title: Transforming growth factor-beta promotes inactivation of extracellular thyroid hormones via transcriptional stimulation of type 3 iodothyronine deiodinase.
abstract: Thyroid hormone is a critical mediator of cellular metabolism and differentiation. Precise tissue-specific regulation of the concentration of the active ligand, T(3), is achieved by iodothyronine monodeiodination. Type 3 iodothyronine deiodinase (D3) is the major inactivating pathway, preventing activation of the prohormone T(4) and terminating the action of T(3). 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 that 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.
authors.affiliation: Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Room 642, Boston, MA 02115, USA. stephen.huang@childrens.harvard.edu
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Huang
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Mulcahey
authors.forename: Alessandra
authors.initials: A
authors.lastname: Crescenzi
authors.forename: Mirra
authors.initials: M
authors.lastname: Chung
authors.forename: Brian W
authors.initials: BW
authors.lastname: Kim
authors.forename: Carmen
authors.initials: C
authors.lastname: Barnes
authors.forename: Wichert
authors.initials: W
authors.lastname: Kuijt
authors.forename: Helen
authors.initials: H
authors.lastname: Turano
authors.forename: John
authors.initials: J
authors.lastname: Harney
authors.forename: P Reed
authors.initials: PR
authors.lastname: Larsen
mesh_terms: D004848:Epithelium / Q000187:drug effects / Q000201:enzymology; D004958:Estradiol / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006391:Hemangioma / Q000201:enzymology; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics*; D032342:Muscle Cells / Q000187:drug effects / Q000201:enzymology; D018482:Muscle, Skeletal / Q000166:cytology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011506:Proteins / Q000494:pharmacology; D051785:Smad Proteins / Q000378:metabolism; D013974:Thyroxine / Q000037:antagonists & inhibitors*; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014284:Triiodothyronine / Q000037:antagonists & inhibitors*; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D011506:Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D014284:Triiodothyronine; D004958:Estradiol; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase; D013974:Thyroxine