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Martin L. Privalsky - One of the best experts on this subject based on the ideXlab platform.

  • Pathological Interactions Between Mutant Thyroid Hormone Receptors and Corepressors and Their Modulation by a Thyroid Hormone Analogue with Therapeutic Potential
    Thyroid, 2018
    Co-Authors: Deborah Harrus, Hélène Déméné, Edwin Vasquez, Abdelhay Boulahtouf, Pierre Germain, Martin L. Privalsky, William Bourguet, Ana Carolina Figueira, Albane Le Maire
    Abstract:

    BACKGROUND: Thyroid Hormone Receptors (TRs) are tightly regulated by the corepressors nuclear receptor corepressor (NCoR) and silencing mediator of retinoic acid and Thyroid Hormone Receptors. Three conserved corepressor/NR signature box motifs (CoRNR1-3) forming the nuclear receptor interaction domain have been identified in these corepressors. Whereas TRs regulate multiple normal physiological and developmental pathways, mutations in TRs can result in endocrine diseases and be associated with cancers due to impairment of corepressor release. Three mutants that are located in helix H11 of TRs are of special interest: TRα-M388I, a mutant associated with the development of renal clear cell carcinomas (RCCCs), and TRβ-Δ430 and TRβ-Δ432, two deletion mutants causing resistance to Thyroid Hormone syndrome. METHODS: Several cell-based and biophysical methods were used to measure the affinity between wild-type and mutant TRα and TRβ and all the CoRNR motifs from corepressors to quantify the effects of different Thyroid Hormone analogues on these interactions. This study was coupled with the measurement of interactions between wild-type and mutant TRs in the context of a heterodimer with RXR to a NCoR fragment in the presence of the same ligands. Structural insights into the binding mode of corepressors to TRs were assessed in parallel by nuclear magnetic resonance spectroscopy. RESULTS: The study shows that TRs interact more avidly with the silencing mediator of retinoic acid and Thyroid Hormone Receptors than with NCoR peptides, and that TRα binds most avidly to S-CoRNR3, whereas TRβ binds preferentially to S-CoRNR2. In the studied TR mutants, a transfer of the CoRNR-specificity toward CoRNR1 was observed, coupled with a significant increase in the binding strength. In contrast to 3,5,3'-triiodothyronine (T3), the agonist TRIAC and the antagonist NH-3 were very efficient at dissociating the abnormally strong interactions between mutant TRβs and corepressors. A strong impairment of T3-binding for TRβ mutants was shown compared to TRIAC and NH-3 and could explain the different efficiencies of the different ligands in releasing corepressors from the studied TRβ mutants. Consequently, TRIAC was found to be more effective than T3 in facilitating coactivator recruitment and decreasing the dominant activity of TRβ-Δ430. CONCLUSION: This study helps to clarify the specific interaction surfaces involved in the pathologic phenotype of TR mutants and demonstrates that TRIAC is a potential therapeutic agent for patients suffering from resistance to Thyroid Hormone syndromes.

  • Pathological Interactions Between Mutant Thyroid Hormone Receptors and Corepressors and Their Modulation by a Thyroid Hormone Analogue with Therapeutic Potential.
    Thyroid : official journal of the American Thyroid Association, 2018
    Co-Authors: Deborah Harrus, Hélène Déméné, Edwin Vasquez, Abdelhay Boulahtouf, Pierre Germain, Ana Carolina Migliorini Figueira, Martin L. Privalsky, William Bourguet, Albane Le Maire
    Abstract:

    Background: Thyroid Hormone Receptors (TRs) are tightly regulated by the corepressors nuclear receptor corepressor (NCoR) and silencing mediator of retinoic acid and Thyroid Hormone Receptors. Thre...

  • isoform specific transcriptional activity of overlapping target genes that respond to Thyroid Hormone Receptors α1 and β1
    Molecular Endocrinology, 2009
    Co-Authors: Ivan H Chan, Martin L. Privalsky
    Abstract:

    Thyroid Hormone Receptors (TRs) are Hormone-regulated transcription factors that control multiple aspects of physiology and development. TRs are expressed in vertebrates as a series of distinct isoforms that exert distinct biological roles. We wished to determine whether the two most widely expressed isoforms, TR alpha 1 and TR beta 1, exert their different biological effects by regulating different sets of target genes. Using stably transformed HepG2 cells and a microarray analysis, we were able to demonstrate that TR alpha 1 and TR beta 1 regulate a largely overlapping repertoire of target genes in response to T(3) Hormone. However, these two isoforms display very different transcriptional properties on each individual target gene, ranging from a much greater T(3)-mediated regulation by TR alpha 1 than by TR beta 1, to near equal regulation by both isoforms. We also identified TR alpha 1 and TR beta 1 target genes that were regulated by these Receptors in a Hormone-independent fashion. We suggest that it is this gene-specific, isoform-specific amplitude of transcriptional regulation that is the likely basis for the appearance and maintenance of TR alpha 1 and TR beta 1 over evolutionary time. In essence, TR alpha 1 and TR beta 1 adjust the magnitude of the transcriptional response at different target genes to different levels; by altering the ratio of these isoforms in different tissues or at different developmental times, the intensity of T(3) response can be individually tailored to different physiological and developmental requirements.

  • the p160 coactivator pas b motif stabilizes nuclear receptor binding and contributes to isoform specific regulation by Thyroid Hormone Receptors
    Journal of Biological Chemistry, 2009
    Co-Authors: Martin L. Privalsky, Johnnie B Hahm, Briana M Young, Rebecca N G Fong, Ivan H Chan
    Abstract:

    Thyroid Hormone Receptors (TRs) are Hormone-regulated transcription factors that play multiple roles in vertebrate endocrinology and development. TRs are expressed as a series of distinct receptor isoforms that mediate different biological functions. The TRβ2 isoform is expressed primarily in the hypothalamus, pituitary, cochlea, and retina, and displays an enhanced response to Hormone agonist relative to the other TR isoforms. We report here that the unusual transcriptional properties of TRβ2 parallel the ability of this isoform to bind p160 coactivators cooperatively through multiple contact surfaces; the more broadly expressed TRβ1 isoform, in contrast, utilizes a single contact mechanism. Intriguingly, the PAS-B domain in the p160 N terminus plays a previously unanticipated role in permitting TRβ2 to recruit coactivator at limiting triiodothyronine concentrations. The PAS-B sequences also play an important role in coactivator binding by estrogen receptor-α. We propose that the PAS-B domain of the p160 coactivators is an important modulator of coactivator recruitment for a specific subset of nuclear Receptors, permitting stronger transcriptional activation at lower Hormone concentrations than would otherwise occur, and allowing isoform-specific mRNA splicing to customize the Hormone response in different tissues.

  • Thyroid Hormone Receptors mutated in liver cancer function as distorted antimorphs
    Oncogene, 2006
    Co-Authors: Ivan H Chan, Martin L. Privalsky
    Abstract:

    Aberrant Thyroid Hormone Receptors (TRs) are found in over 70% of the human hepatocellular carcinomas (HCCs) analysed. To better understand the role(s) of these TR mutants in this neoplasia, we analysed a panel of HCC mutant Receptors for their molecular properties. Virtually all HCC-associated TR mutants tested retained the ability to repress target genes in the absence of T3, yet were impaired in T3-driven gene activation and functioned as dominant-negative inhibitors of wild-type TR activity. Intriguingly, the HCC TRα1 mutants exerted dominant-negative interference at all T3 concentrations tested, whereas the HCC TRβ1 mutants were dominant-negatives only at low and intermediate T3 concentrations, reverting to transcriptional activators at higher Hormone levels. The relative affinity for the SMRT versus N-CoR corepressors was detectably altered for several of the HCC mutant TRs, suggesting changes in corepressor preference and recruitment compared to wild type. Several of the TRα HCC mutations also altered the DNA recognition properties of the encoded Receptors, indicating that these HCC TR mutants may regulate a distinct set of target genes from those regulated by wild-type TRs. Finally, whereas wild-type TRs interfere with c-Jun/AP-1 function in a T3-dependent fashion and suppress anchorage-independent growth when ectopically expressed in HepG2 cells, at least certain of the HCC mutants did not exert these inhibitory properties. These alterations in transcriptional regulation and DNA recognition appear likely to contribute to oncogenesis by reprogramming the differentiation and proliferative properties of the hepatocytes in which the mutant TRs are expressed.

Fredric E. Wondisford - One of the best experts on this subject based on the ideXlab platform.

  • Thyroid Hormone Receptors and resistance to Thyroid Hormone disorders
    Nature reviews. Endocrinology, 2014
    Co-Authors: T. M. Ortiga-carvalho, Aniket Sidhaye, Fredric E. Wondisford
    Abstract:

    Thyroid Hormone action is predominantly mediated by Thyroid Hormone Receptors (THRs), which are encoded by the Thyroid Hormone receptor α (THRA) and Thyroid Hormone receptor β (THRB) genes. Patients with mutations in THRB present with resistance to Thyroid Hormone β (RTHβ), which is a disorder characterized by elevated levels of Thyroid Hormone, normal or elevated levels of TSH and goitre. Mechanistic insights about the contributions of THRβ to various processes, including colour vision, development of the cochlea and the cerebellum, and normal functioning of the adult liver and heart, have been obtained by either introducing human THRB mutations into mice or by deletion of the mouse Thrb gene. The introduction of the same mutations that mimic human THRβ alterations into the mouse Thra and Thrb genes resulted in distinct phenotypes, which suggests that THRA and THRB might have non-overlapping functions in human physiology. These studies also suggested that THRA mutations might not be lethal. Seven patients with mutations in THRα have since been described. These patients have RTHα and presented with major abnormalities in growth and gastrointestinal function. The hypothalamic-pituitary-Thyroid axis in these individuals is minimally affected, which suggests that the central T3 feedback loop is not impaired in patients with RTHα, in stark contrast to patients with RTHβ.

  • Thyroid Hormone Receptors and resistance to Thyroid Hormone disorders
    Nature Reviews Endocrinology, 2014
    Co-Authors: T. M. Ortiga-carvalho, Aniket Sidhaye, Fredric E. Wondisford
    Abstract:

    Mutations in the genes that encode the Thyroid Hormone Receptors (THRs), THRA and THRB, result in resistance to Thyroid Hormone disorders, RTHα and RTHβ, respectively. In this Review, the authors discuss mutations that have been identified in patients with RTH and mouse models of these disorders that have contributed to understanding the physiology and functions of THRs.

Don J Chen - One of the best experts on this subject based on the ideXlab platform.

  • regulation and binding of pregnane x receptor by nuclear receptor corepressor silencing mediator of retinoid and Thyroid Hormone Receptors smrt
    Molecular Pharmacology, 2006
    Co-Authors: David R Johnson, Liuhyow Chen, Jagadish C Ghosh, Don J Chen
    Abstract:

    The pregnane X receptor (PXR) is an orphan nuclear receptor predominantly expressed in liver and intestine. PXR coordinates hepatic responses to prevent liver injury induced by environmental toxins. PXR activates cytochrome P450 3A4 gene expression upon binding to rifampicin (Rif) and clotrimazole (CTZ) by recruiting transcriptional coactivators. It remains unclear whether and how PXR regulates gene expression in the absence of ligand. In this study, we analyzed interactions between PXR and the silencing mediator of retinoid and Thyroid Hormone Receptors (SMRT) and determined the role of SMRT in regulating PXR activity. We show that SMRT interacts with PXR in glutathione S-transferase pull-down, yeast two-hybrid, and mammalian two-hybrid assays. The interaction is mediated through the ligand-binding domain of PXR and the SMRTs' nuclear receptor-interacting domain 2. The PXR-SMRT interaction is sensitive to species-specific ligands, and Rif causes an exchange of the corepressor SMRT with the p160 coactivator known as receptor-associated coactivator 3 (RAC3). Deletion of the PXR's activation function 2 helix enhances SMRT binding and abolishes ligand-dependent dissociation of SMRT. Coexpression of PXR with SMRT results in colocalization at discrete nuclear foci. Finally, transient transfection assays show that overexpression of SMRT inhibits PXR's transactivation of the Cyp3A4 promoter, whereas silencing of SMRT enhances the reporter expression. Taken together, our results suggest that the corepressor SMRT may bind to and regulate the transcriptional activity of PXR.

  • smrte a silencing mediator for retinoid and Thyroid Hormone Receptors extended isoform that is more related to the nuclear receptor corepressor
    Proceedings of the National Academy of Sciences of the United States of America, 1999
    Co-Authors: Eun Ju Park, Daniel J Schroen, Maozhou Yang, Hui Li, Li Li, Don J Chen
    Abstract:

    SMRT (silencing mediator for retinoid and Thyroid Hormone Receptors) and N-CoR (nuclear receptor copressor) mediate transcriptional repression of important regulators that are involved in many signaling pathways. SMRT and N-CoR are related proteins that form complexes with mSin3A/B and histone deacetylases to induce local chromatin condensation and transcriptional repression. However, SMRT is substantially smaller than N-CoR, lacking an N-terminal domain of approximately 1,000 aa that are present in N-CoR. Here, we report the identification of SMRT-extended (SMRTe), which contains an N-terminal sequence that shows striking similarity with N-CoR. As in N-CoR, this SMRTe-N-terminal domain also represses basal transcription. We find that SMRTe expression is regulated during cell cycle progression and SMRTe transcripts are present in many embryonic tissues. These data redefine a structurally and functionally more related nuclear receptor corepressor family and suggest an additional role for SMRTe in the regulation of cycle-specific gene expression in diverse signaling pathways.

Douglas Forrest - One of the best experts on this subject based on the ideXlab platform.

  • Thyroid Hormone Receptors control developmental maturation of the middle ear and the size of the ossicular bones
    Endocrinology, 2012
    Co-Authors: Emily Cordas, Sheue-yann Cheng, Arturo Hernandez, Masahiro Kaneshige, Douglas Forrest
    Abstract:

    Thyroid Hormone is critical for auditory development and has well-known actions in the inner ear. However, less is known of Thyroid Hormone functions in the middle ear, which contains the ossicles (malleus, incus, stapes) that relay mechanical sound vibrations from the outer ear to the inner ear. During the later stages of middle ear development, prior to the onset of hearing, middle ear cavitation occurs, involving clearance of mesenchyme from the middle ear cavity while the immature cartilaginous ossicles attain appropriate size and ossify. Using in situ hybridization, we detected expression of Thra and Thrb genes encoding Thyroid Hormone Receptors α1 and β (TRα1 and TRβ, respectively) in the immature ossicles, surrounding mesenchyme and tympanic membrane in the mouse. Thra+/PV mice that express a dominant-negative TRα1 protein exhibited deafness with elevated auditory thresholds and a range of middle ear abnormalities including chronic persistence of mesenchyme in the middle ear into adulthood, markedl...

  • Thyroid Hormone Receptors
    Nuclear Receptors, 2010
    Co-Authors: Bjorn Vennstrom, Douglas Forrest
    Abstract:

    Thyroid Hormone promotes a diverse range of developmental, neurological and metabolic functions in vertebrate species. Human Thyroid disorders result in a correspondingly wide range of disease symptoms. The functions of Thyroid Hormone are mediated by a small group of Thyroid Hormone Receptors encoded by two conserved genes. Thyroid Hormone Receptors were among the first nuclear Receptors to be identified and act as ligand-regulated transcription factors. These Receptors are particularly versatile since they also have the potential to mediate ligand-independent transcriptional control. Genetic analyses have revealed both specific and overlapping roles for each receptor, revealing how a small receptor family can mediate an extended range of biological functions.

  • international union of pharmacology lix the pharmacology and classification of the nuclear receptor superfamily Thyroid Hormone Receptors
    Pharmacological Reviews, 2006
    Co-Authors: Frederic Flamant, John D Baxter, Bjorn Vennstrom, Douglas Forrest, Thomas S Scanlan, Herbert H Samuels, Samuel Refetoff, Jacques Samarut
    Abstract:

    The initial identification of Thyroid Hormone Receptors (TRs[1][1]) was based on binding studies ([Oppenheimer et al., 1972][2]). The TR main ligand is 3,5,3′-triiodo-l-thyronine (T3). T3 production primarily results from deiodination of thyroxine (T4), which is secreted by the Thyroid gland. Most

  • Neurodevelopmental control by Thyroid Hormone Receptors.
    Current opinion in neurobiology, 2002
    Co-Authors: Douglas Forrest, Thomas A. Reh, Alfons Rüsch
    Abstract:

    Recent studies have provided insights into the neurodevelopmental functions of Thyroid Hormone signaling. The nuclear Thyroid Hormone Receptors (TRs) are ligand-activated transcription factors and a variety of TR isotypes, generated by two genes, mediate distinct processes. In addition, deiodinase enzymes that regulate levels of the main active form of Thyroid Hormone, T3, are likely to cooperate closely with TRs in specifying a localized and timely response to Thyroid Hormones in target tissues. Some of the most sensitive processes controlled by these pathways are in the auditory and visual sensory systems.

  • retardation of cochlear maturation and impaired hair cell function caused by deletion of all known Thyroid Hormone Receptors
    The Journal of Neuroscience, 2001
    Co-Authors: Alfons Rüsch, Bjorn Vennstrom, Richard J Goodyear, Dominik Oliver, Igor Lisoukov, Guy P Richardson, Matthew W Kelley, Douglas Forrest
    Abstract:

    The deafness caused by early onset hypoThyroidism indicates that Thyroid Hormone is essential for the development of hearing. We investigated the underlying roles of the TRa1 and TRs Thyroid Hormone Receptors in the auditory system using receptor-deficient mice. TRa1 and TRs, which act as Hormone-activated transcription factors, are encoded by the Thra and Thrb genes, respectively, and both are expressed in the developing cochlea. TRs is required for hearing because TRs-deficient (Thrb tm1/tm1) mice have a defective auditory-evoked brainstem response and retarded expression of a potassium current (I K,f) in the cochlear inner hair cells. Here, we show that although TRa1 is individually dispensable, TRa1 and TRs synergistically control an extended array of functions in postnatal cochlear development. Compared with Thrb tm1/tm1 mice, the deletion of all TRs inThra tm1/tm1 Thrb tm1/tm1mice produces exacerbated and novel phenotypes, including delayed differentiation of the sensory epithelium, malformation of the tectorial membrane, impairment of electromechanical transduction in outer hair cells, and a low endocochlear potential. The induction ofI K,f in inner hair cells was not markedly more retarded than in Thrb tm1/tm1mice, suggesting that this feature of hair cell maturation is primarily TRs-dependent. These results indicate that distinct pathways mediated by TRs alone or by TRs and TRa1 together facilitate control over an extended range of functions during the maturation of the cochlea.

T. M. Ortiga-carvalho - One of the best experts on this subject based on the ideXlab platform.

  • Thyroid Hormone Receptors and resistance to Thyroid Hormone disorders
    Nature reviews. Endocrinology, 2014
    Co-Authors: T. M. Ortiga-carvalho, Aniket Sidhaye, Fredric E. Wondisford
    Abstract:

    Thyroid Hormone action is predominantly mediated by Thyroid Hormone Receptors (THRs), which are encoded by the Thyroid Hormone receptor α (THRA) and Thyroid Hormone receptor β (THRB) genes. Patients with mutations in THRB present with resistance to Thyroid Hormone β (RTHβ), which is a disorder characterized by elevated levels of Thyroid Hormone, normal or elevated levels of TSH and goitre. Mechanistic insights about the contributions of THRβ to various processes, including colour vision, development of the cochlea and the cerebellum, and normal functioning of the adult liver and heart, have been obtained by either introducing human THRB mutations into mice or by deletion of the mouse Thrb gene. The introduction of the same mutations that mimic human THRβ alterations into the mouse Thra and Thrb genes resulted in distinct phenotypes, which suggests that THRA and THRB might have non-overlapping functions in human physiology. These studies also suggested that THRA mutations might not be lethal. Seven patients with mutations in THRα have since been described. These patients have RTHα and presented with major abnormalities in growth and gastrointestinal function. The hypothalamic-pituitary-Thyroid axis in these individuals is minimally affected, which suggests that the central T3 feedback loop is not impaired in patients with RTHα, in stark contrast to patients with RTHβ.

  • Thyroid Hormone Receptors and resistance to Thyroid Hormone disorders
    Nature Reviews Endocrinology, 2014
    Co-Authors: T. M. Ortiga-carvalho, Aniket Sidhaye, Fredric E. Wondisford
    Abstract:

    Mutations in the genes that encode the Thyroid Hormone Receptors (THRs), THRA and THRB, result in resistance to Thyroid Hormone disorders, RTHα and RTHβ, respectively. In this Review, the authors discuss mutations that have been identified in patients with RTH and mouse models of these disorders that have contributed to understanding the physiology and functions of THRs.