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Reciprocal Negative Regulation between Thyrotropin/3',5'-Cyclic Adenosine Monophosphate-Mediated Proliferation and Caveolin-1 Expression in Human and Murine Thyrocytes

Institut de Recherche Interdisciplinaire (M.J.C., F.V.R., J.E.D., J.V.S.), Faculté de Médecine, Université Libre de Bruxelles, 1070 Brussels, Belgium; Faculté de Médecine (M.S., C.D., M.-C.M.), Université Catholique de Louvain, 1200 Brussels, Belgium; Institut National de la Santé et de la Recherche Médicale Unité 555 (J.R.), Faculté de Médecine Timone, Université de la Méditerranée, 13284 Marseille, France; Hôpital Erasme (M.C.), 1070 Brussels, Belgium; and Institut Jules Bordet (D.D., P.L.), 1000 Brussels, Belgium

Address all correspondence and requests for reprints to: Jacqueline Van Sande, Institut de Recherche Interdisciplinaire, Campus Erasme, Université Libre de Bruxelles, 808 Route de Lennik, Building C, 1070 Brussels, Belgium. E-mail: jvsande{at}ulb.ac.be.

The expression of caveolins is down-regulated in tissue samples of human thyroid autonomous adenomas and in the animal model of this disease. Because several cell types present in thyroid express caveolins, it remained unclear if this down-regulation occurs in thyrocytes and which are the mechanism and role of this down-regulation in the tumor context. Here we show that prolonged stimulation of isolated human thyrocytes by TSH/cAMP/cAMP-dependent protein kinase inhibits caveolins’ expression. The expression of caveolins is not down-regulated by activators of other signaling pathways relevant to thyroid growth/function. Therefore, the down-regulation of caveolins’ expression in autonomous adenomas is a direct consequence of the chronic activation of the TSH/cAMP pathway in thyrocytes. The down-regulation of caveolin-1 occurs at the mRNA level, with a consequent protein decrease. TSH/cAMP induces a transcription-dependent, translation-independent destabilization of the caveolin-1 mRNA. This effect is correlated to the known proliferative role of that cascade in thyrocytes. In vivo, thyrocytes of caveolin-1 knockout mice display enhanced proliferation. This demonstrates, for the first time, the in vivo significance of the specific caveolin-1 down-regulation by one mitogenic cascade and its relation to a human disease.

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