Cellular Action of Thyroid Hormone (original) (raw)
Related papers
New insights into thyroid hormone action
Best Practice & Research Clinical Endocrinology & Metabolism, 2007
Thyroid hormones (THs) have important effects on cellular development, growth, and metabolism. They bind to thyroid hormone receptors (TRs), TRa and TRb, which belong to the nuclear hormone receptor superfamily. These receptors also bind to enhancer elements in the promoters of target genes, and can regulate both positive and negative transcription. Recent emerging evidence has characterized some of the molecular mechanisms by which THs regulate transcription as co-repressors, and co-activators have been identified and their effects on histone acetylation examined. THs also have rapid effects that do not require transcription. These can occur via TRs or other cellular proteins, and typically occur outside the nucleus. It appears that THs regulate multiple cellular functions using a diverse array of receptors and signaling systems. TR isoform-or pathway-specific drugs might provide the therapeutic benefits of TH action such as decreasing obesity or lowering cholesterol levels without some of the side effects of hyperthyroidism.
Molecular Endocrinology, 2006
Thyroid hormone receptors (TRs) are ligand-regulated transcription factors that bind to thyroid hormone response elements of target genes. Upon ligand binding, they recruit coactivator complexes that increase histone acetylation and recruit RNA polymerase II (Pol II) to activate transcription. Recent studies suggest that nuclear receptors and coactivators may have temporal recruitment patterns on hormone response elements, yet little is known about the nature of the patterns at multiple endogenous target genes. We thus performed chromatin immunoprecipitation assays to investigate coactivator recruitment and histone acetylation patterns on the thyroid hormone response elements of four endogenous target genes (GH, sarcoplasmic endoplasmic reticulum calcium-adenosine triphosphatase, phosphoenolpyruvate carboxykinase, and cholesterol 7α-hydroxylase) in a rat pituitary cell line that expresses TRs. We found that TRβ, several associated coactivators (steroid receptor coactivator-1, glucoc...
Thyroid hormone action at the cellular, genomic and target gene levels
Molecular and Cellular Endocrinology, 2006
Thyroid hormone (TH) plays important roles in metabolism, growth and differentiation. Thyroid hormone receptors (TRs) are ligand-regulatable transcription factors that bind both TH and DNA enhancer sequences in the promoter region of target genes where they can interact with co-repressor and co-activator complexes. These interactons, in turn, have consequent effects on transcription. This review describes studies on TH action from our laboratory examining the cellular localization and motility of TRs using green fluorescent fusion proteins, gene expression profiles of TH in WT and TR␣ and TR KO mice, as well as general transcription factor and co-activator recruitment on the promoters of target genes by TH in chromatin immunoprecipitation assays.
Regulation of gene transcription by the thyroid hormone receptors
2006
Thyroid hormone (TH) has important effects on postnatal development as well as on adult metabolic homeostasis. TH meditates its effects through different isoforms of the thyroid hormone receptors (TRs) encoded by the TRalpha and TRbeta genes, respectively. TRs belong to the nuclear hormone receptor superfamily. These receptors are ligand-modulated transcription factors that bind to specific DNA elements located in the regulatory regions of target genes. The nature of these elements determines the effect TR will have on transcription. On what is called a positive TH response element (pTRE), the un-liganded receptor binds to DNA and represses transcription. Hormone binding induces a conformational change in the receptor, allowing for activation of transcription. In contrast, on a negative TH response element (nTRE), activation of transcription is mediated by the un-liganded receptor, whereas the liganded receptor represses transcription. The mechanism behind the regulation of a pTRE i...
Novel Transcriptional Mechanisms for Regulating Metabolism by Thyroid Hormone
International Journal of Molecular Sciences, 2018
The thyroid hormone plays a key role in energy and nutrient metabolisms in many tissues and regulates the transcription of key genes in metabolic pathways. It has long been believed that thyroid hormones (THs) exerted their effects primarily by binding to nuclear TH receptors (THRs) that are associated with conserved thyroid hormone response elements (TREs) located on the promoters of target genes. However, recent transcriptome and ChIP-Seq studies have challenged this conventional view as discordance was observed between TH-responsive genes and THR binding to DNA. While THR association with other transcription factors bound to DNA, TH activation of THRs to mediate effects that do not involve DNA-binding, or TH binding to proteins other than THRs have been invoked as potential mechanisms to explain this discrepancy, it appears that additional novel mechanisms may enable TH to regulate the mRNA expression. These include activation of transcription factors by SIRT1 via metabolic actio...
Molecular Endocrinology, 2003
Transcriptional regulation by heterodimers of thyroid hormone receptor (TR) and the 9-cis retinoid X receptor (RXR) is a highly complex process involving a large number of accessory factors, as well as chromatin remodeling. We have used a biochemical approach, including an in vitro chromatin assembly and transcription system that accurately recapitulates ligand-and activation function (AF)-2-dependent transcriptional activation by TR/ RXR␣ heterodimers, as well as in vitro chromatin immunoprecipitation assays, to study the mechanisms of TR-mediated transcription with chromatin templates. Using this approach, we show that chromatin is required for robust ligand-dependent activation by TR. We also show that the binding of liganded TR to chromatin induces promoterproximal chromatin remodeling and histone acetylation, and that histone acetylation is correlated with increased TRdependent transcription. Additionally, we find that steroid receptor coactiva-tors (SRCs) and p300 function synergistically to stimulate TR-dependent transcription, with multiple functional domains of p300 contributing to its coactivator activity with TR. A major conclusion from our experiments is that the primary role of the SRC proteins is to recruit p300/cAMP response element binding protein-binding protein to hormone-regulated promoters. Together, our results suggest a multiple step pathway for transcriptional regulation by liganded TR, including chromatin remodeling, recruitment of coactivators, targeted histone acetylation, and recruitment of the RNA polymerase II transcriptional machinery. Our studies highlight the functional importance of chromatin in transcriptional control and further define the molecular mechanisms by which the SRC and p300 coactivators facilitate transcriptional activation by liganded TR. (Molecular Endocrinology 17: 908-922, 2003) T HE MOLECULAR ACTIONS of thyroid hormone (T 3) are mediated through thyroid hormone receptors (TR␣ and TR). TRs belong to the nuclear receptor (NR) superfamily and play important roles in development, differentiation, homeostasis, and tumorigenesis through their ability to regulate gene expression (1). TRs function as heterodimers with the 9-cis retinoic acid receptor (RXR) and, in the absence of hormone, the heterodimers bind to thyroid hormone response elements (TREs) and actively repress transcription (2, 3). In contrast to unliganded TRs, ligand-bound TRs function as transcriptional activators. Ligand-dependent activation by TR/RXR heterodimers requires an intact activation domain residing at the carboxyl terminus of the TR ligand-binding domain [known as activation function (AF)-2], as well as cellular coactivators (4). Many coactivators have been implicated in T 3dependent activation, including the steroid receptor coactivator (SRC) family of proteins, p300/cAMP response element binding protein-binding protein (CBP), p300/CBP associated factor (PCAF), and the mediatorlike TR associated proteins (TRAP)/vitamin D receptorinteracting proteins (DRIP)/SRB/mediator-containing cofactor complex (SMCC) (hereafter referred to as the TRAP complex; for reviews, see Refs. 5-9). The SRC family contains three highly related and possibly functionally redundant proteins referred to herein under the unified nomenclature SRC-1, SRC-2, and SRC-3 (5).
Molecular Endocrinology, 2009
Currently, little is known about histone modifications and molecular mechanisms of negatively regulated transcription. In pituitary cells, thyroid hormone (T3) decreased transcription, and surprisingly increased histone acetylation, of TSHα promoter. This increase was mediated directly by thyroid hormone receptor. Histone acetylation of H3K9 and H3K18 sites, two modifications usually associated with transcriptional activation, occur in negative regulation of TSHα promoter. T3 also caused release of a corepressor complex composed of histone deacetylase 3 (HDAC3), transducin β-like protein 1, and nuclear receptor coprepressor (NCoR)/ silencing mediator for retinoic and thyroid hormone receptor from TSHα promoter in chromatin immunoprecipitation assays. NCoR and HDAC3 overexpression selectively increased ligand-independent basal transcription. Two histone acetyltransferase inhibitors increased overall transcription but did not abrogate negative regulation or NCoR/HDAC3 complex release ...
Thyroid hormone dependent gene expression
Advancements in Life Sciences, 2016
The presented work is destined to review the advances that had been made to study the role of thyroid hormone and thyroid hormone nuclear receptors in regulating the gene expression. Triiodothyronine (T3) and tetraiodothyronine (thyroxine or T4) are most important thyroid hormones. The thyroid hormones bind to their specific nuclear hormone receptors, as ligand, and play important role in gene expression and transcriptional gene regulation in human and higher animals. Thyroid hormone receptors form heterodimers by making combination with retinoid X receptors. The capability of heterodimerization of thyroid hormones generates novel complexes which allow altered specificity and higher affinity for DNA-receptor binding. Thyroid hormone receptors work as ligand activated transcription factor and play with transcriptional gene expression process. The consensus structural features of thyroid hormone receptors are N-terminal regulatory domain that contains activation function, the domain f...