Disease relevance of Thrb

• CONCLUSIONS: Treatment of hypothyroid rats with the TRbeta-specific agonist GC-1 partially reverts the skeletal development and maturation defects resultant of hypothyroidism [1].
• Transient cotransfection of P450R promoter/chloramphenicol acetyl transferase (CAT) constructs and the thyroid hormone receptor beta1 (TR beta1) expression plasmid into rat hepatoma H4IIE cells resulted in a 2.4-fold induction of promoter activity that was both T3 and TR beta1 dependent [2].
• The purpose of this study was to determine whether modest (5-10%) increases in metabolic rate could also be observed with minimal tachycardia after TRbeta stimulation [3].
• Therefore, selective TRbeta activation may be a potentially usefully treatment for obesity and reduction of low density lipoprotein cholesterol and reduction of the atherogenic risk factor lipoprotein (a) [3].
• We conclude that chronic, selective activation of the TR beta isoform does not result in bone loss typical of T3-induced thyrotoxicosis, suggesting that the TR beta isoform is not critical in this process [4].

High impact information on Thrb

• Since there are two major thyroid hormone receptor (TR) isoforms, TR alpha and TR beta, it is not known how the mutant receptor mediates a dominant negative effect [5].
• Here, we present direct molecular evidence for potassium channel stimulation in a rat pituitary cell line (GH(4)C(1)) by a nuclear receptor for thyroid hormone, TRbeta, acting rapidly at the plasma membrane through phosphatidylinositol 3-kinase (PI3K) to slow the deactivation of KCNH2 channels already in the membrane [6].
• We found an inserted cREL binding sequence in the 5' flanking sequence of the Abca4 gene associated with an increased expression level of that gene, and we found a mutation of the gene encoding thyroid hormone receptor beta2 associated with a decreased expression level of the gene encoding short-wavelength sensitive opsin (Opn1sw) [7].
• T3 acts through nuclear receptors (TR) of two types, TRalpha1 and TRbeta, that either repress or activate gene expression [8].
• Rat c-erbA beta 1 mRNA rises in cerebrum during the first 10 days of life, coincident with an increase in tissue triiodothyronine (T3) levels and T3-dependent brain development [9].

Chemical compound and disease context of Thrb

• Recent studies suggest that thyroid hormone receptor subtype beta (TRbeta) selective agonists have a profile in which cholesterol can be reduced with minimal tachycardia [3].

Biological context of Thrb

• Thyroid hormone (T(3)) activates nuclear receptor transcription factors, encoded by the TRalpha (NR1A1) and TRbeta (NR1A2) genes, to regulate target gene expression [10].
• We investigated the effects of GC-1, a TRbeta-selective thyromimetic, on bone development of hypothyroid rats [1].
• We conclude that liver TR beta 1 expression is most clearly affected by food intake [11].
• The down-regulation of TR beta 2 mRNA occurs at a concentration of sodium butyrate between 5 and 10 mM and is maximal by 8 h of treatment [12].
• The thyroid hormone receptor-beta agonist GC-1 induces cell proliferation in rat liver and pancreas [13].

Anatomical context of Thrb

• Diurnal variation in rat liver thyroid hormone receptor (TR)-alpha messenger ribonucleic acid (mRNA) is dependent on the biological clock in the suprachiasmatic nucleus, whereas diurnal variation of TR beta 1 mRNA is modified by food intake [11].
• The results indicate that the TRbeta-selective agonist GC-1 is a strong mitogen for hepatocytes and pancreatic acinar cells [13].
• These results show that TR beta 1 is localized to the nuclei of neuronal cells, and that c-erbA alpha 2 is restricted to the nuclei of astrocytes [14].
• Previous studies suggested that TRbeta receptors may mediate the effect of TH on oligodendrocyte precursor cells (OPCs) [15].
• Surprisingly, however, we find that postnatal TRbeta-/- mice have a normal number of oligodendrocytes in their optic nerves and that TRbeta-/- OPCs stop dividing and differentiate normally in response to TH in vitro [15].

Associations of Thrb with chemical compounds

• In the presence of the transcriptional inhibitor, actinomycin D, the half-life of TR beta 2 mRNA was approximately 3 h in the presence or absence of sodium butyrate [12].
• The reduction of receptor caused by retinoic acid is accompanied by a decreased expression of c-erbA alpha 1 and alpha 2 mRNAs, but the retinoid did not reduce the abundance of c-erbA beta mRNA [16].
• Moreover, when various ligand binding forms of mouse or chicken TRbeta and TRalpha were expressed with TRH-luciferase, all forms of TRbeta gave T3-dependent regulation of TRH transcription, whereas transcription was T3 insensitive with each TRalpha tested [17].
• The Northern analyses showed that MtT/S cells express retinoic acid receptor alpha2 mRNA and thyroid hormone receptor beta2 mRNA, and DEX did not affect the levels of these mRNAs [18].
• Additional dose-response studies in hypercholesteremic rats confirmed the preferential effect of GC-1 on TRbeta-mediated parameters by showing a much higher potency to influence cholesterol and TSH than heart rate [19].

Physical interactions of Thrb

• Triiodothyronine (T3) activates rat liver S14 gene transcription through T3 receptors (TRbeta) binding distal thyroid hormone response elements located between -2.8 and -2.5 kilobase pairs upstream from the transcription start site [20].

Other interactions of Thrb

• This cDNA (c-erbA alpha-2), like rat c-erbA alpha, hybridizes to a 2.6 kilobase (kb) mRNA which is distinct from a 6.2 kb species that hybridizes to c-erbA beta [21].
• Tibial growth plate sections were obtained from 12-wk-old rats rendered euthyroid, thyrotoxic, or hypothyroid at 6 wk of age, 14-d-old congenitally hypothyroid Pax8-null mice, and TRalpha/TRbeta double-null mice lacking all thyroid hormone receptors [22].
• In H4Flox liver, GS, ornithine aminotransferase (OAT) and thyroid hormone-receptor beta1 (TRbeta1) were exclusively expressed in pericentral hepatocytes [23].
• Thyroid hormone receptors (TRs) are ligand-dependent nuclear transcription factors that are encoded by two different genes, TR alpha and TR beta, and bind to thyroid hormone response elements (TREs) in the promoters of thyroid hormone (T3)-regulated genes [24].
• Subsequent studies employed TR beta and RXR alpha mutants in which their P-boxes were replaced with the P-box of the glucocorticoid receptor [25].

Analytical, diagnostic and therapeutic context of Thrb

• Immunocytochemistry using isoform-specific anti-sera revealed that TR beta 1 was exclusively localized to neuronal nuclei, and c-erbA alpha 2 was only found in the nuclei of astrocytes [14].
• Hence, we used the electrophoretic mobility shift assay to compare the effect of T3 on the DNA binding of mutant TR beta-1 (Mf-1) from a kindred with GRTH with normal TR beta [5].
• Genetic dissection of thyroid hormone receptor beta: identification of mutations that separate hormone binding and transcriptional activation [26].
• Reverse transcription polymerase chain reaction detected low levels of TR beta 2 mRNA in the adult tissues [27].
• TR beta 1 was undetectable by immunoprecipitation of hepatic extracts from fetuses on G19 [28].

References