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The Rat Thyroid Hormone Receptor (TR) ß3 Displays Cell-, TR Isoform-, and Thyroid Hormone Response Element-Specific Actions

Molecular Endocrinology Group (C.B.H., J.H.D.B., G.R.W.), Division of Medicine and Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom; Molecular Regulation and Neuroendocrinology Section (P.M., P.M.Y.), Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and Cancer Biomarkers Research Group (P.M.), Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; and Endocrinology Division (P.M.Y.), Department of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, Maryland 21224

Address all correspondence and requests for reprints to: Graham Williams, Molecular Endocrinology Group, MRC Clinical Sciences Centre, Clinical Research Building 5th Floor, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. E-mail: graham.williams{at}imperial.ac.uk.

The THRB gene encodes the well-described thyroid hormone (T₃) receptor (TR) isoforms TRß1 and TRß2 and two additional variants, TRß3 and TRß3, of unknown physiological significance. TRß1, TRß2, and TRß3 are bona fide T₃ receptors that bind DNA and T₃ and regulate expression of T₃-responsive target genes. TRß3 retains T₃ binding activity but lacks a DNA binding domain and does not activate target gene transcription. TRß3 can be translated from a specific TRß3 mRNA or is coexpressed with TRß3 from a single transcript that contains an internal TRß3 translation start site. In these studies, we provide evidence that the TRß3/ß3 locus is present in rat but not in other vertebrates, including humans. We compared the activity of TRß3 with other TR isoforms and investigated mechanisms of action of TRß3 at specific thyroid hormone response elements (TREs) in two cell types. TRß3 was the most potent isoform, but TR potency was TRE dependent. TRß3 acted as a cell-specific and TRE-dependent modulator of TRß3 when coexpressed at low concentrations. At higher concentrations, TRß3 was a TRE-selective and cell-specific antagonist of TR1, -ß1, and -ß3. Both TRß3 and TRß3 were expressed in the nucleus in the absence and presence of hormone, and their actions were determined by cell type and TRE structure, whereas TRß3 actions were also dependent on the TR isoform with which it interacted. Analysis of these complex responses implicates a range of nuclear corepressors and coactivators as cell-, TR isoform-, and TRE-specific modulators of T₃ action.

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