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Endocr Res ; 41(1): 34-42, 2016.
Article in English | MEDLINE | ID: mdl-26513165

ABSTRACT

Thyroid hormone exerts a pleiotropic effect on development, differentiation, and metabolism through thyroid hormone receptor (TR). A novel thyroid hormone receptor ß isoform (TRß4) was cloned using PCR from a human pituitary cDNA library as a template. We report here the characterization of TRß4 from a molecular basis. Temporal expression of TRß4 during the fetal period is abundant in the brain and kidney, comparable with the adult pattern. Western blot analysis revealed that TRs are ubiquitination labile proteins, while TRß1 is potentially stable. TRß1, peroxisome proliferator-activated receptors (PPAR), and vitamin D receptor (VDR), which belong to class II transcription factors that function via the formation of heterodimeric complexes with retinoid X receptor (RXR), were suppressed by TRß4 in a dose-dependent manner. Thus, TRß4 exhibits ligand-independent transcriptional silencing, possibly as a substitute for dimerized RXR. In this study, TRß1 and TRß4 transcripts were detected in several cell lines. Quantitative RT-PCR assay showed that the expression of TRß4 in human embryonic carcinoma cells of the testis was suppressed by sex hormone in a reciprocal manner to TRß1. In contrast, TRß4 was expressed under a high dose of triiodothyronine (T3) in a reciprocal manner to TRß1. Finally, in transiently transfected NIH-3T3 cells, green fluorescence protein (GFP)-tagged TRß4 was mostly nuclear in both the absence and the presence of T3. By mutating defined regions of both TRßs, we found that both TRß1 and TRß4 had altered nuclear/cytoplasmic distribution as compared with wild-type, and different to T3 and the nuclear receptor corepressor (NCoR). Thus, site-specific DNA binding is not essential for maintaining TRßs within the nucleus.


Subject(s)
Thyroid Hormone Receptors beta/genetics , Adult , Animals , Cells, Cultured , Cloning, Molecular , HEK293 Cells , Humans , Mice , NIH 3T3 Cells , Pituitary Gland/chemistry , Pituitary Gland/metabolism , Protein Isoforms/genetics , Protein Isoforms/metabolism , Thyroid Hormone Receptors beta/isolation & purification , Thyroid Hormone Receptors beta/metabolism
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