scholarly journals New Interfaces of Thyroid Hormone Actions With Blood Coagulation and Thrombosis

2018 ◽  
Vol 24 (7) ◽  
pp. 1014-1019 ◽  
Author(s):  
Paul J. Davis ◽  
Shaker A. Mousa ◽  
Geraldine P. Schechter
Keyword(s):  
Thyroid Hormone ◽  
Clinical Evidence ◽  
Thyroid Hormone Receptor ◽  
Integrin Αvβ3 ◽  
Cell Interaction ◽  
Cytokines And Chemokines ◽  
Routine Measurement ◽  
Clinically Significant ◽  
Platelet Functions

Substantial clinical evidence indicates hyperthyroidism enhances coagulation and increases the risk of thrombosis. In vitro and clinical evidence implicate multiple mechanisms for this risk. Genomic actions of thyroid hormone as 3,5,3′-triiodo-L-thyronine (T3) via a nuclear thyroid hormone receptor have been implicated, but recent evidence shows that nongenomic mechanisms initiated at the receptor for L-thyroxine (T4) on platelet integrin αvβ3 are prothrombotic. The T4-initiated mechanisms involve platelet activation and, in addition, cellular production of cytokines and chemokines such as CX3CL1 with procoagulatory activities. These procoagulant actions of T4 are particulary of note because within cells T4 is not seen to be functional, but to be only a prohormone for T3. Finally, it is also possible that thyroid hormone stimulates platelet-endothelial cell interaction involved in local thrombus generation. In this brief review, we survey mechanisms by which thyroid hormone is involved in coagulation and platelet functions. It is suggested that the threshold should be lowered for considering the possibility that clinically significant clotting may complicate hyperthyroidism. The value of routine measurement of partial thromboplastin time or circulating D-dimer in patients with hyperthyroid or in patients treated with thyrotropin-suppressing dosage of T4 requires clinical testing.

scholarly journals Desethylamiodarone antagonizes the effect of thyroid hormone at the molecular level

2001 ◽  
pp. 59-64 ◽  
Author(s):  
F Bogazzi ◽  
L Bartalena ◽  
S Brogioni ◽  
A Burelli ◽  
F Raggi ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Molecular Mechanisms ◽  
Thyroid Hormone Receptor ◽  
Molecular Level ◽  
Inhibitory Effect ◽  
Mobility Shift ◽  
Down Regulation ◽  
Nih3t3 Cells ◽  
Peripheral Tissues

OBJECTIVE: To evaluate the molecular mechanisms of the inhibitory effects of amiodarone and its active metabolite, desethylamiodarone (DEA) on thyroid hormone action. MATERIALS AND METHODS: The reporter construct ME-TRE-TK-CAT or TSHbeta-TRE-TK-CAT, containing the nucleotide sequence of the thyroid hormone response element (TRE) of either malic enzyme (ME) or TSHbeta genes, thymidine kinase (TK) and chloramphenicol acetyltransferase (CAT) was transiently transfected with RSV-TRbeta into NIH3T3 cells. Gel mobility shift assay (EMSA) was performed using labelled synthetic oligonucleotides containing the ME-TRE and in vitro translated thyroid hormone receptor (TR)beta. RESULTS: Addition of 1 micromol/l T4 or T3 to the culture medium increased the basal level of ME-TRE-TK-CAT by 4.5- and 12.5-fold respectively. Amiodarone or DEA (1 micromol/l) increased CAT activity by 1.4- and 3.4-fold respectively. Combination of DEA with T4 or T3 increased CAT activity by 9.4- and 18.9-fold respectively. These data suggested that DEA, but not amiodarone, had a synergistic effect with thyroid hormone on ME-TRE, rather than the postulated inhibitory action; we supposed that this was due to overexpression of the transfected TR into the cells. When the amount of RSV-TRbeta was reduced until it was present in a limited amount, allowing competition between thyroid hormone and the drug, addition of 1 micromol/l DEA decreased the T3-dependent expression of the reporter gene by 50%. The inhibitory effect of DEA was partially due to a reduced binding of TR to ME-TRE, as assessed by EMSA. DEA activated the TR-dependent down-regulation by the negative TSH-TRE, although at low level (35% of the down-regulation produced by T3), whereas amiodarone was ineffective. Addition of 1 micromol/l DEA to T3-containing medium reduced the T3-TR-mediated down-regulation of TSH-TRE to 55%. CONCLUSIONS: Our results demonstrate that DEA, but not amiodarone, exerts a direct, although weak, effect on genes that are regulated by thyroid hormone. High concentrations of DEA antagonize the action of T3 at the molecular level, interacting with TR and reducing its binding to TREs. This effect may contribute to the hypothyroid-like effect observed in peripheral tissues of patients receiving amiodarone treatment.

scholarly journals Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development

2019 ◽  
Vol 116 (45) ◽  
pp. 22754-22763 ◽  
Author(s):  
Teresa G. Krieger ◽  
Carla M. Moran ◽  
Alberto Frangini ◽  
W. Edward Visser ◽  
Erik Schoenmakers ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Progenitor Cells ◽  
Hormone Receptor ◽  
Progenitor Cell ◽  
Thyroid Hormone Receptor ◽  
Cortical Development ◽  
Neural Progenitor Cell ◽  
Cortical Layer ◽  
Lineage Tracing

Mutations in the thyroid hormone receptor α 1 gene (THRA) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microencephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived induced pluripotent stem cells to forebrain neural progenitors is markedly reduced, but mutant progenitor cells can generate deep and upper cortical layer neurons and form functional neuronal networks. Quantitative lineage tracing shows that THRA mutation-containing progenitor cells exit the cell cycle prematurely, resulting in reduced clonal output. Using a micropatterned chip assay, we find that spatial self-organization of mutation-containing progenitor cells in vitro is impaired, consistent with down-regulated expression of cell–cell adhesion genes. These results reveal that thyroid hormone receptor α1 is required for normal neural progenitor cell proliferation in human cerebral cortical development. They also exemplify quantitative approaches for studying neurodevelopmental disorders using patient-derived cells in vitro.

Fatty Acyl-CoAs Are Potent Inhibitors of the Nuclear Thyroid Hormone Receptor In Vitro

1990 ◽  
Vol 107 (5) ◽  
pp. 699-702 ◽  
Author(s):  
Qiulin Li ◽  
Naoki Yamamoto ◽  
Akira Inoue ◽  
Seiji Morisawa
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Fatty Acyl

scholarly journals Mutations in the conserved C-terminal sequence in thyroid hormone receptor dissociate hormone-dependent activation from interference with AP-1 activity.

1997 ◽  
Vol 17 (8) ◽  
pp. 4687-4695 ◽  
Author(s):  
F Saatcioglu ◽  
G Lopez ◽  
B L West ◽  
E Zandi ◽  
W Feng ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Thyroid Hormone ◽  
Transcriptional Activation ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Mutational Analysis ◽  
Binding Domain ◽  
Yeast Cells ◽  
Terminal Sequence

A short C-terminal sequence that is deleted in the v-ErbA oncoprotein and conserved in members of the nuclear receptor superfamily is required for normal biological function of its normal cellular counterpart, the thyroid hormone receptor alpha (T3R alpha). We carried out an extensive mutational analysis of this region based on the crystal structure of the hormone-bound ligand binding domain of T3R alpha. Mutagenesis of Leu398 or Glu401, which are surface exposed according to the crystal structure, completely blocks or significantly impairs T3-dependent transcriptional activation but does not affect or only partially diminishes interference with AP-1 activity. These are the first mutations that clearly dissociate these activities for T3R alpha. Substitution of Leu400, which is also surface exposed, does not affect interference with AP-1 activity and only partially diminishes T3-dependent transactivation. None of the mutations affect ligand-independent transactivation, consistent with previous findings that this activity is mediated by the N-terminal domain of T3R alpha. The loss of ligand-dependent transactivation for some mutants can largely be reversed in the presence of GRIP1, which acts as a strong ligand-dependent coactivator for wild-type T3R alpha. There is excellent correlation between T3-dependent in vitro association of GRIP1 with T3R alpha mutants and their ability to support T3-dependent transcriptional activation. Therefore, GRIP1, previously found to interact with the glucocorticoid, estrogen, and androgen receptors, may also have a role in T3R alpha-mediated ligand-dependent transcriptional activation. When fused to a heterologous DNA binding domain, that of the yeast transactivator GAL4, the conserved C terminus of T3R alpha functions as a strong ligand-independent activator in both mammalian and yeast cells. However, point mutations within this region have drastically different effects on these activities compared to their effect on the full-length T3R alpha. We conclude that the C-terminal conserved region contains a recognition surface for GRIP1 or a similar coactivator that facilitates its interaction with the basal transcriptional apparatus. While important for ligand-dependent transactivation, this interaction surface is not directly involved in transrepression of AP-1 activity.

Carbaryl, 1-naphthol and 2-naphthol inhibit the beta-1 thyroid hormone receptor-mediated transcription in vitro

Toxicology ◽  
2008 ◽  
Vol 249 (2-3) ◽  
pp. 238-242 ◽  
Author(s):  
Hong Sun ◽  
Ou-Xi Shen ◽  
Xiao-Lin Xu ◽  
Lin Song ◽  
Xin-Ru Wang
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Transcription In Vitro

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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