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This version published online on August 26, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0255
Molecular Endocrinology Vol. 0, No. 2004 200402551-
doi:10.1210/me.2004-0255
Copyright © 2004 by the Endocrine Society.
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Submitted on June 24, 2004
Accepted on August 9, 2004

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

Sung-Woo Kim*, Seong-June Hong, Kyung Min Kim, Sung-Chul Ho, Edward C. So, John W. Harney, and P. Reed Larsen

Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Institute of Medicine, 77 Ave Louis Pasteur, Boston, Massachusetts 02115

* To whom correspondence should be addressed. E-mail: swkim{at}rics.bwh.harvard.edu.

We have identified a cell-type specific, negative thyroid hormone-responsive element (nTRE) in the human Type 1 iodothyronine deiodinase (hdio1) gene. This fragment, termed a JEG response element (JRE), bound tightly to a JEG-cell nuclear protein (JTF) also present in placenta but not in COS-7, HeLa or HEK-293 cells. In JEG-3 cells, three copies of the JRE conferred a >40 fold transcriptional stimulation to the heterologous rGH promoter which was further increased two-fold by APO-thyroid hormone receptor (TR) and reduced three-fold by T3. DMS footprinting showed overlapping contact sites for the high affinity interaction of JTF and low affinity binding of TR-RXR. 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 TRE binding P-box amino acids EG to GS in TR(1 or TR(2 eliminated the APO-TR and T3-TR effects. These studies identify a novel mechanism for cell-type specific, promoter independent negative regulation by T3.
Key words: negative TRE • triiodothyronine • thyroid hormone receptor • gene transcription

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  RXRα
Coregulators:   NCOR
Ligands:   Thyroid hormone



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