The Rat Thyroid Hormone Receptor (TR) Δβ3 Displays Cell-, TR Isoform-, and Thyroid Hormone Response Element-Specific Actions

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Abstract
The THRB gene encodes the well-described thyroid hormone (T3) receptor (TR) isoforms TRβ1 and TRβ2 and two additional variants, TRβ3 and TRΔβ3, of unknown physiological significance. TRβ1, TRβ2, and TRβ3 are bona fide T3 receptors that bind DNA and T3 and regulate expression of T3-responsive target genes. TRΔβ3 retains T3 binding activity but lacks a DNA binding domain and does not activate target gene transcription. TRΔβ3 can be translated from a specific TRΔβ3 mRNA or is coexpressed with TRβ3 from a single transcript that contains an internal TRΔβ3 translation start site. In these studies, we provide evidence that the TRβ3/Δβ3 locus is present in rat but not in other vertebrates, including humans. We compared the activity of TRβ3 with other TR isoforms and investigated mechanisms of action of TRΔβ3 at specific thyroid hormone response elements (TREs) in two cell types. TRβ3 was the most potent isoform, but TR potency was TRE dependent. TRΔβ3 acted as a cell-specific and TRE-dependent modulator of TRβ3 when coexpressed at low concentrations. At higher concentrations, TRΔβ3 was a TRE-selective and cell-specific antagonist of TRα1, -β1, and -β3. Both TRβ3 and TRΔβ3 were expressed in the nucleus in the absence and presence of hormone, and their actions were determined by cell type and TRE structure, whereas TRΔβ3 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.