ELEVATED CAMP GIVES SHORT-TERM INHIBITION AND LONG-TERM STIMULATION OF HEPATOCYTE DNA-REPLICATION - ROLES OF THE CAMP-DEPENDENT PROTEIN-KINASE SUBUNITS

The study reports the role of the isozyme forms (cA-PKI and cA-PKII) a nd subunits (R and C) of cAMP-dependent protein kinase in mediating th e acute depression of hepatocyte DNA replication by elevated cAMP. Com binations of cAMP analogs preferentially activating cA-PKI or II showe d that either isozyme could inhibit DNA replication. The effects of gl ucagon and cAMP analogs were counteracted by the cAMP antagonist RpcAM PS, implicating the necessity for cA-PK dissociation in cAMP action. T he effect of elevated cAMP was mimicked by microinjected C subunit, bu t not by the RI subunit of cA-PK. Hepatocytes under continuous cAMP ch allenge more than regained their replicative activity. This tardive st imulatory effect of cAMP was enhanced by insulin and blocked by dexame thasone, and was preceded by downregulation of cA-PK. In conclusion, a burst of cAMP acutely inhibits hepatocyte G1/S transition in late G1 regardless of hormonal state. In the presence of high glucocorticoid/l ow insulin the inhibition persists. At high insulin/low glucocorticoid the inhibitory phase is followed by a prolonged stimulation of DNA re plication. Downregulation of endogenous cA-PK is a mechanism for escap e from the inhibitory action of highly elevated cAMP. (C) 1993 Wiley-L iss, Inc.