scholarly journals Regulation of β-Catenin by a Novel Nongenomic Action of Thyroid Hormone β Receptor

2008 ◽  
Vol 28 (14) ◽  
pp. 4598-4608 ◽  
Author(s):  
Celine J. Guigon ◽  
Li Zhao ◽  
Changxue Lu ◽  
Mark C. Willingham ◽  
Sheue-yann Cheng
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Critical Role ◽  
Human Thyroid ◽  
Binding Studies ◽  
Nongenomic Action ◽  
Oncogenic Protein ◽  
In Cells

ABSTRACT We previously created a knock-in mutant mouse harboring a dominantly negative mutant thyroid hormone receptor β (TRβPV/PV mouse) that spontaneously develops a follicular thyroid carcinoma similar to human thyroid cancer. We found that β-catenin, which plays a critical role in oncogenesis, was highly elevated in thyroid tumors of TRβPV/PV mice. We sought to understand the molecular basis underlying aberrant accumulation of β-catenin by mutations of TRβ in vivo. Cell-based studies showed that thyroid hormone (T3) induced the degradation of β-catenin in cells expressing TRβ via proteasomal pathways. In contrast, no T3-induced degradation occurred in cells expressing the mutant receptor (TRβPV). In vitro binding studies and cell-based analyses revealed that β-catenin physically associated with unliganded TRβ or TRβPV. However, in the presence of T3, β-catenin was dissociated from TRβ-β-catenin complexes but not from TRβPV-β-catenin complexes. β-Catenin signaling was repressed by T3 in TRβ-expressing cells through decreasing β-catenin-mediated transcription activity and target gene expression, whereas sustained β-catenin signaling was observed in TRβPV-expressing cells. The stabilization of β-catenin, via association with a mutated TRβ, represents a novel activating mechanism of the oncogenic protein β-catenin that could contribute to thyroid carcinogenesis in TRβPV/PV mice.

scholarly journals Acrylamide does not induce tumorigenesis or major defects in mice in vivo

2008 ◽  
Vol 198 (2) ◽  
pp. 301-307 ◽  
Author(s):  
Ling Jin ◽  
Vanessa Chico-Galdo ◽  
Claude Massart ◽  
Christine Gervy ◽  
Viviane De Maertelaere ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Chronic Administration ◽  
Serum Levels ◽  
Human Thyroid ◽  
Thyroid Cell ◽  
Thyroid Cells ◽  
Hormone Synthesis ◽  
Rat Thyroid

Chronic administration of acrylamide has been shown to induce thyroid tumors in rat. In vitro acrylamide also causes DNA damage, as demonstrated by the comet assay, in various types of cells including human thyroid cells and lymphocytes, as well as rat thyroid cell lines. In this work, mice were administered acrylamide in their drinking water in doses comparable with those used in rats, i.e., around 3–4 mg/kg per day for mice treated 2, 6, and 8 months. Some of the mice were also treated with thyroxine (T4) to depress the activity of the thyroid. Others were treated with methimazole that inhibits thyroid hormone synthesis and consequently secretion and thus induces TSH secretion and thyroid activation. These moderate treatments were shown to have their known effect on the thyroid (e.g. thyroid hormone and thyrotropin serum levels, thyroid gland morphology…). Besides, T4 induced an important polydipsia and degenerative hypertrophy of adrenal medulla. Acrylamide exerted various discrete effects and at high doses caused peripheral neuropathy, as demonstrated by hind-leg paralysis. However, it did not induce thyroid tumorigenesis. These results show that the thyroid tumorigenic effects of acrylamide are not observed in another rodent species, the mouse, and suggest the necessity of an epidemiological study in human to conclude on a public health policy.

scholarly journals Distinct Tissue-Specific Roles for Thyroid Hormone Receptors β and α1 in Regulation of Type 1 Deiodinase Expression

2001 ◽  
Vol 15 (3) ◽  
pp. 467-475 ◽  
Author(s):  
Lori L. Amma ◽  
Angel Campos-Barros ◽  
Zhendong Wang ◽  
Björn Vennström ◽  
Douglas Forrest
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Critical Role ◽  
Thyroid Hormone Receptors ◽  
Minor Role ◽  
Tissue Specific ◽  
Mice Liver

Abstract Type 1 deiodinase (D1) metabolizes different forms of thyroid hormones to control levels of T3, the active ligand for thyroid hormone receptors (TR). The D1 gene is itself T3-inducible and here, the regulation of D1 expression by TRα1 and TRβ, which act as T3-dependent transcription factors, was investigated in receptor-deficient mice. Liver and kidney D1 mRNA and activity levels were reduced in TRβ−/− but not TRα1−/− mice. Liver D1 remained weakly T3 inducible in TRβ–/– mice whereas induction was abolished in double mutant TRα1–/–TRβ–/– mice. This indicates that TRβ is primarily responsible for regulating D1 expression whereas TRα1 has only a minor role. In kidney, despite the expression of both TRα1 and TRβ, regulation relied solely on TRβ, thus revealing a marked tissue restriction in TR isotype utilization. Although TRβ and TRα1 mediate similar functions in vitro, these results demonstrate differential roles in regulating D1 expression in vivo and suggest that tissue-specific factors and structural distinctions between TR isotypes contribute to functional specificity. Remarkably, there was an obligatory requirement for a TR, whether TRβ or TRα1, for any detectable D1 expression in liver. This suggests a novel paradigm of gene regulation in which the TR sets both basal expression and the spectrum of induced states. Physiologically, these findings suggest a critical role for TRβ in regulating the thyroid hormone status through D1-mediated metabolism.

The thyroid hormone analogue SKF L-94901: nuclear occupancy and serum binding studies

1989 ◽  
Vol 76 (5) ◽  
pp. 495-501 ◽  
Author(s):  
John W. Barlow ◽  
Lorna E. Raggatt ◽  
Chen-Fee Lim ◽  
Sharon L. Munro ◽  
Duncan J. Topliss ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Serum Proteins ◽  
Binding Studies ◽  
Hormone Analogue ◽  
Isolated Nuclei ◽  
Whole Cells ◽  
High Affinity ◽  
Nuclear Extracts

1. We studied a brominated thyroid hormone analogue, SKF L-94901, which has the potential to lower serum cholesterol without adverse cardiovascular effects. This compound is about 50% as active as tri-iodothyronine (T3) in liver nuclear receptor binding in vivo but only 1% as active in vitro and has nearly 200 times more enzyme-inducing activity in liver than in heart. Our aim was to examine the interaction of SKF L-94901 with [125I]T3 binding to the intact nuclei in whole cells, isolated nuclei and nuclear extracts of human HeLa cells and to investigate the binding of this compound to human serum. 2. Relative to thyroxine (T4), the affinity of this compound for T4-binding globulin was 0.0035%, for transthyretin 1.66% and for albumin 1.26%. Low affinity for serum proteins, with a relatively high circulating free fraction, could explain why SKF L-94901 is more potent in vivo than in vitro. 3. Human HeLa cell nuclei, isolated after whole-cell incubations, bound [125I]T3 with high affinity (Kd = 78 ± 8 pmol/l, mean ± sem), which was displaceable by T3 analogues in the order Triac {[4-(4-hydroxy-3-iodophenoxy)-3,5-di-iodophenyl]acetic acid} > T3 > T4 ≫ reverse T3. Similar high-affinity (Kd = 58 ± 6 pmol/l, mean ± sem) and identical specificity was observed in high-salt (0.4 mol/l KCl) nuclear extracts. In nuclei of whole cells incubated with [125I]T3 and SKF L-94901, the analogue was 0.8% as potent as T3, whereas in experiments with nuclear extract, the analogue was 7.7% as potent as T3. Results from incubation of T3 with isolated nuclei were virtually identical to those obtained with nuclear extracts. 4. These results suggest an extranuclear component may be involved in restricting access of SKF L-94901 to the nucleus. Whether such mechanisms account for observed differences in its effects on different tissues with reduced influence of SKF L-94901 on cardiac tissue remains to be established. 5. We conclude that SKF L-94901 is weakly bound in serum and shows less potent competition for T3 nuclear binding after incubation of whole cells than after incubation with nuclear extracts or isolated nuclei. This compound may allow further analysis of intracellular mechanisms of thyroid hormone transport and action.

scholarly journals Regulation of gene transcription by thyroid hormone receptor β agonists in clinical development for the treatment of non-alcoholic steatohepatitis (NASH)

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0240338
Author(s):  
Xuan G. Luong ◽  
Sarah K. Stevens ◽  
Andreas Jekle ◽  
Tse-I Lin ◽  
Kusum Gupta ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Fatty Acid Biosynthesis ◽  
Thyroid Hormone Receptor ◽  
Density Lipoprotein ◽  
Liver Fat ◽  
Alcoholic Steatohepatitis

Thyroid hormones are important modulators of metabolic activity in mammals and alter cholesterol and fatty acid levels through activation of the nuclear thyroid hormone receptor (THR). Currently, there are several THRβ agonists in clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) that have demonstrated the potential to reduce liver fat and restore liver function. In this study, we tested three THRβ-agonism-based NASH treatment candidates, GC-1 (sobetirome), MGL-3196 (resmetirom), and VK2809, and compared their selectivity for THRβ and their ability to modulate the expression of genes specific to cholesterol and fatty acid biosynthesis and metabolism in vitro using human hepatic cells and in vivo using a rat model. Treatment with GC-1 upregulated the transcription of CPT1A in the human hepatocyte-derived Huh-7 cell line with a dose-response comparable to that of the native THR ligand, triiodothyronine (T3). VK2809A (active parent of VK2809), MGL-3196, and VK2809 were approximately 30-fold, 1,000-fold, and 2,000-fold less potent than T3, respectively. Additionally, these relative potencies were confirmed by quantification of other direct gene targets of THR, namely, ANGPTL4 and DIO1. In primary human hepatocytes, potencies were conserved for every compound except for VK2809, which showed significantly increased potency that was comparable to that of its active counterpart, VK2809A. In high-fat diet fed rats, a single dose of T3 significantly reduced total cholesterol levels and concurrently increased liver Dio1 and Me1 RNA expression. MGL-3196 treatment resulted in concentration-dependent decreases in total and low-density lipoprotein cholesterol with corresponding increases in liver gene expression, but the compound was significantly less potent than T3. In conclusion, we have implemented a strategy to rank the efficacy of THRβ agonists by quantifying changes in the transcription of genes that lead to metabolic alterations, an effect that is directly downstream of THR binding and activation.

scholarly journals Dronerarone Acts as a Selective Inhibitor of 3,5,3′-Triiodothyronine Binding to Thyroid Hormone Receptor-α1: In Vitro and in Vivo Evidence

Endocrinology ◽  
2003 ◽  
Vol 144 (2) ◽  
pp. 552-558 ◽  
Author(s):  
H. C. van Beeren ◽  
W. M. C. Jong ◽  
E. Kaptein ◽  
T. J. Visser ◽  
O. Bakker ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Density Lipoprotein ◽  
Inhibitory Effect ◽  
Selective Inhibitor ◽  
Receptor Protein ◽  
Qtc Interval

Dronedarone (Dron), without iodine, was developed as an alternative to the iodine-containing antiarrhythmic drug amiodarone (AM). AM acts, via its major metabolite desethylamiodarone, in vitro and in vivo as a thyroid hormone receptor α1 (TRα1) and TRβ1 antagonist. Here we investigate whether Dron and/or its metabolite debutyldronedarone inhibit T3 binding to TRα1 and TRβ1in vitro and whether dronedarone behaves similarly to amiodarone in vivo. In vitro , Dron had a inhibitory effect of 14% on the binding of T3 to TRα1, but not on TRβ1. Desethylamiodarone inhibited T3 binding to TRα1 and TRβ1 equally. Debutyldronedarone inhibited T3 binding to TRα1 by 77%, but to TRβ1 by only 25%. In vivo , AM increased plasma TSH and rT3, and decreased T3. Dron decreased T4 and T3, rT3 did not change, and TSH fell slightly. Plasma total cholesterol was increased by AM, but remained unchanged in Dron-treated animals. TRβ1-dependent liver low density lipoprotein receptor protein and type 1 deiodinase activities decreased in AM-treated, but not in Dron-treated, animals. TRα1-mediated lengthening of the QTc interval was present in both AM- and Dron-treated animals. The in vitro and in vivo findings suggest that dronedarone via its metabolite debutyldronedarone acts as a TRα1-selective inhibitor.

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 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 Unliganded thyroid hormone receptor alpha can target TATA-binding protein for transcriptional repression.

1996 ◽  
Vol 16 (1) ◽  
pp. 281-287 ◽  
Author(s):  
J D Fondell ◽  
F Brunel ◽  
K Hisatake ◽  
R G Roeder
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Transcriptional Repression ◽  
Thyroid Hormone Receptor ◽  
Binding Protein ◽  
Tata Binding Protein ◽  
Human Thyroid ◽  
Terminal Ligand ◽  
Receptor Alpha

Unliganded human thyroid hormone receptor alpha (hTR alpha) can repress transcription by inhibiting the formation of a functional preinitiation complex (PIC) on promoters bearing thyroid hormone receptor (TR)-binding elements. Here we demonstrate that hTR alpha directly contacts the TATA-binding protein (TBP) and that preincubation of hTR alpha with TBP completely alleviates TR-mediated repression in vitro. Using stepwise preassembled PICs, we show that hTR alpha targets either the TBP/TFIIA or the TBP/TFIIA/TFIIB steps of PIC assembly for repression. We also show that the repression domain of hTR alpha maps to the C-terminal ligand-binding region and that direct TR-TBP interactions can be inhibited by thyroid hormone. Together, these results suggest a model in which unliganded hTR alpha contacts promoter-bound TBP and interferes with later steps in the initiation of transcription.

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