The localization and activity of cAMP-dependent protein kinase affect cellcycle progression in thyroid cells

cAMP signals are received and transmitted by multiple isoforms of cAMP-depe ndent protein kinases (PKAs), typically determined by their specific regula tory subunits. We describe changes in the cAMP signal transduction pathway during cell cycle progression in synchronized rat thyroid cells. Both PKA t ype II (PKAII) localization and nuclear cAMP signaling are significantly mo dified during G(0) and G(1)-S transitions. G(1) is characterized by PKA act ivation and amplified cAMP signal transduction. This is associated with a d ecrease in the concentration of RI and RII regulatory subunits and enhanced anchoring of PKAII to the Golgi-centrosome region. Just prior to S, the cA MP pathway is depressed. Up-regulation of the pathway by exogenous cAMP in G(1) inhibited the subsequent decay of the Cdk inhibitor p27 and delayed th e onset of S phase. Forced translocation of endogenous PKAII to the cytosol downregulated cAMP signaling, advancing the timing of p27 decay and induci ng premature exit from G(1). These data indicate that membrane-bound PKA am plifies the transduction of cAMP signals in G(1) and that the length of G(1 ) is influenced by cAMP-PKA.