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The DREAM Protein Is Associated with Thyroid Enlargement and Nodular Development

Departamento Biología Molecular y Celular (M.R., B.M., B.T., J.R.N.), Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Cientificas (CSIC), 28049 Madrid, Spain; CIBERNED-CNB Centro Investigacion Biomedica en Red de Enfermedades Neurodegerenativas (M.R., B.M., B.T.); Instituto di Endocrinologia ed Oncologia Sperimentale-Consiglio Nazionale delle Ricerche and Dipartimento di Biologia e Patologia Cellulare e Molecolare (G.C., A.M.F., D.T., M.Z.), 80131 Napoli, Italy; and Instituto de Investigaciones Biomédicas, CIBERER-IIB Centro Investigacion Biomedica en Red de Enfermedades Raras (G.M.d.E.), CSIC, 28029 Madrid, Spain

Address all correspondence and requests for reprints to: Jose R. Naranjo, CNB-CSIC, Darwin, 3 28049 Madrid, Spain. E-mail: naranjo{at}cnb.csic.es.

G protein-coupled receptors (GPCRs) are involved in the pathophysiology of a wide range of diseases and constitute an attractive therapeutic target. In the thyroid gland, TSH receptor (TSHR), a member of the GPCR family, is a major regulator of thyroid differentiation and function. Alterations in TSHR activity are often involved in the development of pathologies such as thyroid cancer and thyroid enlargement (goiter). Here we show that DREAM (downstream regulatory element antagonist modulator) modulates TSHR activity through a direct protein-protein interaction that promotes coupling between the receptor and Gs. In transgenic mice, DREAM overexpression provokes a marked enlargement of the thyroid gland. Increased levels of DREAM protein were observed in human multinodular goiters, suggesting a novel etiopathogenic mechanism in nodular development in humans. Taken together, these findings identify a mechanism for the control of TSHR activity and provide a new approach for the study and treatment of thyroid pathologies associated with impaired TSHR function.