DOWN-REGULATION OF THE PROTEIN-KINASE-A PATHWAY BY ACTIVATORS OF PROTEIN-KINASE-C AND INTRACELLULAR CA2+ IN FIBROBLAST CELLS

Many genes are regulated by the intracellular calcium, protein kinase C (PKC) and protein kinase A (PKA) pathways and it has been shown that these pathways synergize in some cell types, whereas they antagonize in others, Here we show that the calcium and PKC pathways suppress the effects mediated by the PKA pathway in a fibroblast cell line. The su ppressing effect of elevated intracellular Ca2+ levels, but not of the PKC pathway, can be abrogated by the addition of cyclosporin A (CsA), indicating that the effect of Ca2+ is mediated by phosphatase-2B (PP- 2B/calcineurin). Suppression by the PKC pathway is not mediated by the proto-oncogenes c-fos, c-jun and junB, as the co-transfection of thes e genes does not block the effects of the PKA stimulator 8-Br-cAMP. In addition, cotransfection with the catalytic subunit of PKA shows that the inhibitory effect of PKC occurs upstream of PKA activation.