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Induction of Specific Phosphodiesterase Isoforms by Constitutive Activation of the cAMP Pathway in Autonomous Thyroid Adenomas¹

Institute of Endocrine Sciences, University of Milan, Istituto Auxologico Italiano IRCCS (L.P., L.A.), and Ospedale Maggiore IRCCS (A.L., R.R., G.M., A.S.), 20145 Milan, Italy; Cattedra di Endocrinologia, Università di Catanzaro (S.F.), 88100 Catanzaro, Italy; and Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University (M.C.), Stanford, California 94305

Address all correspondence and requests for reprints to: Luca Persani, M.D., Ph.D., Laboratorio di Ricerche Endocrinologiche, Istituto Auxologico Italiano IRCCS, Via Ariosto 13, 20145 Milan, Italy. E-mail: persani{at}auxologico.it

Thyrocytes largely depend on cAMP signaling for replication and differentiation. This pathway may be constitutively activated by mutations of the TSH receptor (TSHR) and G_s in autonomous thyroid adenomas (ATAs). Because steady state cAMP results from production by adenylyl cyclase and degradation by phosphodiesterases (PDEs), we evaluated PDE activity and expression in ATAs with wild-type and mutant TSHR and G_s. Activating mutations of TSHR and G_s were identified in 7 and 1 of 18 ATAs, respectively. No difference was observed in the cAMP content in ATAs with or without activating mutants. In the surrounding normal thyroid tissue (NTs), PDE activity was 80% isobutylmethylxanthine sensitive, with the major contribution by PDE1 and a minor contribution by PDE4. No differences were observed in PDE activities between NTs and ATAs with wild-type TSHR and G_s. In contrast, in the presence of mutant TSHRs or G_s, total PDE activity was higher. This increase was primarily due to PDE4 induction (917 ± 116% over NTs), associated with a minor PDE1 increase only in ATAs with mutant TSHR. By RT-PCR, increments of PDE4D and 4C messenger ribonucleic acids were found in the ATAs with mutant TSHR or G_s, whereas messenger ribonucleic acids encoding other cAMP-specific PDEs were not significantly increased. This study provides a characterization of the PDEs expressed in human thyroid and demonstrates a dramatic PDE4 induction in the ATAs bearing mutant TSHR or G_s genes. The increase in cAMP-degrading activity may represent a marker of constitutive adenylyl cyclase activation and constitutes an intracellular feedback mechanism with significant impact on the phenotypic expression of the activating mutations.

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