Genomes and Genes
thyroid hormone receptors alpha
Summary: High affinity receptors for THYROID HORMONES, especially TRIIODOTHYRONINE. These receptors are usually found in the nucleus where they regulate DNA transcription. They are encoded by the THRA gene (also known as NR1A1, THRA1, ERBA or ERBA1 gene) as several isoforms produced by alternative splicing.
- Poguet A, Legrand C, Feng X, Yen P, Meltzer P, Samarut J, et al. Microarray analysis of knockout mice identifies cyclin D2 as a possible mediator for the action of thyroid hormone during the postnatal development of the cerebellum. Dev Biol. 2003;254:188-99 pubmed
- Sjogren M, Alkemade A, Mittag J, Nordstrom K, Katz A, Rozell B, et al. Hypermetabolism in mice caused by the central action of an unliganded thyroid hormone receptor alpha1. EMBO J. 2007;26:4535-45 pubmed..Furthermore, the data demonstrate that a nuclear hormone receptor affecting sympathetic signaling can override its autonomous effects in peripheral tissues. ..
- Quignodon L, Vincent S, Winter H, Samarut J, Flamant F. A point mutation in the activation function 2 domain of thyroid hormone receptor alpha1 expressed after CRE-mediated recombination partially recapitulates hypothyroidism. Mol Endocrinol. 2007;21:2350-60 pubmed..Both respective abundance and intrinsic properties of TRalpha1 and TRbeta1/2 seem to govern specificity of action. ..
- Zandieh Doulabi B, Dop E, Schneiders M, Schiphorst M, Mansen A, Vennstrom B, et al. Zonal expression of the thyroid hormone receptor alpha isoforms in rodent liver. J Endocrinol. 2003;179:379-85 pubmed..This finding, together with the observed diurnal rhythm, has major implications for interpreting and timing experiments concerning the TR and its downstream actions in liver. ..
- Bochukova E, Schoenmakers N, Agostini M, Schoenmakers E, Rajanayagam O, Keogh J, et al. A mutation in the thyroid hormone receptor alpha gene. N Engl J Med. 2012;366:243-9 pubmed publisher..Our observations are consistent with defective human TR?-mediated thyroid hormone resistance and substantiate the concept of hormone action through distinct receptor subtypes in different target tissues. ..
- Nascimento A, Dias S, Nunes F, Aparicio R, Ambrosio A, Bleicher L, et al. Structural rearrangements in the thyroid hormone receptor hinge domain and their putative role in the receptor function. J Mol Biol. 2006;360:586-98 pubmed
- Baxter J, Webb P, Grover G, Scanlan T. Selective activation of thyroid hormone signaling pathways by GC-1: a new approach to controlling cholesterol and body weight. Trends Endocrinol Metab. 2004;15:154-7 pubmed..Although more study is required, compounds of this class deserve further investigation for treating lipid disorders and obesity. ..
- Liu Y, Schultz J, Brent G. A thyroid hormone receptor alpha gene mutation (P398H) is associated with visceral adiposity and impaired catecholamine-stimulated lipolysis in mice. J Biol Chem. 2003;278:38913-20 pubmed..The physiologic significance of these findings will ultimately depend on understanding the full range of actions of this mutation. ..
- Velasco L, Togashi M, Walfish P, Pessanha R, Moura F, Barra G, et al. Thyroid hormone response element organization dictates the composition of active receptor. J Biol Chem. 2007;282:12458-66 pubmed..TRE complex. We propose that interactions of particular TR oligomers with different elements play unappreciated roles in TRE-selective actions of liganded TRs in vivo. ..
- Liu Y, Heymann R, Moatamed F, Schultz J, Sobel D, Brent G. A mutant thyroid hormone receptor alpha antagonizes peroxisome proliferator-activated receptor alpha signaling in vivo and impairs fatty acid oxidation. Endocrinology. 2007;148:1206-17 pubmed..The P398H mutant is a potential probe to characterize the physiological role of thyroid hormone receptor/PPARalpha interactions. ..
- Yen P, Feng X, Flamant F, Chen Y, Walker R, Weiss R, et al. Effects of ligand and thyroid hormone receptor isoforms on hepatic gene expression profiles of thyroid hormone receptor knockout mice. EMBO Rep. 2003;4:581-7 pubmed..This large-scale study of hormonal regulation reveals the functions of Th and of Tr isoforms in the regulation of gene expression patterns. ..
- Barca Mayo O, Liao X, Alonso M, Di Cosmo C, Hernandez A, Refetoff S, et al. Thyroid hormone receptor ? and regulation of type 3 deiodinase. Mol Endocrinol. 2011;25:575-83 pubmed publisher..We conclude that the absence of TR? results in decreased clearance of TH by D3 and contributes to the TH hypersensitivity. ..
- Yuan C, Lin J, Sieglaff D, Ayers S, Denoto Reynolds F, Baxter J, et al. Identical gene regulation patterns of T3 and selective thyroid hormone receptor modulator GC-1. Endocrinology. 2012;153:501-11 pubmed publisher..Our data suggest that T(3) and GC-1 exhibit almost identical gene regulation properties and that gene-selective actions of GC-1 and similar STRM will be subtle and rare. ..
- Plateroti M, Kress E, Mori J, Samarut J. Thyroid hormone receptor alpha1 directly controls transcription of the beta-catenin gene in intestinal epithelial cells. Mol Cell Biol. 2006;26:3204-14 pubmed..As Wnt/beta-catenin plays a crucial role in intestinal tumorigenesis, our observations open a new perspective on the study of TRs as potential tumor inducers. ..
- Kress E, Skah S, Sirakov M, Nadjar J, Gadot N, Scoazec J, et al. Cooperation between the thyroid hormone receptor TRalpha1 and the WNT pathway in the induction of intestinal tumorigenesis. Gastroenterology. 2010;138:1863-74 pubmed publisher..Because the WNT pathway is a major player in controlling intestinal homeostasis, we addressed whether the TRalpha1 receptor has tumor-inducing potential...
- Vennstrom B, Mittag J, Wallis K. Severe psychomotor and metabolic damages caused by a mutant thyroid hormone receptor alpha 1 in mice: can patients with a similar mutation be found and treated?. Acta Paediatr. 2008;97:1605-10 pubmed publisher..Our studies on mice suggest the existence of a potentially debilitating disease caused by a mutant TRalpha1, and provide insights for identification and treatment of corresponding patients. ..
- Holsberger D, Kiesewetter S, Cooke P. Regulation of neonatal Sertoli cell development by thyroid hormone receptor alpha1. Biol Reprod. 2005;73:396-403 pubmed..Thus, effects of exogenous manipulation of T3 on neonatal Sertoli cell development are predominately mediated through TRalpha1. ..
- Xu B, Koenig R. An RNA-binding domain in the thyroid hormone receptor enhances transcriptional activation. J Biol Chem. 2004;279:33051-6 pubmed..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. ..
- Lemkine G, Raj A, Alfama G, Turque N, Hassani Z, Alegria Prévot O, et al. Adult neural stem cell cycling in vivo requires thyroid hormone and its alpha receptor. FASEB J. 2005;19:863-5 pubmed..We conclude that liganded-TRalpha is critical for neurogenesis in the adult mammalian brain. ..
- Martinez L, Nascimento A, Nunes F, Phillips K, Aparicio R, Dias S, et al. Gaining ligand selectivity in thyroid hormone receptors via entropy. Proc Natl Acad Sci U S A. 2009;106:20717-22 pubmed publisher..Similar effects could potentially be exploited in nuclear receptor drug design. ..
- Flamant F, Samarut J. Thyroid hormone receptors: lessons from knockout and knock-in mutant mice. Trends Endocrinol Metab. 2003;14:85-90 pubmed
- Ye L, Li Y, Mellstrom K, Mellin C, Bladh L, Koehler K, et al. Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1. J Med Chem. 2003;46:1580-8 pubmed..to have a profound effect on affinity and selectivity in a radioreceptor binding assay for the human thyroid hormone receptors alpha(1) and beta(1) (TRalpha(1) and TRbeta(2)) as well as a reporter cell assay employing CHOK1-cells (..
- van Mullem A, Chrysis D, Eythimiadou A, Chroni E, Tsatsoulis A, de Rijke Y, et al. Clinical phenotype of a new type of thyroid hormone resistance caused by a mutation of the TR?1 receptor: consequences of LT4 treatment. J Clin Endocrinol Metab. 2013;98:3029-38 pubmed publisher..These patients have low free T?, low T?, high T?, low rT?, and normal TSH serum levels, in combination with growth retardation, delayed bone development, and constipation...
- Keijzer R, Blommaart P, Labruyere W, Vermeulen J, Doulabi B, Bakker O, et al. Expression of thyroid hormone receptors A and B in developing rat tissues; evidence for extensive posttranscriptional regulation. J Mol Endocrinol. 2007;38:523-35 pubmed..The data indicate that the TR-dependent regulatory cascades are controlled differently in organs with a complementary tissue expression pattern and in those with cellular co-expression of the TRalpha and TRbeta genes. ..
- Wallis K, Dudazy S, van Hogerlinden M, Nordstrom K, Mittag J, Vennstrom B. The thyroid hormone receptor alpha1 protein is expressed in embryonic postmitotic neurons and persists in most adult neurons. Mol Endocrinol. 2010;24:1904-16 pubmed publisher..Because the role of TR?1 in most neuronal cell types in vivo is largely unknown, our findings suggest that novel functions for thyroid hormone remain to be identified in the brain. ..
- Venero C, Guadaño Ferraz A, Herrero A, Nordstrom K, Manzano J, de Escobar G, et al. Anxiety, memory impairment, and locomotor dysfunction caused by a mutant thyroid hormone receptor alpha1 can be ameliorated by T3 treatment. Genes Dev. 2005;19:2152-63 pubmed..Here, the hormone treatment normalized the otherwise delayed cerebellar development. The data thus identify two novel and distinct functions of an unliganded TRalpha1 during development and adulthood, respectively. ..
- Casas F, Busson M, Grandemange S, Seyer P, Carazo A, Pessemesse L, et al. Characterization of a novel thyroid hormone receptor alpha variant involved in the regulation of myoblast differentiation. Mol Endocrinol. 2006;20:749-63 pubmed..We suggest that this novel TRalpha variant may act as down regulator of overall T3 receptor activity, including its ability to repress MyoD transcriptional activity during myoblast proliferation. ..
- Xu B, Koenig R. Regulation of thyroid hormone receptor alpha2 RNA binding and subcellular localization by phosphorylation. Mol Cell Endocrinol. 2005;245:147-57 pubmed..Since RNA binding is a property of unphosphorylated TRalpha2, the TRalpha2-RNA interaction likely represents a nuclear function of TRalpha2. ..
- Salato V, Rediske N, Zhang C, Hastings M, Munroe S. An exonic splicing enhancer within a bidirectional coding sequence regulates alternative splicing of an antisense mRNA. RNA Biol. 2010;7:179-90 pubmed..They also demonstrate the ability of the genetic code to accommodate multiple layers of information within a given sequence, an important property of the code recently suggested on theoretical grounds. ..
- Bassett J, Williams G. The skeletal phenotypes of TRalpha and TRbeta mutant mice. J Mol Endocrinol. 2009;42:269-82 pubmed publisher..Detailed future analysis of the molecular mechanisms of T(3) action in bone will enhance our understanding of this emerging field and has the potential to identify novel strategies for the prevention and treatment of osteoporosis. ..
- Kress E, Rezza A, Nadjar J, Samarut J, Plateroti M. The frizzled-related sFRP2 gene is a target of thyroid hormone receptor alpha1 and activates beta-catenin signaling in mouse intestine. J Biol Chem. 2009;284:1234-41 pubmed publisher..Moreover, we describe in this study a novel mechanism of action of sFRP2, responsible for the activation of beta-catenin signaling. ..
- Tinnikov A, Nordstrom K, Thoren P, Kindblom J, Malin S, Rozell B, et al. Retardation of post-natal development caused by a negatively acting thyroid hormone receptor alpha1. EMBO J. 2002;21:5079-87 pubmed..The data demonstrate a novel array of effects mediated by a dominant negative TRalpha1, and may provide important clues for identification of a potentially unrecognized human disorder and its treatment. ..
- Bonamy G, Guiochon Mantel A, Allison L. Cancer promoted by the oncoprotein v-ErbA may be due to subcellular mislocalization of nuclear receptors. Mol Endocrinol. 2005;19:1213-30 pubmed..These results define a new mode of action of v-ErbA and illustrate the importance of cellular compartmentalization in transcriptional regulation and oncogenesis. ..
- Ying H, Araki O, Furuya F, Kato Y, Cheng S. Impaired adipogenesis caused by a mutated thyroid hormone alpha1 receptor. Mol Cell Biol. 2007;27:2359-71 pubmed..The present study suggests that defects in adipogenesis could contribute to the phenotypic manifestation of reduced body weight in TRalpha1(PV/+) mice. ..
- Engelhard A, Christiano A. The hairless promoter is differentially regulated by thyroid hormone in keratinocytes and neuroblastoma cells. Exp Dermatol. 2004;13:257-64 pubmed..These findings illustrate a molecular distinction between the regulation of hr expression in defined cell populations. ..
- Takayama S, Hostick U, Haendel M, Eisen J, Darimont B. An F-domain introduced by alternative splicing regulates activity of the zebrafish thyroid hormone receptor alpha. Gen Comp Endocrinol. 2008;155:176-89 pubmed
- Ramis J, Taxt Lamolle S, Lyngstadaas S, Reseland J, Ellingsen J, Monjo M. Identification of early response genes to roughness and fluoride modification of titanium implants in human osteoblasts. Implant Dent. 2012;21:141-9 pubmed publisher..Our strategy was useful for identifying novel genes that might be involved in the early response of osteoblasts to rough and fluoride-modified titanium implants. ..
- Kanaho Y, Endo D, Park M. Molecular characterization of thyroid hormone receptors from the leopard gecko, and their differential expression in the skin. Zoolog Sci. 2006;23:549-56 pubmed..This provides good evidence that THs play important roles in the skin, and that the roles of their two receptor isoforms are distinct from each other. ..
- Dufourny L, Gennetay D, Martinet S, Lomet D, Caraty A. The Content of Thyroid Hormone Receptor Î± in Ewe Kisspeptin Neurones is not Season-Dependent. J Neuroendocrinol. 2016;28:12344 pubmed publisher..Our data emphasise that the effects of thyroid hormone on Kiss synthesis are not one-sided and may affect a wide range of functions. ..
- Shi G, Xing L, Liu Z, Qu Z, Wu X, Dong Z, et al. Dual roles of FBXL3 in the mammalian circadian feedback loops are important for period determination and robustness of the clock. Proc Natl Acad Sci U S A. 2013;110:4750-5 pubmed publisher..These two separate roles of FBXL3 in circadian feedback loops provide a mechanism that contributes to the period determination and robustness of the clock. ..
- Gassanov N, Er F, Endres Becker J, Wolny M, Schramm C, Hoppe U. Distinct regulation of cardiac I(f) current via thyroid receptors alpha1 and beta1. Pflugers Arch. 2009;458:1061-8 pubmed publisher..TH-induced positive chronotropic effects are likely to be mediated by TR alpha 1 through enhanced expression of I(f) pacemaker current and its underlying genes. ..
- Sørensen H, van der Deure W, Hansen P, Peeters R, Breteler M, Kyvik K, et al. Identification and consequences of polymorphisms in the thyroid hormone receptor alpha and beta genes. Thyroid. 2008;18:1087-94 pubmed publisher..Analysis of the T3 receptor genes revealed 15 SNPs, including 7 novel. Only THRB-in9-G/A was associated with higher serum TSH in a large population of Danish twins. ..
- Choi K, Oh S, Kang H, Lee Y, Haam S, Kim H, et al. The functional relationship between co-repressor N-CoR and SMRT in mediating transcriptional repression by thyroid hormone receptor alpha. Biochem J. 2008;411:19-26 pubmed..Collectively, these results suggest that both SMRT and N-CoR are limited in cells and that knocking down either of them results in co-repressor-free TR and consequently de-repression of TR target genes. ..
- Ocasio C, Scanlan T. Characterization of thyroid hormone receptor alpha (TRalpha)-specific analogs with varying inner- and outer-ring substituents. Bioorg Med Chem. 2008;16:762-70 pubmed..At best, several agonists exhibit an approximately 6-12-fold preference in transactivation when tested with TRalpha in HeLa cells. One analog, CO24, showed in vivo TRalpha-specific action in a tadpole metamorphosis assay. ..
- Valadares N, Castilho M, Polikarpov I, Garratt R. 2D QSAR studies on thyroid hormone receptor ligands. Bioorg Med Chem. 2007;15:4609-17 pubmed..Contribution map analysis identified a number of positions that are promising for the development of receptor isoform specific ligands. ..
- Olateju T, Vanderpump M. Thyroid hormone resistance. Ann Clin Biochem. 2006;43:431-40 pubmed..Although occasionally desirable, no specific treatment is available for RTH; however, the diagnosis allows appropriate genetic counselling. ..
- Raine J, Cameron C, Vijayan M, MacKenzie D, Leatherland J. Effect of fasting on thyroid hormone levels, and TR(alpha) and TR(beta) mRNA accumulation in late-stage embryo and juvenile rainbow trout, Oncorhynchus mykiss. Comp Biochem Physiol A Mol Integr Physiol. 2005;140:452-9 pubmed..The lower TR gene expression in the intestinal tract of fasted embryos may suggest a role for THs in the transitional stage of intestinal development during this period of development. ..
- Cheng S. Thyroid hormone receptor mutations and disease: beyond thyroid hormone resistance. Trends Endocrinol Metab. 2005;16:176-82 pubmed..The phenotypic manifestations of mutated THRB and THRA genes are distinct, indicating isoform-dependent actions of TR mutants in vivo. Therefore, mutant TRs provide a new paradigm to understand the molecular basis of receptor disease...
- Crescenzi A, Graziano M, Carosa E, Papini E, Rucci N, Nardi F, et al. Localization and expression of thyroid hormone receptors normal and neoplastic human thyroid. J Endocrinol Invest. 2003;26:1008-12 pubmed
- Zhang X, Kaneshige M, Kamiya Y, Kaneshige K, McPhie P, Cheng S. Differential expression of thyroid hormone receptor isoforms dictates the dominant negative activity of mutant Beta receptor. Mol Endocrinol. 2002;16:2077-92 pubmed..These results indicate that in vivo, differential expression of TR isoforms in tissues dictates the dominant negative activity of mutant beta receptor, thereby resulting in variable phenotypic expression in RTH. ..
- Vedani A, Zumstein M, Lill M, Ernst B. Simulating alpha/beta selectivity at the human thyroid hormone receptor: consensus scoring using multidimensional QSAR. ChemMedChem. 2007;2:78-87 pubmed..Consensus was achieved as, on average, the calculated activities of the training set differ only by a factor of 2.2 in K(i) and those of the test set by a factor of 2.8 when predicted by Quasar and Raptor, respectively. ..
- Nelson E, Habibi H. Molecular characterization and sex-related seasonal expression of thyroid receptor subtypes in goldfish. Mol Cell Endocrinol. 2006;253:83-95 pubmed..The results provide a frame work for better understanding of the functional significance of novel TR forms and TR subtypes in fish and other vertebrates. ..
- Bahi L, Garnier A, Fortin D, Serrurier B, Veksler V, Bigard A, et al. Differential effects of thyroid hormones on energy metabolism of rat slow- and fast-twitch muscles. J Cell Physiol. 2005;203:589-98 pubmed
- Sadow P, Chassande O, Koo E, Gauthier K, Samarut J, Xu J, et al. Regulation of expression of thyroid hormone receptor isoforms and coactivators in liver and heart by thyroid hormone. Mol Cell Endocrinol. 2003;203:65-75 pubmed..We have demonstrated that TR isoforms and NCoAs are autoregulated transcription factors with tissue specificity. ..
- Guissouma H, Dupré S, Becker N, Jeannin E, Seugnet I, Desvergne B, et al. Feedback on hypothalamic TRH transcription is dependent on thyroid hormone receptor N terminus. Mol Endocrinol. 2002;16:1652-66 pubmed..Thus N-terminal sequences specify TR T(3)-dependent repression of TRH transcription but not DNA recognition, emphasizing as yet unknown neuron-specific contributions to protein-promoter interactions in vivo. ..