Cyclic 3,5 adenoise monophosphate and cyclosporin A inhibit cellular proliferation and serine/threonine protein phosphatase activity in pituitary cells.
cAMP and cyclosporin A exert antiproliferative effects in many different cell types. In cultured pituitary cells, the antiproliferative effects 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 phosphorylation and activation. On the other hand, cyclosporin A, inhibiting the calcium-dependent serine/threonine phosphatase calcineurin, prevents the dephosphorylation and inactivation of inhibitor-1. This dual regulation by cAMP and calcium on the inhibitor-1 activity parallel the effects of these agents on DNA synthesis and serine/threonine phosphatase activity. Because inhibitor-1 is the main regulator of protein phosphatase 1 activity, these results suggest that protein phosphatase 1 may be the common target of cAMP and cyclosporin A in regulating cell proliferation. We propose that protein-phosphatase 1 stimulates growth in these cells and that cAMP and cyclosporin A block this effect through their actions on inhibitor-1.
Florio
T
T
Vollum Institute for Advanced Biomedical Research, Portland, Oregon 97201-3098, USA. florio@sirio.cba.unige.it
Perrino
B A
BA
Stork
P J
PJ
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D000242:Cyclic AMP / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D004298:Dopamine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism
D004791:Enzyme Inhibitors; D016572:Cyclosporine; D000242:Cyclic AMP; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases; D004298:Dopamine