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Activation of Thyroid Hormone Is Transcriptionally Regulated by Epidermal Growth Factor in Human Placenta-Derived JEG3 Cells

Laboratory of Molecular Endocrinology and Physiopathology (A.F., M.D.G., M.G.S, M.C.) and Laboratory of Molecular Oncology (G.C.), Department of Experimental Medicine, University "Sapienza," 00161 Rome, Italy; The Burnham Institute (I.M.), La Jolla, California 92037; and Division of Endocrinology, Diabetes, and Hypertension (J.W.H., P.R.L.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Gianluca Canettieri, M.D., Ph.D., Laboratory of Molecular Oncology, Dipartimento di Medicina Sperimentale, Viale Regina Elena, 324-00161 Rome, Italy. E-mail: gianluca.canettieri{at}uniroma1.it; or Marco Centanni, M.D., Laboratory of Molecular Endocrinology and Physiopathology, Dipartimento di Medicina Sperimentale, Viale Regina Elena 324-00161 Rome, Italy. E-mail: marco.centanni{at}uniroma1.it.

Human type II deiodinase is a master regulator of thyroid hormone activation in several tissues. In placenta, type II deiodinase mRNA levels and enzymatic activity are elevated only during the first trimester of pregnancy and then progressively decline. During this early stage, mitogens such as epidermal growth factor (EGF) have been shown to promote the proliferation of the trophoblast by acting through multiple mechanisms. Here we show that EGF modulates transcription of human type II deiodinase gene (Dio2) through distinct signaling pathways, leading to the assembly of a heterogeneous transcription factor complex. Gene expression and deiodination assays have shown that EGF promptly induces a short-lived Dio2 mRNA and enzymatic activity. The induction is mediated by ERK and p38 kinases, as demonstrated by selective inhibition or overexpression of different mitogen-activated kinases. Reporter assays of mutant constructs indicate that EGF-induced transcriptional activity on Dio2 promoter is mediated by the cAMP response element (CRE) and does not involve the activating protein 1 site. With functional and biochemical approaches, we have demonstrated that the EGF stimulation culminates with the assembly and recruitment over the Dio2 CRE of a composite complex, which consists of c-Jun, c-Fos, and CRE-binding protein. These results further support the hypothesis that placental iodothyronine metabolism is critical during early pregnancy.