CYCLIC 3,5-ADENOISE MONOPHOSPHATE AND CYCLOSPORINE-A INHIBIT CELLULARPROLIFERATION AND SERINE THREONINE PROTEIN PHOSPHATASE-ACTIVITY IN PITUITARY-CELLS/

cAMP and cyclosporin A exert antiproliferative effects in many differe nt cell types. In cultured pituitary cells, the antiproliferative effe cts of both agents correlate with the inhibition of a serine/threonine protein phosphatase activity. This inhibition is mediated by the heat -stable protein, inhibitor-1. The increase of cAMP levels, through the activation of the protein kinase A, induces inhibitor-1 phosphorylati on and activation. On the other hand, cyclosporin A, inhibiting the ca lcium-dependent serine/threonine phosphatase calcineurin, prevents the dephosphorylation and inactivation of inhibitor-1. This dual regulati on by cAMP and calcium on the inhibitor 1 activity parallel the effect s of these agents on DNA synthesis and serine/threonine phosphatase ac tivity. Because inhibitor-1 is the main regulator of protein phosphata se 1 activity, these results suggest that protein phosphatase 1 may be the common target of cAMP and cy closporin A in regulating cell proli feration. We propose that protein-phosphatase 1 stimulates growth in t hese cells and that cAMP and cyclosporin A block this effect through t heir actions on inhibitor-1.