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Selective Modulation of Protein Kinase A I and II Reveals Distinct Roles in Thyroid Cell Gene Expression and Growth

Department of Medical Sciences (D.C., P.B.-P., L.P.) and Institute of General Pathology (F.M., M.L.), University of Milan, 20100 Milan, Italy; Laboratory of Experimental Endocrinology (D.C., T.d.F., S.L. P.P., R.T., L.P.), Istituto Auxologico Italiano Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20095 Cusano Milanino, Italy; Istituto Clinico Humanitas IRCCS (F.M., M.L.), 20089 Rozzano, Italy; and Fondazione Ospedale Maggiore Policlinico IRCCS (P.B.-P.), 20122 Milan, Italy

Address all correspondence and requests for reprints to: Luca Persani, M.D., Ph.D., Laboratory of Experimental Endocrinology, Istituto Auxologico Italiano IRCCS, Via Zucchi 18, 20095 Cusano Milanino (MI), Italy. E-mail: luca.persani{at}unimi.it.

A global gene expression profiling of TSH stimulation on differentiated (FRTL5) and partially dedifferentiated [FRT/TSHR (TSH receptor)] rat thyroid cells was performed. A total of 123 TSH-regulated genes (95 newly described) were identified in FRTL5, whereas no significant transcriptional modifications were seen in FRT/TSHR cells. Because regulatory subunit IIß (RIIß) of protein kinase A (PKA), a key element downstream of cAMP, was expressed in FRTL5 but not in cAMP-refractory FRT/TSHR cells, we hypothesized that this gene may play an important role in TSH signaling. We therefore performed a series of experiments to investigate the involvement of RIIß and the different PKA isoforms. A positive effect of PKA II- but not of PKA I-selective activation on gene transcription and proliferation in FRTL5 cells, as well as an impairment of TSH nuclear effects after RIIß silencing were observed, suggesting that PKA II plays an essential role in TSH signaling. This view was supported by the restoration of TSH nuclear effects after reexpression of RIIß in FRT/TSHR cells. Because PKA I stimulation could increase iodide uptake in FRTL5 cells without affecting gene transcription, PKA I may mediate TSH actions at posttranscriptional levels. Analyses on three human cancer cell lines confirmed the possible loss of RIIß expression and antiproliferative activity of PKA I-selective cAMP analogs (60% at 200 µM in BRAF-mutated cells). The inhibitory effect of PKA I apparently required constitutive MAPK activation and was associated with an inhibition of ERK phosphorylation. These findings may open new therapeutic perspectives in patients with thyroid cancer.

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