scholarly journals PGC-1α regulates the isoform mRNA ratio of the alternatively spliced thyroid hormone receptor α transcript

2006 ◽  
Vol 37 (2) ◽  
pp. 251-257 ◽  
Author(s):  
D C Thijssen-Timmer ◽  
M Platvoet-Ter Schiphorst ◽  
J Kwakkel ◽  
R Emter ◽  
A Kralli ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Rna Processing ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Mrna Levels ◽  
Negative Effect ◽  
Alternatively Spliced ◽  
Thyroid Hormone Receptor Α

Transcripts derived from the thyroid hormone receptor α (TRα) gene are alternatively spliced resulting in a functional receptor TRα1 and a non-T3-binding variant TRα2 that can exert a dominant negative effect on the transactivation functions of other TRs. There is evidence that the ratio of TRα isoform transcripts can be modulated and here, we investigate whether the PPARγ co-activator α (PGC-1α) has an effect on this splicing process. PGC-1α was discovered not only as a transcriptional co-activator, but also has certain motifs characteristic of splicing factors. We demonstrate that PGC-1α alters the ratio of endogenously expressed TRα isoform transcripts in HepG2 cells, by decreasing TRα1 mRNA levels twofold. This change in isoform ratio is accompanied by a decrease in 5′-deiodinase expression, whereas no differences were found in TRβ1 expression. Deletion of the RNA-processing domain of PGC-1α abrogated the effect on the TRα splicing, whereas expression of only the RNA-processing domain favored TRα1 expression. PGC-1α showed a similar effect on the splicing of a TRα minigene containing only the last four exons and introns of the TRα gene. These data suggest that PGC-1α is involved in the RNA processing of TRα transcripts.

scholarly journals Connexin40 Messenger Ribonucleic Acid Is Positively Regulated by Thyroid Hormone (TH) Acting in Cardiac Atria via the TH Receptor

Endocrinology ◽  
2008 ◽  
Vol 150 (1) ◽  
pp. 546-554 ◽  
Author(s):  
Norma A. S. Almeida ◽  
Aline Cordeiro ◽  
Danielle S. Machado ◽  
Luana L. Souza ◽  
Tânia M. Ortiga-Carvalho ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Dominant Negative ◽  
P Wave ◽  
Dominant Negative Mutant ◽  
Mrna Levels ◽  
Messenger Ribonucleic Acid ◽  
Wave Duration ◽  
P Wave Duration

Thyroid hormone (TH) regulates many cardiac genes via nuclear thyroid receptors, and hyperthyroidism is frequently associated with atrial fibrillation. Electrical activity propagation in myocardium depends on the transfer of current at gap junctions, and connexins (Cxs) 40 and 43 are the predominant junction proteins. In mice, Cx40, the main Cx involved in atrial conduction, is restricted to the atria and fibers of the conduction system, which also express Cx43. We studied cardiac expression of Cx40 and Cx43 in conjunction with electrocardiogram studies in mice overexpressing the dominant negative mutant thyroid hormone receptor-β Δ337T exclusively in cardiomyocytes [myosin heavy chain (MHC-mutant)]. These mice develop the cardiac hypothyroid phenotype in the presence of normal serum TH. Expression was also examined in wild-type mice rendered hypothyroid or hyperthyroid by pharmacological treatment. Atrial Cx40 mRNA and protein levels were decreased (85 and 55%, respectively; P < 0.001) in MHC-mt mice. Atrial and ventricular Cx43 mRNA levels were not significantly changed. Hypothyroid and hyperthyroid animals showed a 25% decrease and 40% increase, respectively, in Cx40 mRNA abundance. However, MHC-mt mice presented very low Cx40 mRNA expression regardless of whether they were made hypothyroid or hyperthyroid. Atrial depolarization velocity, as represented by P wave duration in electrocardiograms of unanesthetized mice, was extremely reduced in MHC-mt mice, and to a lesser extent also in hypothyroid mice (90 and 30% increase in P wave duration). In contrast, this measure was increased in hyperthyroid mice (19% decrease in P wave duration). Therefore, this study reveals for the first time that Cx40 mRNA is up-regulated by TH acting in cardiac atria via the TH receptor and that this may be one of the mechanisms contributing to atrial conduction alterations in thyroid dysfunctions. Cardiac-specific expression of a mutant thyroid hormone receptor unable to bind thyroid hormone profoundly reduces atrial connexin 40 expression in association with prolonged atrial conduction.

scholarly journals Severe form of thyroid hormone resistance in a patient with homozygous/hemizygous mutation of T3 receptor gene

2004 ◽  
Vol 150 (6) ◽  
pp. 819-823 ◽  
Author(s):  
K Frank-Raue ◽  
A Lorenz ◽  
C Haag ◽  
W Hoppner ◽  
HU Boll ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Intellectual Development ◽  
Thyroid Hormone Receptor ◽  
Receptor Gene ◽  
Signs And Symptoms ◽  
Severe Form ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Negative Effect ◽  
Beta Gene

Resistance to thyroid hormone syndrome (RTH) is a rare disorder, usually inherited as an autosomal dominant trait. Patients with RTH are usually euthyroid but can occasionally present with signs and symptoms of thyrotoxicosis or rarely with hypothyroidism. Affected individuals are usually heterozygous for mutations in the thyroid hormone receptor beta gene (TR-beta).We present a patient with RTH found to be homo-/hemizygous for a mutation in the TR-beta gene. The single nucleotide substitution I280S (1123T-->G) was present either on both alleles or in a hemizygous form with complete deletion of the second allele. The I280S mutation was recently reported in a heterozygous patient. The severe phenotype with seriously impaired intellectual development, hyperkinetic behaviour, tachycardia, hearing and visual impairment is probably due to the dominant negative effect of the I280S mutant protein and the absence of any functional TR-beta.

scholarly journals A novel mutation of thyroid hormone receptor beta (I431V) impairs corepressor release, and induces thyroid hormone resistance syndrome

2008 ◽  
Vol 52 (8) ◽  
pp. 1304-1312 ◽  
Author(s):  
Monalisa Ferreira Azevedo ◽  
Gustavo Barcelos Barra ◽  
Ligiane Dantas de Medeiros ◽  
Luiz Alberto Simeoni ◽  
Luciana Ansaneli Naves ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Novel Mutation ◽  
Plasma Concentrations ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Free T4 ◽  
Functional Studies ◽  
Receptor Beta

Resistance to thyroid hormone (RTH) is a rare disorder characterized by variable tissue hyporesponsiveness to thyroid hormone, usually caused by mutations in the thyroid hormone receptor beta (TRβ). We describe a large Brazilian family harboring a novel mutation affecting TRβ gene and inducing RTH. A 14-year-old girl was found to have elevated free T4 and free T3 plasma concentrations in coexistence with unsuppressed TSH and a questionable goiter. The diagnosis of RTH was verified by identification of a novel mutation (I431V) in the TRβ gene. Sixteen asymptomatic relatives of the proposita are also affected by the mutation. Functional studies showed that I431V mutation exerts dominant-negative effect on wild type TRβ, mainly by impairment of ligand-dependent release of corepressor SMRT. The presence of this mutation reduces potency, but does not affect efficacy of thyroid hormone action, in accordance with the clinical picture of eumetabolism of the affected individuals.

scholarly journals 3,3′,5-Triiodothyroacetic acid (TRIAC) induces embryonic ζ-globin expression via thyroid hormone receptor α

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Huiqiao Chen ◽  
Zixuan Wang ◽  
Shanhe Yu ◽  
Xiao Han ◽  
Yun Deng ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Globin Gene ◽  
Erythroid Cells ◽  
Cell Disease ◽  
Potent Inducer ◽  
Thyroid Hormone Receptor Α

AbstractThe human ζ-globin gene (HBZ) is transcribed in primitive erythroid cells only during the embryonic stages of development. Reactivation of this embryonic globin synthesis would likely alleviate symptoms both in α-thalassemia and sickle-cell disease. However, the molecular mechanisms controlling ζ-globin expression have remained largely undefined. Moreover, the pharmacologic agent capable of inducing ζ-globin production is currently unavailable. Here, we show that TRIAC, a bioactive thyroid hormone metabolite, significantly induced ζ-globin gene expression during zebrafish embryogenesis. The induction of ζ-globin expression by TRIAC was also observed in human K562 erythroleukemia cell line and primary erythroid cells. Thyroid hormone receptor α (THRA) deficiency abolished the ζ-globin-inducing effect of TRIAC. Furthermore, THRA could directly bind to the distal enhancer regulatory element to regulate ζ-globin expression. Our study provides the first evidence that TRIAC acts as a potent inducer of ζ-globin expression, which might serve as a new potential therapeutic option for patients with severe α-thalassemia or sickle-cell disease.

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