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This version published online on July 21, 2005
Molecular Endocrinology, doi:10.1210/me.2005-0173
A more recent version of this article appeared on December 1, 2005
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Submitted on April 29, 2005
Accepted on July 14, 2005

TGF-{beta} promotes inactivation of extracellular thyroid hormones via transcriptional stimulation of type 3 iodothyronine deiodinase

Stephen A. Huang*, Michelle A. Mulcahey, Alessandra Crescenzi, Mirra Chung, Brian W Kim, Carmen Barnes, Wichert Kuijt, Helen Turano, John Harney, and P. Reed Larsen

Institutions: Thyroid Section (S.A.H., B.W.K., H.T., J.H., P.R.L.) of the Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts, USA. Division of Endocrinology (S.A.H., M.A.M., A.C., W.K.) and Vascular Biology Program (C.B.), Childrens Hospital Boston, Boston, Massachusetts, USA. Department of Genetics (M.C.), Harvard Medical School, Boston, Massachusetts, USA

* To whom correspondence should be addressed. E-mail: stephen.huang{at}childrens.harvard.edu.

Thyroid hormone is a critical mediator of cellular metabolism and differentiation. Precise tissue-specific regulation of the concentration of the active ligand, 3, 5, 3'-triiodothyronine (T3), is achieved by iodothyronine monodeiodination. Type 3 iodothyronine deiodinase (D3) is the major inactivating pathway, preventing activation of the prohormone thyroxine (T4) and terminating the action of T3. Using nontransformed human cells, we show that TGF-{beta} stimulates transcription of the hDio3 gene via a Smad-dependent pathway. Combinations of Smad2 or Smad3 with Smad4 stimulate hDio3 gene transcription only in cells which express endogenous D3 activity, indicating that Smads are necessary but not sufficient for D3 induction. TGF-{beta} induces endogenous D3 in diverse human cell types, including fetal and adult fibroblasts from several tissues, hemangioma cells, fetal epithelia, and skeletal muscle myoblasts. Maximum stimulation of D3 by TGF-{beta} also requires MAPK and is synergistic with phorbol ester and several mitogens known to signal through transmembrane receptor tyrosine kinases but not with estradiol. These data reveal a previously unrecognized interaction between two pluripotent systems, TGF-{beta} and thyroid hormone, both of which have major roles in the regulation of cell growth and differentiation.
Key words: Fibroblast • Deiodination • Smad • TGF-{beta} • Thyroid

NURSA Molecule Pages Link:

Ligands:   17β-Estradiol  |  Thyroid hormone



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