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Ronald J Koenig - One of the best experts on this subject based on the ideXlab platform.
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An RNA-binding Domain in the Thyroid Hormone Receptor Enhances Transcriptional Activation*
The Journal of biological chemistry, 2004Co-Authors: Ronald J KoenigAbstract:Abstract Thyroid Hormone plays important roles in development, differentiation, and metabolic homeostasis by binding to nuclear Thyroid Hormone Receptors, which regulate target gene expression by interacting with DNA response elements and coregulatory proteins. We show that Thyroid Hormone Receptors also are single-stranded RNA binding proteins and that this binding is functionally significant. By using a series of deletion mutants, a novel RNA-binding domain was localized to a 41-amino acid segment of Thyroid Hormone Receptor α1 between the second zinc finger and the ligand-binding domain. This RNA-binding domain was necessary and sufficient for Thyroid Hormone Receptor binding to the steroid Receptor RNA activator (SRA). Although SRA does not bind directly to steroid Receptors, it has been identified as a steroid Receptor coactivator, and was thought not to be a coactivator for Thyroid Hormone Receptors. However, transfection studies revealed that SRA enhances Thyroid Hormone induction of appropriate reporter genes and that the Thyroid Hormone Receptor RNA-binding domain is important for this enhancement. We conclude that Thyroid Hormone Receptors bind RNA through a novel domain and that the interaction of this domain with SRA, and perhaps other RNAs, enhances Thyroid Hormone Receptor function.
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Thyroid Hormone response element architecture affects corepressor release from Thyroid Hormone Receptor dimers
Journal of Biological Chemistry, 1998Co-Authors: David P Olson, Baolin Sun, Ronald J KoenigAbstract:Abstract Thyroid Hormone Receptors are ligand-modulated transcription factors that can repress or activate transcription depending upon the absence or presence of Thyroid Hormone and the nature of the Hormone response element to which the Receptors are bound. The ability of Thyroid Hormone Receptors to repress transcription in the absence of ligand is thought to be due to associations with nuclear Hormone Receptor corepressors. Ligand binding by the Thyroid Hormone Receptor is believed to dissociate these corepressors and recruit coactivators to promote transcription from target promoters. We hypothesize that variations in response element architecture may influence both the association and dissociation of corepressors from DNA-bound Thyroid Hormone Receptors. Using a chimeric corepressor, we find that ligand alone does not fully relieve corepressor-mediated repression, particularly in the presence of Thyroid Hormone Receptor and its heterodimerization partner, the retinoid X Receptor. Interestingly, the steroid Receptor coactivator 1 together with ligand is able to mediate full release of corepression, but this relief is dependent upon the architecture of the response element to which the nuclear Receptor dimer-corepressor complex is bound. These studies suggest that other cellular factors in addition to ligand may be required for the release of corepressors from Thyroid Hormone Receptor dimers.
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Thyroid Hormone Receptor coactivators and corepressors
Thyroid : official journal of the American Thyroid Association, 1998Co-Authors: Ronald J KoenigAbstract:The Thyroid Hormone Receptor (TR) acts like a molecular switch. In the absence of ligand, TR binds to specific DNA sequences and actively represses transcription via interactions with other proteins, termed corepressors. The binding of ligand results in a conformational change in the TR that leads t
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Thyroid Hormone Receptor variant α2: Role of the ninth heptad in DNA binding, heterodimerization with retinoid X Receptors, and dominant negative activity
The Journal of biological chemistry, 1996Co-Authors: Ying Zi Yang, María Burgos-trinidad, Ronald J KoenigAbstract:Abstract Thyroid Hormone Receptors bind DNA with highest affinity as heterodimers with retinoid X Receptors, and such heterodimers generally are thought to be the biological mediators of Thyroid Hormone action. An alternative splice product of the Thyroid Hormone Receptor α gene, Thyroid Hormone Receptor variant α2, does not bind Thyroid Hormone and functions as a weak dominant negative inhibitor of Thyroid Hormone action. Thyroid Hormone Receptor variant α2 is missing one-half of the ninth heptad, a region of the bona fide Receptor thought to be important for heterodimerization with retinoid X Receptors. The role of the ninth heptad in heterodimerization has been evaluated further. Thyroid Hormone Receptor variant α2-retinoid X Receptor heterodimers form on a subset of direct repeat response elements but not on palindromic or inverted palindromic elements. Restoration of the missing ninth heptad sequence is critical for restoring heterodimerization on the palindromic DNA, but either the ninth heptad amino acids or a stretch of alanines is equally able to restore heterodimerization on the inverted palindrome. Thus, the role of the ninth heptad in heterodimerization differs on direct repeat, palindromic, and inverted palindromic response elements, suggesting that the protein-protein interactions differ on each of these elements. The dominant negative activity of Thyroid Hormone Receptor variant α2 requires DNA binding, but the relatively weak nature of the dominant negative activity is only partially explained by the weak DNA binding.
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Comparison of the DNA Binding Specificity and Function of v-ErbA and Thyroid Hormone Receptor α1
The Journal of biological chemistry, 1995Co-Authors: Jose S. Subauste, Ronald J KoenigAbstract:Abstract The oncoprotein v-ErbA is a mutated version of Thyroid Hormone Receptor α1. Although the basis for the oncogenic action of v-ErbA is unknown, expression of this protein is known to inhibit Thyroid Hormone and retinoic acid induction of target genes. The DNA binding domain of v-ErbA differs from that of Thyroid Hormone Receptor α1 in two amino acids felt to be crucial for determining the specificity of DNA binding. However, the DNA binding properties of v-ErbA have not been examined independent of a comparison of binding to already known Thyroid Hormone response elements. In the current studies a non-biased strategy was used to select from a pool of random DNA those sequences that bind v-ErbA with high affinity. The highest affinity binding sequence was identified as the decamer 5′-T(A/G)AGGTCACG, which is closely related to the optimal Thyroid Hormone Receptor α1 binding sequence, TAAGGTCA. Transfection studies demonstrate that among equal Thyroid Hormone responsive elements, those that contain the optimal v-ErbA consensus will be repressed by v-ErbA in preference to those that do not. These studies indicate that v-ErbA and Thyroid Hormone Receptor α1 regulate overlapping sets of response elements, and that all sequences that are highly responsive to Thyroid Hormone are not necessarily responsive to v-ErbA.
Thomas S. Scanlan - One of the best experts on this subject based on the ideXlab platform.
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Unliganded Thyroid Hormone Receptor is essential for Xenopus laevis eye development
The EMBO journal, 2006Co-Authors: Emmanuelle Havis, Sébastien Le Mével, Ghislaine Morvan Dubois, De Li Shi, Thomas S. Scanlan, Barbara A. Demeneix, Laurent M. SachsAbstract:Thyroid Hormone Receptors generally activate transcription of target genes in the presence of Thyroid Hormone (T3) and repress their transcription in its absence. Here, we investigated the role of unliganded Thyroid Hormone Receptor (TR) during vertebrate development using an amphibian model. Previous studies led to the hypothesis that before production of endogenous T3, the presence of unliganded Receptor is essential for premetamorphic tadpole growth. To test this hypothesis, we generated a Xenopus laevis TR β mutant construct ineffective for gene repression owing to impaired corepressor NCoR recruitment. Overexpression by germinal transgenesis of the mutant Receptor leads to lethality during early development with numerous defects in cranio-facial and eye development. These effects correlate with TR expression profiles at these early stages. Molecular analysis of transgenic mutants reveals perturbed expression of genes involved in eye development. Finally, treatment with iopanoic acid or NH-3, modulators of Thyroid Hormone action, leads to abnormal eye development. In conclusion, the data reveal a role of unliganded TR in eye development.
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Selective Thyroid Hormone Receptor Modulators
Current topics in medicinal chemistry, 2003Co-Authors: Hikari A. I. Yoshihara, Thomas S. ScanlanAbstract:Thyroid Hormone regulates many important processes in vertebrates. Analysis of the symptoms that accompany hypo- and hyperThyroidism, the most common disorders of the Thyroid, suggests that there are certain desirable biological effects brought about by an excess or deficiency of Thyroid Hormone, and that selective Thyroid Hormone Receptor modulators (STRMs) would be potentially useful therapeutic agents. This review will provide an introduction to Thyroid Hormone biology, and will discuss the chemistry and pharmacology of the first generation STRMs.
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a high affinity subtype selective agonist ligand for the Thyroid Hormone Receptor
Chemistry & Biology, 1998Co-Authors: Grazia Chiellini, James W Apriletti, John D Baxter, Hikari Yoshihara, Ralff C J Ribeiro, Thomas S. ScanlanAbstract:Abstract Background: Thyroid Hormones regulate many different physiological processes in different tissues in vertebrates. Most of the actions of Thyroid Hormones are mediated by the Thyroid Hormone Receptor (TR), which is a member of the nuclear Receptor superfamily of ligand-activated transcription regulators. There are two different genes that encode two different TRs, TRa and TRβ, and these two TRs are often co-expressed at different levels in different tissues. Most Thyroid Hormones do not discriminate between the two TRs and bind both with similar affinities. Results: We have designed and synthesized a Thyroid Hormone analog that has high affinity for the TRs and is selective in both binding and activation functions for TRβ over TRα. The compound, GC-1, was initially designed to solve synthetic problems that limit Thyroid Hormone analog preparation, and contains several structural changes with respect to the natural Hormone 3,5,3′-triiodo-l-thyronine (T 3 ). These changes include replacement of the three iodines with methyl and isopropyl groups, replacement of the biaryl ether linkage with a methylene linkage, and replacement of the amino-acid sidechain with an oxyacetic-acid sidechain. Conclusions: The results of this study show that GC-1 is a member of a new class of thyromimetic compounds that are more synthetically accessible than traditional thyromimetics and have potentially useful Receptor binding and activation properties. The TRβ selectivity of GC-1 is particularly interesting and suggests that GC-1 might be a useful in vivo probe for studying the physiological roles of the different Thyroid Hormone Receptor isoforms.
Robert G Roeder - One of the best experts on this subject based on the ideXlab platform.
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the trap smcc mediator complex and Thyroid Hormone Receptor function
Trends in Endocrinology and Metabolism, 2001Co-Authors: Mitsuhiro Ito, Robert G RoederAbstract:The TRAP/SMCC/Mediator complex is a mammalian transcriptional regulatory complex that contains over 25 polypeptides and is, in part, phylogenetically conserved. It was originally isolated as a Thyroid Hormone Receptor (TR)-associated protein (TRAP) complex that mediates TR-activated transcription from DNA templates in conjunction with the general transcription machinery, and probably acts in vivo after the action of other Receptor-interacting coactivators involved in chromatin remodeling. Subsequently, the TRAP complex was identified as a more broadly used coactivator complex for a wide variety of activators. The TRAP220 subunit mediates ligand-dependent interactions of the complex with TR and other nuclear Receptors; and genetic ablation of murine TRAP220 has revealed that it is essential both for optimal TR function and for a variety of early developmental and adult homeostasis events in mice, but not for cell viability per se.
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ligand induction of a transcriptionally active Thyroid Hormone Receptor coactivator complex
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Joseph D Fondell, Robert G RoederAbstract:Abstract Transcriptional regulation by nuclear Hormone Receptors is thought to involve interactions with putative cofactors that may potentiate Receptor function. Here we show that human Thyroid Hormone Receptor alpha purified from HeLa cells grown in the presence of Thyroid Hormone (T3) is associated with a group of distinct nuclear proteins termed Thyroid Hormone Receptor-associated proteins (TRAPs). In an in vitro system reconstituted with general initiation factors and cofactors (and in the absence of added T3), the "liganded" Thyroid Hormone Receptor (TR)/TRAP complex markedly activates transcription from a promoter template containing T3-response elements. Moreover, whereas the retinoid X Receptor is not detected in the TR/TRAP complex, its presence is required for the function of the complex. In contrast, human Thyroid Hormone Receptor alpha purified from cells grown in the absence of T3 lacks the TRAPs and effects only a low level of activation that is dependent on added ligand. These findings demonstrate the ligand-dependent in vivo formation of a transcriptionally active TR-multisubunit protein complex and suggest a role for TRAPs as positive coactivators for gene-specific transcriptional activation.
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unliganded Thyroid Hormone Receptor alpha can target tata binding protein for transcriptional repression
Molecular and Cellular Biology, 1996Co-Authors: Joseph D Fondell, Franck Brunel, Koji Hisatake, Robert G RoederAbstract: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.
Laurent M. Sachs - One of the best experts on this subject based on the ideXlab platform.
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Unliganded Thyroid Hormone Receptor is essential for Xenopus laevis eye development
The EMBO journal, 2006Co-Authors: Emmanuelle Havis, Sébastien Le Mével, Ghislaine Morvan Dubois, De Li Shi, Thomas S. Scanlan, Barbara A. Demeneix, Laurent M. SachsAbstract:Thyroid Hormone Receptors generally activate transcription of target genes in the presence of Thyroid Hormone (T3) and repress their transcription in its absence. Here, we investigated the role of unliganded Thyroid Hormone Receptor (TR) during vertebrate development using an amphibian model. Previous studies led to the hypothesis that before production of endogenous T3, the presence of unliganded Receptor is essential for premetamorphic tadpole growth. To test this hypothesis, we generated a Xenopus laevis TR β mutant construct ineffective for gene repression owing to impaired corepressor NCoR recruitment. Overexpression by germinal transgenesis of the mutant Receptor leads to lethality during early development with numerous defects in cranio-facial and eye development. These effects correlate with TR expression profiles at these early stages. Molecular analysis of transgenic mutants reveals perturbed expression of genes involved in eye development. Finally, treatment with iopanoic acid or NH-3, modulators of Thyroid Hormone action, leads to abnormal eye development. In conclusion, the data reveal a role of unliganded TR in eye development.
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Modification of Chromatin Structure by the Thyroid Hormone Receptor
Trends in endocrinology and metabolism: TEM, 1999Co-Authors: Laurent M. Sachs, Yun-bo Shi, Alan P. WolffeAbstract:Pioneering experiments and recent observations have established the Thyroid Hormone Receptor as a master manipulator of the chromosomal environment in targeting the activation and repression of transcription. Here we review how the Thyroid Hormone Receptor is assembled into chromatin, where in the absence of Thyroid Hormone the Receptor recruits histone deacetylase to silence transcription. On addition of Hormone, the Receptor undergoes a conformational change that leads to the release of deacetylase, while facilitating the recruitment of transcriptional coactivators that act as histone acetyltransferases. We discuss the biological importance of these observations for gene control by the Thyroid Hormone Receptor and for oncogenic transformation by the mutated Thyroid Hormone Receptor, v-ErbA.
Emmanuelle Havis - One of the best experts on this subject based on the ideXlab platform.
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Unliganded Thyroid Hormone Receptor is essential for Xenopus laevis eye development
The EMBO journal, 2006Co-Authors: Emmanuelle Havis, Sébastien Le Mével, Ghislaine Morvan Dubois, De Li Shi, Thomas S. Scanlan, Barbara A. Demeneix, Laurent M. SachsAbstract:Thyroid Hormone Receptors generally activate transcription of target genes in the presence of Thyroid Hormone (T3) and repress their transcription in its absence. Here, we investigated the role of unliganded Thyroid Hormone Receptor (TR) during vertebrate development using an amphibian model. Previous studies led to the hypothesis that before production of endogenous T3, the presence of unliganded Receptor is essential for premetamorphic tadpole growth. To test this hypothesis, we generated a Xenopus laevis TR β mutant construct ineffective for gene repression owing to impaired corepressor NCoR recruitment. Overexpression by germinal transgenesis of the mutant Receptor leads to lethality during early development with numerous defects in cranio-facial and eye development. These effects correlate with TR expression profiles at these early stages. Molecular analysis of transgenic mutants reveals perturbed expression of genes involved in eye development. Finally, treatment with iopanoic acid or NH-3, modulators of Thyroid Hormone action, leads to abnormal eye development. In conclusion, the data reveal a role of unliganded TR in eye development.
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Unliganded Thyroid Hormone Receptor is essential for Xenopus laevis eye development.
EMBO Journal, 2006Co-Authors: Emmanuelle Havis, Le Mevel S, G. Morvan-duboisAbstract:Thyroid Hormone Receptors generally activate transcription of target genes in the presence of Thyroid Hormone (T(3)) and repress their transcription in its absence. Here, we investigated the role of unliganded Thyroid Hormone Receptor (TR) during vertebrate development using an amphibian model. Previous studies led to the hypothesis that before production of endogenous T(3), the presence of unliganded Receptor is essential for premetamorphic tadpole growth. To test this hypothesis, we generated a Xenopus laevis TR beta mutant construct ineffective for gene repression owing to impaired corepressor NCoR recruitment. Overexpression by germinal transgenesis of the mutant Receptor leads to lethality during early development with numerous defects in cranio-facial and eye development. These effects correlate with TR expression profiles at these early stages. Molecular analysis of transgenic mutants reveals perturbed expression of genes involved in eye development. Finally, treatment with iopanoic acid or NH-3, modulators of Thyroid Hormone action, leads to abnormal eye development. In conclusion, the data reveal a role of unliganded TR in eye development.