scholarly journals The Role of Nuclear Receptor Corepressors NCoR1 and SMRT on Physiologic Function in the Adult Mouse

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A979-A979
Author(s):  
Megan J Ritter ◽  
Izuki Amano ◽  
Lorraine Soares De Oliveira ◽  
Kristen R Vella ◽  
Anthony Neil Hollenberg
Keyword(s):  
Thyroid Hormone ◽  
Energy Expenditure ◽  
Nuclear Receptor ◽  
Adult Mouse ◽  
Thyroid Hormone Receptor ◽  
Rapid Development ◽  
Lethal Phenotype ◽  
Organ Systems ◽  
Physiologic Function

Abstract Thyroid hormone (TH) plays an essential role in maintaining homeostasis and regulating metabolism in all organ systems beginning with embryogenesis and continuing throughout life. TH action is mediated by the thyroid hormone receptor (TR), which is a nuclear receptor, and it’s coregulators. The nuclear receptor corepressor 1 (NCoR1) and the silencing mediator of retinoid and thyroid hormone receptors (SMRT) are two critical corepressors of the TR that inhibit gene transcription in the absence of TH. Repression is mediated by complexing with histone deacetylase 3 (HDAC3), which is stabilized by NCoR1 and SMRT. NCoR1 and SMRT are critical for maintaining metabolic homeostasis and act to mediate energy expenditure, insulin sensitivity, and body weight. We sought to elucidate the roles of NCoR1 and SMRT in maintaining global physiologic function in the adult mouse. In order to study the post-natal role of these corepressors, we used a tamoxifen-inducible Cre recombinase (UBC-Cre-ERT2) to knock-out (KO) NCoR1, SMRT, or NCoR1 and SMRT together in adult mice because global deletion of either corepressor during embryogenesis is lethal. Mice were injected with tamoxifen at 8 weeks of age to KO either NCoR1 (NCoR1-KO; NKO), SMRT (SMRT-KO; SKO), or both NCoR1 and SMRT (double KO; DKO) and metabolic parameters were analyzed. While postnatal deletion of either NCoR1 or SMRT did not impact mortality, KO of both NCoR1 and SMRT resulted in a rapidly lethal phenotype heralded by weight loss, hypoglycemia and hypothermia. Metabolic phenotyping confirmed a loss of body mass and in particular fat mass in addition to a reduction in energy expenditure and increase in fecal caloric density. Further analysis showed the rapid development of hepatosteatosis and disturbances in lipid metabolism with a profound increase in beta-oxidation. We also found a reduction in HDAC3 protein levels in the DKO mice but no rapidly lethal phenotype in HDAC3 KO mice. Overall, we show that NCoR1 and SMRT together are critical for life as their deletion results in a rapidly lethal phenotype. While NCoR1 and SMRT are required to stabilize the corepressor complex, including HDAC3, HDAC3 KO resulted in a distinct and separate phenotype.

scholarly journals A novel orphan receptor specific for a subset of thyroid hormone-responsive elements and its interaction with the retinoid/thyroid hormone receptor subfamily.

1994 ◽  
Vol 14 (10) ◽  
pp. 7025-7035 ◽  
Author(s):  
R Apfel ◽  
D Benbrook ◽  
E Lernhardt ◽  
M A Ortiz ◽  
G Salbert ◽  
...  
Keyword(s):  
Amino Acid ◽  
Thyroid Hormone ◽  
Dna Binding ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Dna Sequences ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Orphan Receptor ◽  
Retinoid Receptor

The steroid/hormone nuclear receptor superfamily comprises several subfamilies of receptors that interact with overlapping DNA sequences and/or related ligands. The thyroid/retinoid hormone receptor subfamily has recently attracted much interest because of the complex network of its receptor interactions. The retinoid X receptors (RXRs), for instance, play a very central role in this subfamily, forming heterodimers with several receptors. Here we describe a novel member of this subfamily that interacts with RXR. Using a v-erbA probe, we obtained a cDNA which encodes a novel 445-amino-acid protein, RLD-1, that contains the characteristic domains of nuclear receptors. Northern (RNA) blot analysis showed that in mature rats, the receptor is highly expressed in spleen, pituitary, lung, liver, and fat. In addition, weaker expression is observed in several other tissues. Amino acid sequence alignment and DNA-binding data revealed that the DNA-binding domain of the new receptor is related to that of the thyroid/retinoid subgroup of nuclear receptors. RLD-1 preferentially binds as a heterodimer with RXR to a direct repeat of the half-site sequence 5'-G/AGGTCA-3', separated by four nucleotides (DR-4). Surprisingly, this binding is dependent to a high degree on the nature of the spacing nucleotides. None of the known nuclear receptor ligands activated RLD-1. In contrast, a DR-4-dependent constitutive transcriptional activation of a chloramphenicol acetyltransferase reporter gene by the RLD-1/RXR alpha heterodimer was observed. Our data suggest a highly specific role for this novel receptor within the network of gene regulation by the thyroid/retinoid receptor subfamily.

scholarly journals Transgenic Analysis Reveals that Thyroid Hormone Receptor Is Sufficient To Mediate the Thyroid Hormone Signal in Frog Metamorphosis

2004 ◽  
Vol 24 (20) ◽  
pp. 9026-9037 ◽  
Author(s):  
Daniel R. Buchholz ◽  
Akihiro Tomita ◽  
Liezhen Fu ◽  
Bindu D. Paul ◽  
Yun-Bo Shi
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Gene Activation ◽  
Inducible Promoter ◽  
Vertebrate Development ◽  
Transcription System

ABSTRACT Thyroid hormone (T3) has long been known to be important for vertebrate development and adult organ function. Whereas thyroid hormone receptor (TR) knockout and transgenic studies of mice have implicated TR involvement in mammalian development, the underlying molecular bases for the resulting phenotypes remain to be determined in vivo, especially considering that T3 is known to have both genomic, i.e., through TRs, and nongenomic effects on cells. Amphibian metamorphosis is an excellent model for studying the role of TR in vertebrate development because of its total dependence on T3. Here we investigated the role of TR in metamorphosis by developing a dominant positive mutant thyroid hormone receptor (dpTR). In the frog oocyte transcription system, dpTR bound a T3-responsive promoter and activated the promoter independently of T3. Transgenic expression of dpTR under the control of a heat shock-inducible promoter in premetamorphic tadpoles led to precocious metamorphic transformations. Molecular analyses showed that dpTR induced metamorphosis by specifically binding to known T3 target genes, leading to increased local histone acetylation and gene activation, similar to T3-bound TR during natural metamorphosis. Our experiments indicated that the metamorphic role of T3 is through genomic action of the hormone, at least on the developmental parameters tested. They further provide the first example where TR is shown to mediate directly and sufficiently these developmental effects of T3 in individual organs by regulating target gene expression in these organs.

scholarly journals Potential role of two novel agonists of thyroid hormone receptor‐β on liver regeneration

2020 ◽  
Vol 53 (5) ◽  
Author(s):  
Andrea Perra ◽  
Marta Anna Kowalik ◽  
Lavinia Cabras ◽  
Massimiliano Runfola ◽  
Simona Sestito ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Liver Regeneration ◽  
Hormone Receptor ◽  
Potential Role ◽  
Thyroid Hormone Receptor ◽  
Thyroid Hormone Receptor Β

scholarly journals Thyroid hormone receptor-β1 signaling is critically involved in regulating secondary ossification via promoting transcription of the Ihh gene in the epiphysis

2016 ◽  
Vol 310 (10) ◽  
pp. E846-E854 ◽  
Author(s):  
Weirong Xing ◽  
Patrick Aghajanian ◽  
Helen Goodluck ◽  
Chandrasekhar Kesavan ◽  
Shaohong Cheng ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Proximal Tibia ◽  
Thyroid Hormone Receptor ◽  
Bone Development ◽  
Day Treatment ◽  
Mrna Level ◽  
Ossification Center ◽  
Mobility Shift ◽  
Distal Promoter

Thyroid hormone (TH) action is mediated through two nuclear TH receptors, THRα and THRβ. Although the role of THRα is well established in bone, less is known about the relevance of THRβ-mediated signaling in bone development. On ther basis of our recent finding that TH signaling is essential for initiation and formation of secondary ossification center, we evaluated the role of THRs in mediating TH effects on epiphysial bone formation. Two-day treatment of TH-deficient Tshr −/− mice with TH increased THRβ1 mRNA level 3.4-fold at day 7 but had no effect on THRα1 mRNA level at the proximal tibia epiphysis. Treatment of serum-free cultures of tibias from 3-day-old mice with T3 increased THRβ1 expression 2.1- and 13-fold, respectively, at 24 and 72 h. Ten-day treatment of Tshr −/− newborns ( days 5–14) with THRβ1 agonist GC1 at 0.2 or 2.0 μg/day increased BV/TV at day 21 by 225 and 263%, respectively, compared with vehicle treatment. Two-day treatment with GC1 (0.2 μg/day) increased expression levels of Indian hedgehog ( Ihh) 100-fold, osterix 15-fold, and osteocalcin 59-fold compared with vehicle at day 7 in the proximal tibia epiphysis. Gel mobility shift assay demonstrated that a putative TH response element in the distal promoter of mouse Ihh gene interacted with THRβ1. GC1 treatment (1 nM) increased Ihh distal promoter activity 20-fold after 48 h in chondroctyes. Our data suggest a novel role for THRβ1 in secondary ossification at the epiphysis that involves transcriptional upregulation of Ihh gene.

scholarly journals Activation of the thyroid hormone receptor α gene promoter by the orphan nuclear receptor ERRα

Oncogene ◽  
1998 ◽  
Vol 17 (19) ◽  
pp. 2429-2435 ◽  
Author(s):  
Jean-Marc Vanacker ◽  
Edith Bonnelye ◽  
Cateline Delmarre ◽  
Vincent Laudet
Keyword(s):  
Thyroid Hormone ◽  
Nuclear Receptor ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Gene Promoter ◽  
Orphan Nuclear Receptor ◽  
Thyroid Hormone Receptor Α

scholarly journals Lacking thyroid hormone receptor β gene does not influence alterations in peripheral thyroid hormone metabolism during acute illness

2008 ◽  
Vol 197 (1) ◽  
pp. 151-158 ◽  
Author(s):  
J Kwakkel ◽  
O Chassande ◽  
H C van Beeren ◽  
W M Wiersinga ◽  
A Boelen
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Hormone Metabolism ◽  
Thyroid Hormone Metabolism ◽  
Males And Females ◽  
Induced Changes ◽  
Thyroid Hormone Receptor Β

The downregulation of liver deiodinase type 1 (D1) is supposed to be one of the mechanisms behind the decrease in serum tri-iodothyronine (T3) observed during non-thyroidal illness (NTI). Liver D1 mRNA expression is positively regulated by T3, mainly via the thyroid hormone receptor (TR)β1. One might thus expect that lacking the TRβ gene would result in diminished downregulation of liver D1 expression and a smaller decrease in serum T3 during illness. In this study, we used TRβ−/− mice to evaluate the role of TRβ in lipopolysaccharide (LPS, a bacterial endotoxin)-induced changes in thyroid hormone metabolism. Our results show that the LPS-induced serum T3 and thyroxine and liver D1 decrease takes place despite the absence of TRβ. Furthermore, we observed basal differences in liver D1 mRNA and activity between TRβ−/− and wild-type mice and TRβ−/− males and females, which did not result in differences in serum T3. Serum T3 decreased rapidly after LPS administration, followed by decreased liver D1, indicating that the contribution of liver D1 during NTI may be limited with respect to decreased serum T3 levels. Muscle D2 mRNA did not compensate for the low basal liver D1 observed in TRβ−/− mice and increased in response to LPS in TRβ−/− and WT mice. Other (TRβ independent) mechanisms like decreased thyroidal secretion and decreased binding to thyroid hormone-binding proteins probably play a role in the early decrease in serum T3 observed in this study.

scholarly journals Novel Mechanism of Nuclear Receptor Corepressor Interaction Dictated by Activation Function 2 Helix Determinants

2002 ◽  
Vol 22 (19) ◽  
pp. 6831-6841 ◽  
Author(s):  
Anna N. Moraitis ◽  
Vincent Giguère ◽  
Catherine C. Thompson
Keyword(s):  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Ligand Binding ◽  
Nuclear Receptor ◽  
Thyroid Hormone Receptor ◽  
Activation Function ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Cerebellar Development ◽  
Nuclear Receptor Corepressor

ABSTRACT Transcriptional regulation by nuclear receptors is controlled by the concerted action of coactivator and corepressor proteins. The product of the thyroid hormone-regulated mammalian gene hairless (Hr) was recently shown to function as a thyroid hormone receptor corepressor. Here we report that Hr acts as a potent repressor of transcriptional activation by RORα, an orphan nuclear receptor essential for cerebellar development. In contrast to other corepressor-nuclear receptor interactions, Hr binding to RORα is mediated by two LXXLL-containing motifs, a mechanism associated with coactivator interaction. Mutagenesis of conserved amino acids in the ligand binding domain indicates that RORα activity is ligand-dependent, suggesting that corepressor activity is maintained in the presence of ligand. Despite similar recognition helices shared with coactivators, Hr does not compete for the same molecular determinants at the surface of the RORα ligand binding domain, indicating that Hr-mediated repression is not simply through displacement of coactivators. Remarkably, the specificity of Hr corepressor action can be transferred to a retinoic acid receptor by exchanging the activation function 2 (AF-2) helix. Repression of the chimeric receptor is observed in the presence of retinoic acid, demonstrating that in this context, Hr is indeed a ligand-oblivious nuclear receptor corepressor. These results suggest a novel molecular mechanism for corepressor action and demonstrate that the AF-2 helix can play a dynamic role in controlling corepressor as well as coactivator interactions. The interaction of Hr with RORα provides direct evidence for the convergence of thyroid hormone and RORα-mediated pathways in cerebellar development.

scholarly journals The Ability of Thyroid Hormone Receptors to Sense T4 as an Agonist Depends on Receptor Isoform and on Cellular Cofactors

2014 ◽  
Vol 28 (5) ◽  
pp. 745-757 ◽  
Author(s):  
Amy Schroeder ◽  
Robyn Jimenez ◽  
Briana Young ◽  
Martin L. Privalsky
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Cell Types ◽  
Receptor Associated Protein ◽  
Steroid Receptor Coactivator ◽  
Different Cell Types

Abstract T4 (3,5,3′,5′-tetraiodo-l-thyronine) is classically viewed as a prohormone that must be converted to the T3 (3,5,3′-triiodo-l-thyronine) form for biological activity. We first determined that the ability of reporter genes to respond to T4 and to T3 differed for the different thyroid hormone receptor (TR) isoforms, with TRα1 generally more responsive to T4 than was TRβ1. The response to T4 vs T3 also differed dramatically in different cell types in a manner that could not be attributed to differences in deiodinase activity or in hormone affinity, leading us to examine the role of TR coregulators in this phenomenon. Unexpectedly, several coactivators, such as steroid receptor coactivator-1 (SRC1) and thyroid hormone receptor-associated protein 220 (TRAP220), were recruited to TRα1 nearly equally by T4 as by T3 in vitro, indicating that TRα1 possesses an innate potential to respond efficiently to T4 as an agonist. In contrast, release of corepressors, such as the nuclear receptor coreceptor NCoRω, from TRα1 by T4 was relatively inefficient, requiring considerably higher concentrations of this ligand than did coactivator recruitment. Our results suggest that cells, by altering the repertoire and abundance of corepressors and coactivators expressed, may regulate their ability to respond to T4, raising the possibility that T4 may function directly as a hormone in specific cellular or physiological contexts.

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