Thyrocytes largely depend on cAMP signaling for replication and differentiation. This pathway may be constitutively activated by mutations of the TSH receptor (TSHR) and Gsalpha 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 Gsalpha. Activating mutations of TSHR and Gsalpha 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 Gsalpha. In contrast, in the presence of mutant TSHRs or Gsalpha, 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 Gsalpha, 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 Gsalpha 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.
Induction of specific phosphodiesterase isoforms by constitutive activation of the cAMP pathway in autonomous thyroid adenomas / L. Persani, A. Lania, L. Alberti, R. Romoli, G. Mantovani, S. Filetti, A. Spada, M. Conti. - In: THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM. - ISSN 0021-972X. - 85:8(2000 Aug), pp. 2872-8-2878.
|Titolo:||Induction of specific phosphodiesterase isoforms by constitutive activation of the cAMP pathway in autonomous thyroid adenomas|
PERSANI, LUCA (Primo)
LANIA, ANDREA GERARDO ANTONIO (Secondo)
SPADA, ANNAMARIA (Penultimo)
|Parole Chiave:||Thyroid Neoplasms; Humans; Cyclic AMP; Transcription, Genetic; Receptors, Thyrotropin; Gene Expression Regulation, Neoplastic; RNA, Messenger; GTP-Binding Protein alpha Subunits, Gs; Phosphoric Diester Hydrolases; Isoenzymes; Mutation; Adenoma; Signal Transduction|
|Settore Scientifico Disciplinare:||Settore MED/13 - Endocrinologia|
|Data di pubblicazione:||ago-2000|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1210/jc.85.8.2872|
|Appare nelle tipologie:||01 - Articolo su periodico|