scholarly journals Tri-iodothyronine-induced increase in rat liver nuclear thyroid-hormone receptors associated with increased mitochondrial α-glycerophosphate dehydrogenase activity

1979 ◽  
Vol 182 (2) ◽  
pp. 371-375 ◽  
Author(s):  
S Hamada ◽  
H Nakamura ◽  
M Nanno ◽  
H Imura
Keyword(s):  
Thyroid Hormone ◽  
Dehydrogenase Activity ◽  
Nuclear Receptors ◽  
Rat Liver ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Histone Protein ◽  
Glycerophosphate Dehydrogenase ◽  
Hormonal Modulation

The effect of tri-iodothyronine injection on the nuclear tri-iodothyronine receptor (putative thyroid-hormone receptor) was examined in rat liver. Nuclear receptors were extracted from isolated nuclei with 0.4 M-KCl, and their association constants (Ka) and maximal binding capacities (Cmax.) were determined by Scatchard analyses with and without correction for the endogenous hormone. The amount of endogenous tri-iodothyronine bound to non-histone protein was estimated on the basis of the specific radio-activity of [125I]tri-iodothyronine injected 2 h before the rats were killed. It was demonstrated that Cmax. of the nuclear receptors was 2.5-fold higher in severely hyperthyroid than in hypothyroid rats. However, irrespective of the thyroid status, the Ka of the receptors remained unchanged when corrected for endogenous tri-iodothyronine bound to non-histone protein. The validity of the correction was supported by experiments in vitro in which nuclear receptors were preincubated with unlabelled tri-iodothyronine. The increase in Cmax. of nuclear receptors was directly related to mitochondrial alpha-glycerophosphate dehydrogenase activity. These results suggest a hormonal modulation of the nuclear receptors which is associated with hormonal action.

scholarly journals Sequential changes in rat liver nuclear tri-iodothyronine receptors and mitochondrial α-glycerophosphate dehydrogenase activity after administeration of tri-iodothyronine

1979 ◽  
Vol 182 (2) ◽  
pp. 377-382 ◽  
Author(s):  
Hirotoshi Nakamura ◽  
Satoshi Hamada ◽  
Hiroo Imura
Keyword(s):  
Dehydrogenase Activity ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Rat Liver ◽  
Time Course ◽  
Delayed Response ◽  
Histone Proteins ◽  
Glycerophosphate Dehydrogenase ◽  
Receptor Concentration ◽  
Hormonal Modulation

The dynamics of the induction of nuclear tri-iodothyronine receptors and mitochondrial α-glycerophosphate dehydrogenase were studied in rat liver after a single injection of tri-iodothyronine. The maximal binding capacity (Cmax.) and association constant (Ka) of the nuclear receptors were determined by Scatchard analyses with and without correction for the endogenous tri-iodothyronine measured by radioimmunoassay. The administration of tri-iodothyronine induced sequential increases in the concentration of nuclear receptors and α-glycerophosphate dehydrogenase activity in the liver. The nuclear-receptor concentration was increased to 2.5 times that in the hypothyroid rat 1 day after the administration of hormone, and then decreased, with a half-life of about 2 days. α-Glycerophosphate dehydrogenase activity changed in parallel with the nuclear-receptor concentration, showing a delayed response. The total amount of non-histone protein in the liver was significantly increased 3 days after the administration. It seems likely therefore that the tri-iodothyronine-induced increase in nuclear-receptor concentration is responsible, at least in part, for the induction of this enzyme. The possibility is also suggested that nuclear receptors may be one of the non-histone proteins selectively synthesized at an early stage of the hormonal stimulation. Throughout the time course, the Ka values of the nuclear receptors for tri-iodothyronine remained unchanged, when corrected for endogenous tri-iodothyronine bound to the non-histone proteins, although they were apparently changed when the correction was not made. The results obtained provide further evidence for hormonal modulation of the nuclear receptors which is closely linked with the hormonal effect.

Possible role of histones in the organization of rat liver thyroid hormone receptors in chromatin

1989 ◽  
Vol 121 (2) ◽  
pp. 337-341 ◽  
Author(s):  
A. Sakurai ◽  
K. Ichikawa ◽  
K. Hashizume ◽  
T. Miyamoto ◽  
K. Yamauchi ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Dna Binding ◽  
Rat Liver ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Dna Interaction ◽  
H1 Histone ◽  
Potent Inhibition ◽  
Core Histones

ABSTRACT The effects of histone subfractions on rat liver thyroid hormone receptor–DNA interaction were examined using an in-vitro DNA-cellulose binding assay. H1 histones bound to DNA showed reversible and potent inhibition of receptor–DNA binding without affecting receptor–hormone binding. Poly-lysine, bovine serum albumin, ovalbumin and cytochrome c did not alter receptor–DNA binding. H1 histone subfractions (calf thymus lysine-rich histone (CTL)-1, CTL-2 and CTL-3) showed potent inhibition of receptor–DNA binding indistinguishable from each other. The quantity of H1 histone subfractions bound to DNA was the same. Although each subfraction has different functional properties, inhibition of receptor–DNA binding was a common feature of all the H1 histone subfractions, which is important for the non-random distribution of the receptor in chromatin. Binding of the receptor to core histones was investigated; it was found to bind to core histones more potently than to other proteins (H1 histone, ovalbumin and cytochrome c). Among core histone subfractions, H4 histone bound to the receptor most potently and is the candidate to be one of the acceptor sites of the receptor in chromatin. Journal of Endocrinology (1989) 121, 337–341

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.

scholarly journals Thyroid hormone-stimulated differentiation of primary rib chondrocytes in vitro requires thyroid hormone receptor β

2006 ◽  
Vol 191 (1) ◽  
pp. 221-228 ◽  
Author(s):  
Bénédicte Rabier ◽  
Allan J Williams ◽  
Frederic Mallein-Gerin ◽  
Graham R Williams ◽  
O Chassande
Keyword(s):  
Thyroid Hormone ◽  
Growth Plate ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Primary Cultures ◽  
Wild Type ◽  
Proliferation And Differentiation ◽  
Thyroid Hormone Receptor Β

The active thyroid hormone, triiodothyronine (T3), binds to thyroid hormone receptors (TR) and plays an essential role in the control of chondrocyte proliferation and differentiation. Hypo- and hyperthyroidism alter the structure of growth plate cartilage and modify chondrocyte gene expression in vivo, whilst TR mutations or deletions in mice result in altered growth plate architecture. Nevertheless, the particular roles of individual TR isoforms in mediating T3 action in chondrocytes have not been studied and are difficult to determine in vivo because of complex cellular and molecular interactions that regulate growth plate maturation. Therefore, we studied the effects of TRα and TRβ on chondrocyte growth and differentiation in primary cultures of neonatal rib chondrocytes isolated from TRα- and TRβ-deficient mice. T3 decreased proliferation but accelerated differentiation of rib chondrocytes from wild-type mice. T3 treatment resulted in similar effects in TRα-deficient chondrocytes, but in TRβ-deficient chondrocytes, all T3 responses were abrogated. Furthermore, T3 increased TRβ1 expression in wild-type and TRα-deficient chondrocytes. These data indicate that T3-stimulated differentiation of primary rib chondrocytes in vitro requires TRβ and suggest that the TRβ1 isoform mediates important T3 actions in mouse rib chondrocytes.

scholarly journals NRIF3 Is a Novel Coactivator Mediating Functional Specificity of Nuclear Hormone Receptors

1999 ◽  
Vol 19 (10) ◽  
pp. 7191-7202 ◽  
Author(s):  
Dangsheng Li ◽  
Vandana Desai-Yajnik ◽  
Eric Lo ◽  
Matthieu Schapira ◽  
Ruben Abagyan ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Transcriptional Activation ◽  
Hormone Receptors ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Specific Interaction ◽  
Minor Role ◽  
Receptor Specificity ◽  
Terminal Domain

ABSTRACT Many nuclear receptors are capable of recognizing similar DNA elements. The molecular event(s) underlying the functional specificities of these receptors (in regulating the expression of their native target genes) is a very important issue that remains poorly understood. Here we report the cloning and analysis of a novel nuclear receptor coactivator (designated NRIF3) that exhibits a distinct receptor specificity. Fluorescence microscopy shows that NRIF3 localizes to the cell nucleus. The yeast two-hybrid and/or in vitro binding assays indicated that NRIF3 specifically interacts with the thyroid hormone receptor (TR) and retinoid X receptor (RXR) in a ligand-dependent fashion but does not bind to the retinoic acid receptor, vitamin D receptor, progesterone receptor, glucocorticoid receptor, or estrogen receptor. Functional experiments showed that NRIF3 significantly potentiates TR- and RXR-mediated transactivation in vivo but has little effect on other examined nuclear receptors. Domain and mutagenesis analyses indicated that a novel C-terminal domain in NRIF3 plays an essential role in its specific interaction with liganded TR and RXR while the N-terminal LXXLL motif plays a minor role in allowing optimum interaction. Computer modeling and subsequent experimental analysis suggested that the C-terminal domain of NRIF3 directly mediates interaction with liganded receptors through an LXXIL (a variant of the canonical LXXLL) module while the other part of the NRIF3 protein may still play a role in conferring its receptor specificity. Identification of a coactivator with such a unique receptor specificity may provide new insight into the molecular mechanism(s) of receptor-mediated transcriptional activation as well as the functional specificities of nuclear receptors.

scholarly journals Preparation of unoccupied thyroid-hormone receptor

1994 ◽  
Vol 297 (1) ◽  
pp. 75-78 ◽  
Author(s):  
Q Li ◽  
A Inoue
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Binding Capacity ◽  
Fatty Acyl ◽  
Receptor Complex ◽  
Simple Method ◽  
Sephadex Column

Thyroid hormone (3,5,3′-tri-iodothyronine; T3) regulates gene expression through binding to its specific receptor in the nucleus. In euthyroid animals, roughly half of all receptors are occupied by the hormone. Nuclear extracts thus yield mixtures of occupied and unoccupied receptors. We present here a simple method for transforming occupied receptors into unoccupied ones. In vitro, the T3-receptor complex dissociated in a half-dissociation time exceeding 100 h at 0 degrees C, and at temperatures that accelerated the dissociation the receptor was quickly inactivated. Long-chain-fatty-acyl-CoAs, on the other hand, greatly accelerated the dissociation of T3-receptor complex at 0 degree C. The receptor was extracted from rat liver nuclei, incubated with oleoyl-CoA to release the bound hormone, and passed through a small column of Lipidex, which strongly adsorbed both oleoyl-CoA and the dissociated hormone. The receptor was recovered in the flow-through fraction in its unoccupied form, as seen by the results of DEAE-Sephadex column chromatography and the loss of all previously bound [125I]T3. The maximum T3-binding capacity of the unoccupied receptor was about 1.5-fold that of the untreated sample, and the dissociation constant was unaltered. The results suggest that most nuclear thyroid-hormone receptors occupied by the hormone were transformed into unoccupied ones. From the T3-binding capacity before and after oleoyl-CoA treatment, the in vivo T3 occupancy of the receptor was estimated. The procedure is easy to perform, and the method should be useful for studies of unoccupied receptors.

scholarly journals Antithyroid Drugs Inhibit Thyroid Hormone Receptor-Mediated Transcription

2007 ◽  
Vol 92 (3) ◽  
pp. 1066-1072 ◽  
Author(s):  
Kenji Moriyama ◽  
Tetsuya Tagami ◽  
Takeshi Usui ◽  
Mitsuhide Naruse ◽  
Takuo Nambu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Transient Gene Expression ◽  
Antithyroid Drugs ◽  
Transcriptional Level ◽  
Dependent Manner ◽  
Peripheral Tissues

Abstract Context: Methimazole (MMI) and propylthiouracil (PTU) are widely used as antithyroid drugs (ATDs) for the treatment of Graves’ disease. Both MMI and PTU reduce thyroid hormone levels by several mechanisms, including inhibition of thyroid hormone synthesis and secretion. In addition, PTU decreases 5′-deiodination of T4 in peripheral tissues. ATDs may also interfere with T3 binding to nuclear thyroid hormone receptors (TRs). However, the effect of ATDs on the transcriptional activities of T3 mediated by TRs has not been studied. Objective: The present study was undertaken to determine whether ATDs have an effect on the gene transcription regulated by T3 and TRs in vitro. Methods: Transient gene expression experiments and GH secretion assays were performed. To elucidate possible mechanisms of the antagonistic action of ATDs, the interaction between TR and nuclear cofactors was examined. Results: In the transient gene expression experiments, both MMI and PTU significantly suppressed transcriptional activities mediated by the TR and T3 in a dose-dependent manner. In mammalian two-hybrid assays, both drugs recruited one of the nuclear corepressors, nuclear receptor corepressor, to the TR in the absence of T3. In addition, PTU dissociated nuclear coactivators, such as steroid receptor coactivator-1 and glucocorticoid receptor interacting protein-1, from the TR in the presence of T3. Finally, MMI decreased the GH release that was stimulated by T3. Conclusions: ATDs inhibit T3 action by recruitment of transcriptional corepressors and/or dissociation of coactivators. This is the first report to show that ATDs can modulate T3 action at the transcriptional level.

Estrogen and Thyroid Hormone Receptor Interactions: Physiological Flexibility by Molecular Specificity

2002 ◽  
Vol 82 (4) ◽  
pp. 923-944 ◽  
Author(s):  
Nandini Vasudevan ◽  
Sonoko Ogawa ◽  
Donald Pfaff
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Hormone Signaling ◽  
Cell Type ◽  
Reproductive Behaviors ◽  
Receptor Interactions ◽  
Molecular Specificity

The influence of thyroid hormone on estrogen actions has been demonstrated both in vivo and in vitro. In transient transfection assays, the effects of liganded thyroid hormone receptors (TR) on transcriptional facilitation by estrogens bound to estrogen receptors (ER) display specificity according to the following: 1) ER isoform, 2) TR isoform, 3) the promoter through which transcriptional facilitation occurs, and 4) cell type. Some of these molecular phenomena may be related to thyroid hormone signaling of seasonal limitations upon reproduction. The various combinations of these molecular interactions provide multiple and flexible opportunities for relations between two major hormonal systems important for neuroendocrine feedbacks and reproductive behaviors.

scholarly journals Coactivator Recruitment Is Essential for Liganded Thyroid Hormone Receptor To Initiate Amphibian Metamorphosis

2005 ◽  
Vol 25 (13) ◽  
pp. 5712-5724 ◽  
Author(s):  
Bindu Diana Paul ◽  
Liezhen Fu ◽  
Daniel R. Buchholz ◽  
Yun-Bo Shi
Keyword(s):  
Gene Regulation ◽  
Thyroid Hormone ◽  
Transcriptional Activation ◽  
Hormone Receptors ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Dominant Negative ◽  
Amphibian Metamorphosis

ABSTRACT Thyroid hormone receptors (TRs) can repress or activate target genes depending on the absence or presence of thyroid hormone (T3), respectively. This hormone-dependent gene regulation is mediated by recruitment of corepressors in the absence of T3 and coactivators in its presence. Many TR-interacting coactivators have been characterized in vitro. In comparison, few studies have addressed the developmental roles of these cofactors in vivo. We have investigated the role of coactivators in transcriptional activation by TR during postembryonic tissue remodeling by using amphibian metamorphosis as a model system. We have previously shown that steroid receptor coactivator 3 (SRC3) is expressed and upregulated during metamorphosis, suggesting a role in gene regulation by liganded TR. Here, we have generated transgenic tadpoles expressing a dominant negative form of SRC3 (F-dnSRC3). The transgenic tadpoles exhibited normal growth and development throughout embryogenesis and premetamorphic stages. However, transgenic expression of F-dnSRC3 inhibits essentially all aspects of T3-induced metamorphosis, as well as natural metamorphosis, leading to delayed or arrested metamorphosis or the formation of tailed frogs. Molecular analysis revealed that F-dnSRC3 functioned by blocking the recruitment of endogenous coactivators to T3 target genes without affecting corepressor release, thereby preventing the T3-dependent gene regulation program responsible for tissue transformations during metamorphosis. Our studies thus demonstrate that coactivator recruitment, aside from corepressor release, is required for T3 function in development and further provide the first example where a specific coactivator-dependent gene regulation pathway by a nuclear receptor has been shown to underlie specific developmental events.

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