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Cellular and Molecular Basis of Deiodinase-Regulated Thyroid Hormone Signaling¹

Laboratory of Endocrine Neurobiology (B.G., A.Z.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, H-1083 Hungary; Thyroid Section (A.M.Z., S.R., B.W.K., A.C.B.), Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115; Laboratory for Physiology (W.S.S.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands; Division of Endocrinology and Metabolism (S.A.H.), Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115; and Division of Endocrinology (A.C.B.), Diabetes and Metabolism, University of Miami, Miller School of Medicine, Miami, Florida 33136

Correspondence: Address all correspondence and requests for reprints to: Antonio C. Bianco, M.D., Ph.D., Division of Endocrinology, Diabetes and Metabolism, Suite 816, Dominion Towers, 1400 NW 10th Avenue, Miami, Florida 33136. E-mail: abianco{at}deiodinase.org

The iodothyronine deiodinases initiate or terminate thyroid hormone action and therefore are critical for the biological effects mediated by thyroid hormone. Over the years, research has focused on their role in preserving serum levels of the biologically active molecule T₃ during iodine deficiency. More recently, a fascinating new role of these enzymes has been unveiled. The activating deiodinase (D2) and the inactivating deiodinase (D3) can locally increase or decrease thyroid hormone signaling in a tissue- and temporal-specific fashion, independent of changes in thyroid hormone serum concentrations. This mechanism is particularly relevant because deiodinase expression can be modulated by a wide variety of endogenous signaling molecules such as sonic hedgehog, nuclear factor-B, growth factors, bile acids, hypoxia-inducible factor-1, as well as a growing number of xenobiotic substances. In light of these findings, it seems clear that deiodinases play a much broader role than once thought, with great ramifications for the control of thyroid hormone signaling during vertebrate development and metamorphosis, as well as injury response, tissue repair, hypothalamic function, and energy homeostasis in adults.

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