The DREAM protein is associated with thyroid enlargement and nodular development.
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 Galphas. 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.
Rivas
Marcos
M
Departamento Biología Molecular y Celular, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Cientificas, Madrid, Spain.
Mellström
Britt
B
Torres
Begoña
B
Cali
Gaetano
G
Ferrara
Alfonso M
AM
Terracciano
Daniela
D
Zannini
Mariastella
M
Morreale de Escobar
Gabriella
G
Naranjo
Jose R
JR
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002417:Cattle; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D000242:Cyclic AMP / Q000378:metabolism; D006042:Goiter / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051605:Kv Channel-Interacting Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding; D011989:Receptors, Thyrotropin / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013961:Thyroid Gland / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology*
D015415:Biomarkers; C496756:Csen protein, mouse; C496749:KCNIP3 protein, human; D051605:Kv Channel-Interacting Proteins; D010455:Peptides; D011989:Receptors, Thyrotropin; D012097:Repressor Proteins; D000242:Cyclic AMP