The Rat Thyroid Hormone Receptor (TR) Delta {szligbeta}3 Displays Cell-, TR Isoform-, and Thyroid Hormone Response Element-Specific Actions

• Published in: Endocrinology (Philadelphia) Vol. 148; no. 4; pp. 1764 - 1773
• Main Authors: Harvey, Clare B, Bassett, JHDuncan, Maruvada, Padma, Yen, Paul M, Williams, Graham R
• Format: Journal Article
• Language: English
• Published: 01.04.2007
• ISSN: 0013-7227

The THRB gene encodes the well-described thyroid hormone (T sub(3)) receptor (TR) isoforms TR{szligbeta}1 and TR{szligbeta}2 and two additional variants, TR{szligbeta}3 and TR Delta {szligbeta}3, of unknown physiological significance. TR{szligbeta}1, TR{szligbeta}2, and TR{szligbeta}3 are bona fide T sub(3) receptors that bind DNA and T sub(3) and regulate expression of T sub(3)-responsive target genes. TR Delta {szligbeta}3 retains T sub(3) binding activity but lacks a DNA binding domain and does not activate target gene transcription. TR Delta {szligbeta}3 can be translated from a specific TR Delta {szligbeta}3 mRNA or is coexpressed with TR{szligbeta}3 from a single transcript that contains an internal TR Delta {szligbeta}3 translation start site. In these studies, we provide evidence that the TR{szligbeta}3/ Delta {szligbeta}3 locus is present in rat but not in other vertebrates, including humans. We compared the activity of TR{szligbeta}3 with other TR isoforms and investigated mechanisms of action of TR Delta {szligbeta}3 at specific thyroid hormone response elements (TREs) in two cell types. TR{szligbeta}3 was the most potent isoform, but TR potency was TRE dependent. TR Delta {szligbeta}3 acted as a cell-specific and TRE-dependent modulator of TR{szligbeta}3 when coexpressed at low concentrations. At higher concentrations, TR Delta {szligbeta}3 was a TRE-selective and cell-specific antagonist of TR alpha 1, -{szligbeta}1, and -{szligbeta}3. Both TR{szligbeta}3 and TR Delta {szligbeta}3 were expressed in the nucleus in the absence and presence of hormone, and their actions were determined by cell type and TRE structure, whereas TR Delta {szligbeta}3 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 T sub(3) action.