Effect of transient cyclic AMP elevation on DNA synthesis in rat hepatocytes at G1 phase

Maintaining high levels of intracellular cyclic AMP (cAMP) is known to inhibit the growth of various proliferating cells including hepatocytes. We show here that transient (30 min) elevations of cAMP induced by addition of 8-bromo-cAMP (1 mmol/L) to rat hepatocytes in primary culture at three time points (12 h, 16 h and 20 h) after seeding stimulated DNA synthesis. Sustained levels of cAMP stimulated DNA synthesis to a lesser degree at a lower concentration (1 mumol/L), but inhibited it at concentrations higher than 100 mumol/L. We also determined cyclin-dependent kinase 2 (cdk2) activity in the hepatocytes during this incubation period. The transient addition of 8-bromo-cAMP at the late G1 phase increased cdk2 activity. This suggests that transient cAMP elevation in hepatocytes at the late G1 phase has a growth stimulation effect. Up-regulation of cdk2 activity may have a role in this process.