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A Novel Cell Type-Specific Mechanism for Thyroid Hormone-Dependent Negative Regulation of the Human Type 1 Deiodinase Gene

Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Harvard Institute of Medicine, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: S.-W. Kim, Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Harvard Institute of Medicine, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115. E-mail: swkim{at}rics.bwh.harvard.edu.

We have identified a cell type-specific, negative thyroid hormone-responsive element in the human type 1 iodothyronine deiodinase (hdio1) gene. This fragment, termed a JEG response element, bound tightly to a JEG-cell nuclear protein [JEG cell-specific transcription factor (JTF)] also present in placenta but not in COS-7, HeLa, or human embryonic kidney-293 cells. In JEG-3 cells, three copies of the JEG response element conferred a more than 40-fold transcriptional stimulation to the heterologous rat GH promoter which was further increased 2-fold by apo-thyroid hormone receptor (TR) and reduced 3-fold by T₃. Dimethyl sulfide footprinting showed overlapping contact sites for the high-affinity interaction of JTF and low-affinity binding of TR-retinoid X receptor. Expression of the same construct was unaffected by TR or T₃ in COS cells, indicating JTF was required for negative regulation by T₃-TR. Mutations of the critical thyroid hormone responsive element binding P box amino acids EG to GS in TR1 or TRß2 eliminated the apo-TR and T₃-TR effects. These studies identify a novel mechanism for cell type-specific, promoter-independent negative regulation by T₃.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  RXRα

Coregulators:   NCOR

Ligands:   Thyroid hormone

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