic effects of CsA. (C) 1996 Academic Press, Inc.