The localization and activity of cAMP-dependent protein kinase affect cell cycle progression in thyroid cells.
cAMP signals are received and transmitted by multiple isoforms of cAMP-dependent protein kinases (PKAs), typically determined by their specific regulatory subunits. We describe changes in the cAMP signal transduction pathway during cell cycle progression in synchronized rat thyroid cells. Both PKA type II (PKAII) localization and nuclear cAMP signaling are significantly modified during G(0) and G(1)-S transitions. G(1) is characterized by PKA activation and amplified cAMP signal transduction. This is associated with a decrease in the concentration of RI and RII regulatory subunits and enhanced anchoring of PKAII to the Golgi-centrosome region. Just prior to S, the cAMP 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 the onset of S phase. Forced translocation of endogenous PKAII to the cytosol down-regulated cAMP signaling, advancing the timing of p27 decay and inducing premature exit from G(1). These data indicate that membrane-bound PKA amplifies the transduction of cAMP signals in G(1) and that the length of G(1) is influenced by cAMP-PKA.
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Dipartimento di Biologia e Patologia Molecolare e Cellulare, Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Napoli, 80131 Italy.
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Gottesman
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D000818:Animals; D001692:Biological Transport; D002451:Cell Compartmentation; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000201:enzymology; D000242:Cyclic AMP / Q000378:metabolism*; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000302:isolation & purification / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D015536:Down-Regulation; D016193:G1 Phase / Q000502:physiology; D008566:Membranes / Q000201:enzymology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013961:Thyroid Gland / Q000166:cytology*; D025521:Tumor Suppressor Proteins
C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000242:Cyclic AMP; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D018844:Cyclin-Dependent Kinases