Genomes and Genes
thyroid hormone receptors beta
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 THRB gene (also known as NR1A2, THRB1, or ERBA2 gene) as several isoforms produced by alternative splicing. Mutations in the THRB gene cause THYROID HORMONE RESISTANCE SYNDROME.
- Ferrara A, Onigata K, Ercan O, Woodhead H, Weiss R, Refetoff S. Homozygous thyroid hormone receptor ?-gene mutations in resistance to thyroid hormone: three new cases and review of the literature. J Clin Endocrinol Metab. 2012;97:1328-36 pubmed publisher..The most common cause of resistance to thyroid hormone (RTH) is heterozygous thyroid hormone receptor ? (THRB) gene mutations. Homozygous mutations in the THRB gene are a rare event...
- Fugier C, Tousaint J, Prieur X, Plateroti M, Samarut J, Delerive P. The lipoprotein lipase inhibitor ANGPTL3 is negatively regulated by thyroid hormone. J Biol Chem. 2006;281:11553-9 pubmed..Taken together, our results lead to the identification of ANGPTL3 as a novel TRbeta target gene and provide a new potential mechanism to explain the hypotriglyceridemic properties of TRbeta agonists in vivo. ..
- Johansson L, Rudling M, Scanlan T, Lundåsen T, Webb P, Baxter J, et al. Selective thyroid receptor modulation by GC-1 reduces serum lipids and stimulates steps of reverse cholesterol transport in euthyroid mice. Proc Natl Acad Sci U S A. 2005;102:10297-302 pubmed..Use of TRbeta and uptake selective agonists such as GC-1 should be further explored as a strategy to improve lipid metabolism in dyslipoproteinemia. ..
- Alberobello A, Congedo V, Liu H, Cochran C, Skarulis M, Forrest D, et al. An intronic SNP in the thyroid hormone receptor ? gene is associated with pituitary cell-specific over-expression of a mutant thyroid hormone receptor ?2 (R338W) in the index case of pituitary-selective resistance to thyroid hormone. J Transl Med. 2011;9:144 pubmed publisher..This case illustrates the role of regulatory regions in modifying the clinical presentation of genetic diseases. ..
- Figueira A, Dias S, Santos M, Apriletti J, Baxter J, Webb P, et al. Human thyroid receptor forms tetramers in solution, which dissociate into dimers upon ligand binding. Cell Biochem Biophys. 2006;44:453-62 pubmed
- Matsuse M, Saenko V, Sedliarou I, Rogounovitch T, Nakazawa Y, Mitsutake N, et al. A novel role for thyroid hormone receptor beta in cellular radiosensitivity. J Radiat Res. 2008;49:17-27 pubmed..Mutant THRB produced a radioprotective effect, attenuated radiation-induced growth inhibition and cellular senescence. The results suggest that THRB may modulate cellular radiosensitivity and stress-induced senescence. ..
- 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. ..
- 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. ..
- Li J, Ma M, Wang Z. A two-hybrid yeast assay to quantify the effects of xenobiotics on thyroid hormone-mediated gene expression. Environ Toxicol Chem. 2008;27:159-67 pubmed..The results are further evidence of thyroid-related effects of environmentally relevant PHAHs. ..
- Garcia Silva S, Martínez Iglesias O, Ruiz Llorente L, Aranda A. Thyroid hormone receptor ?1 domains responsible for the antagonism with the ras oncogene: role of corepressors. Oncogene. 2011;30:854-64 pubmed publisher..This shows an important functional role of endogenous corepressors in suppression of ras-mediated transformation and tumorigenesis by TR?1. ..
- 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
- Saelim N, Holstein D, Chocron E, Camacho P, Lechleiter J. Inhibition of apoptotic potency by ligand stimulated thyroid hormone receptors located in mitochondria. Apoptosis. 2007;12:1781-94 pubmed..We conclude that T3 acutely regulates cytochrome c release in a potential dependent manner by activating TRs located within mitochondria. ..
- Ornellas D, Gomes A, Santiago L, Novaira H, Ortiga Carvalho T, Morales M. Thyroid hormone beta receptor mutation causes renal dysfunction and impairment of ClC-2 chloride channel expression in mouse kidney. Cell Physiol Biochem. 2010;26:227-34 pubmed publisher..This work emphasizes the importance of thyroid hormone in electrolyte handling along the nephron and suggests its participation in renal ClC-2 gene transcription via the TR-beta receptor pathway. ..
- Moeller L, Haselhorst N, Dumitrescu A, Cao X, Seo H, Refetoff S, et al. Stanniocalcin 1 induction by thyroid hormone depends on thyroid hormone receptor Î² and phosphatidylinositol 3-kinase activation. Exp Clin Endocrinol Diabetes. 2011;119:81-5 pubmed publisher..These results establish STC1 as a TH target gene in humans. Furthermore, we show that STC1 induction by TH depends on both TRÎ² and PI3K activation. ..
- Yamauchi M, Kambe F, Cao X, Lu X, Kozaki Y, Oiso Y, et al. Thyroid hormone activates adenosine 5'-monophosphate-activated protein kinase via intracellular calcium mobilization and activation of calcium/calmodulin-dependent protein kinase kinase-beta. Mol Endocrinol. 2008;22:893-903 pubmed publisher..These results demonstrate that T3 nontranscriptionally activates AMPK via intracellular Ca2+ mobilization and CaMKKbeta activation, thereby stimulating mitochondrial fatty acid oxidation. ..
- 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. ..
- Iwamuro S, Yamada M, Kato M, Kikuyama S. Effects of bisphenol A on thyroid hormone-dependent up-regulation of thyroid hormone receptor alpha and beta and down-regulation of retinoid X receptor gamma in Xenopus tail culture. Life Sci. 2006;79:2165-71 pubmed
- Verga Falzacappa C, Mangialardo C, Raffa S, Mancuso A, Piergrossi P, Moriggi G, et al. The thyroid hormone T3 improves function and survival of rat pancreatic islets during in vitro culture. Islets. 2010;2:96-103 pubmed publisher..The strong increment shown in Akt activation suggests the involvement of this pathway in the observed phenomena. In conclusion we indicate T3 as a good factor to improve ex vivo islets cell culture. ..
- Kim J, Park T, Baek H, Kim G, Yoo H, Park J. A newly identified insertion mutation in the thyroid hormone receptor-beta gene in a Korean family with generalized thyroid hormone resistance. J Korean Med Sci. 2007;22:560-3 pubmed..This insertion mutation, specifically the insertion of a cytosine at nucleotide 1358 of the THRB gene, is, to the best of our knowledge, the first such mutation reported among RTH patients in Korea...
- Hashimoto K, Cohen R, Yamada M, Markan K, Monden T, Satoh T, et al. Cross-talk between thyroid hormone receptor and liver X receptor regulatory pathways is revealed in a thyroid hormone resistance mouse model. J Biol Chem. 2006;281:295-302 pubmed..Electromobility shift analysis revealed that LXR/RXR heterodimers bound to the DR+4 element in the presence of MUT but not WT TR-beta. A mechanism for cross-talk, and potential antagonism, between TR-beta and LXR-alpha is proposed. ..
- Ortiga Carvalho T, Shibusawa N, Nikrodhanond A, Oliveira K, Machado D, Liao X, et al. Negative regulation by thyroid hormone receptor requires an intact coactivator-binding surface. J Clin Invest. 2005;115:2517-23 pubmed..Therefore, the AF-2 domain of TR-beta is required for positive and, paradoxically, for negative regulation by TH in vivo. ..
- Weinhofer I, Kunze M, Rampler H, Forss Petter S, Samarut J, Plateroti M, et al. Distinct modulatory roles for thyroid hormone receptors TRalpha and TRbeta in SREBP1-activated ABCD2 expression. Eur J Cell Biol. 2008;87:933-45 pubmed publisher..These findings show that TRalpha and TRbeta differentially modulate SREBP1-activated ABCD2 expression at overlapping SRE/DR-4 elements, suggesting a novel mode of cross-talk between TR and SREBP in gene regulation. ..
- Ribeiro M. Effects of thyroid hormone analogs on lipid metabolism and thermogenesis. Thyroid. 2008;18:197-203 pubmed publisher..The available studies indicate that achieving selective activation of different TR-mediated pathways is a promising strategy for treating lipid disorders and obesity. ..
- Borngraeber S, Budny M, Chiellini G, Cunha Lima S, Togashi M, Webb P, et al. Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor. Proc Natl Acad Sci U S A. 2003;100:15358-63 pubmed..Our data suggest that increased specificity of ligand recognition derives from creating a new hydrophobic cluster with ligand and protein components. ..
- Krain L, Denver R. Developmental expression and hormonal regulation of glucocorticoid and thyroid hormone receptors during metamorphosis in Xenopus laevis. J Endocrinol. 2004;181:91-104 pubmed..laevis. The synergy of CORT with T(3) on tadpole tail resorption may depend on the accelerated accumulation of GR transcripts in this tissue during metamorphosis, which may be driven by rising plasma thyroid hormone titers. ..
- López Fontal R, Zeini M, Traves P, Gomez Ferreria M, Aranda A, Saez G, et al. Mice lacking thyroid hormone receptor Beta show enhanced apoptosis and delayed liver commitment for proliferation after partial hepatectomy. PLoS ONE. 2010;5:e8710 pubmed publisher..Taken together, these results indicate that TRbeta contributes significantly to the rapid initial round of hepatocyte proliferation following PH, and improves the survival of the regenerating liver at later times. ..
- 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, Xia X, Fondell J, Yen P. Thyroid hormone-regulated target genes have distinct patterns of coactivator recruitment and histone acetylation. Mol Endocrinol. 2006;20:483-90 pubmed..Our findings suggest that thyroid hormone-regulated target genes may have distinct patterns of coactivator recruitment and histone acetylation that may enable highly specific regulation. ..
- Hörkkö T, Tuppurainen K, George S, Jernvall P, Karttunen T, Mäkinen M. Thyroid hormone receptor beta1 in normal colon and colorectal cancer-association with differentiation, polypoid growth type and K-ras mutations. Int J Cancer. 2006;118:1653-9 pubmed
- 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...
- Roberts M, Srinivas M, Forrest D, Morreale de Escobar G, Reh T. Making the gradient: thyroid hormone regulates cone opsin expression in the developing mouse retina. Proc Natl Acad Sci U S A. 2006;103:6218-23 pubmed..These results also suggest that the ratio and patterning of cone types may be determined by TH availability during retinal development. ..
- Kim J, Choi E, Lee J, Lee K, Kim Y, Kim S, et al. Resistance to thyroid hormone with missense mutation (V349M) in the thyroid hormone receptor beta gene. Korean J Intern Med. 2008;23:45-8 pubmed..We report the first case of a woman with RTH, which was found to be caused by a missense mutation (V349M) in the TR beta gene...
- Frankton S, Harvey C, Gleason L, Fadel A, Williams G. Multiple messenger ribonucleic acid variants regulate cell-specific expression of human thyroid hormone receptor beta1. Mol Endocrinol. 2004;18:1631-42 pubmed
- Anselmo J, Refetoff S. Regression of a large goiter in a patient with resistance to thyroid hormone by every other day treatment with triiodothyronine. Thyroid. 2004;14:71-4 pubmed..The required dose of 250 microg suppressing TSH to values below 0.1 mU/L was derived by titration. Supraphysiological doses of L-T3 can be given safely as long-term treatment of goiter in patients RTH. ..
- Amorim B, Ueta C, Freitas B, Nassif R, Gouveia C, Christoffolete M, et al. A TRbeta-selective agonist confers resistance to diet-induced obesity. J Endocrinol. 2009;203:291-9 pubmed publisher..In conclusion, during high-fat feeding treatment with the TRbeta-selective agonist, GC-24 only partially improves metabolic control probably as a result of accelerating the resting metabolic rate. ..
- 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. ..
- Freitas F, Capelo L, O Shea P, Jorgetti V, Moriscot A, Scanlan T, et al. The thyroid hormone receptor beta-specific agonist GC-1 selectively affects the bone development of hypothyroid rats. J Bone Miner Res. 2005;20:294-304 pubmed..This finding suggests that TRbeta1 has an important role in bone development. ..
- 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. ..
- Kowalik M, Perra A, Pibiri M, Cocco M, Samarut J, Plateroti M, et al. TRbeta is the critical thyroid hormone receptor isoform in T3-induced proliferation of hepatocytes and pancreatic acinar cells. J Hepatol. 2010;53:686-92 pubmed publisher..The same isoform seems to also mediate the proliferation of mouse pancreatic acinar cells. ..
- Martínez Iglesias O, Garcia Silva S, Tenbaum S, Regadera J, Larcher F, Paramio J, et al. Thyroid hormone receptor beta1 acts as a potent suppressor of tumor invasiveness and metastasis. Cancer Res. 2009;69:501-9 pubmed publisher..These results define a novel role for the thyroid hormone receptor as a metastasis suppressor gene, providing a starting point for the development of novel therapeutic strategies for the treatment of human cancer. ..
- Roberts M, Hendrickson A, McGuire C, Reh T. Retinoid X receptor (gamma) is necessary to establish the S-opsin gradient in cone photoreceptors of the developing mouse retina. Invest Ophthalmol Vis Sci. 2005;46:2897-904 pubmed..These results demonstrate a critical role for RXRs in regulating cell differentiation in the CNS and highlight a remarkable conservation of opsin regulation from Drosophila to mammals. ..
- de Lange P, Feola A, Ragni M, Senese R, Moreno M, Lombardi A, et al. Differential 3,5,3'-triiodothyronine-mediated regulation of uncoupling protein 3 transcription: role of Fatty acids. Endocrinology. 2007;148:4064-72 pubmed..All promoters share a response element common to TR and PPAR (TRE 1), but the observed species differences may be attributable to different localizations of the MyoD response element, which in the rat maps to exon 1. ..
- Kojima H, Takeuchi S, Uramaru N, Sugihara K, Yoshida T, Kitamura S. Nuclear hormone receptor activity of polybrominated diphenyl ethers and their hydroxylated and methoxylated metabolites in transactivation assays using Chinese hamster ovary cells. Environ Health Perspect. 2009;117:1210-8 pubmed publisher
- Jones I, Ng L, Liu H, Forrest D. An intron control region differentially regulates expression of thyroid hormone receptor beta2 in the cochlea, pituitary, and cone photoreceptors. Mol Endocrinol. 2007;21:1108-19 pubmed..This specialized genomic organization underlies the unique expression pattern and functions of TRbeta2. ..
- Manzano J, Morte B, Scanlan T, Bernal J. Differential effects of triiodothyronine and the thyroid hormone receptor beta-specific agonist GC-1 on thyroid hormone target genes in the b ain. Endocrinology. 2003;144:5480-7 pubmed..However, in the caudate, RC3 and Rhes are expressed in the same cells, and therefore, they may represent specific gene responses linked to specific thyroid hormone receptor isoforms. ..
- Swanson E, Gloss B, Belke D, Kaneshige M, Cheng S, Dillmann W. Cardiac expression and function of thyroid hormone receptor beta and its PV mutant. Endocrinology. 2003;144:4820-5 pubmed..In summary, although TR beta is expressed at much lower levels in all regions of the heart than TR alpha 1, expression of the strong dominant negative TR beta PV mutant results in decreased contractile function and heart rate. ..
- Iwamuro S, Sakakibara M, Terao M, Ozawa A, Kurobe C, Shigeura T, et al. Teratogenic and anti-metamorphic effects of bisphenol A on embryonic and larval Xenopus laevis. Gen Comp Endocrinol. 2003;133:189-98 pubmed..Furthermore, BPA suppressed thyroid hormone receptor (TR) beta gene expression both in vivo and in vitro. Thus, we concluded that BPA at the concentrations examined affects both embryonic development and larval metamorphosis. ..
- Lazar M. Thyroid hormone action: a binding contract. J Clin Invest. 2003;112:497-9 pubmed
- Suzuki H, Willingham M, Cheng S. Mice with a mutation in the thyroid hormone receptor beta gene spontaneously develop thyroid carcinoma: a mouse model of thyroid carcinogenesis. Thyroid. 2002;12:963-9 pubmed
- Crump D, Werry K, Veldhoen N, Van Aggelen G, Helbing C. Exposure to the herbicide acetochlor alters thyroid hormone-dependent gene expression and metamorphosis in Xenopus Laevis. Environ Health Perspect. 2002;110:1199-205 pubmed..The morphologic changes observed are preceded by alterations in gene expression profiles detected in the tadpole tail, and the nature of these profiles suggest a novel mechanism of action for acetochlor...
- Sadow P, Chassande O, Gauthier K, Samarut J, Xu J, O Malley B, et al. Specificity of thyroid hormone receptor subtype and steroid receptor coactivator-1 on thyroid hormone action. Am J Physiol Endocrinol Metab. 2003;284:E36-46 pubmed
- Puzianowska Kuznicka M, Krystyniak A, Madej A, Cheng S, Nauman J. Functionally impaired TR mutants are present in thyroid papillary cancer. J Clin Endocrinol Metab. 2002;87:1120-8 pubmed..These findings suggest a possible role for mutated thyroid hormone receptors in the tumorigenesis of human papillary thyroid carcinoma. ..
- Kamiya Y, Zhang X, Ying H, Kato Y, Willingham M, Xu J, et al. Modulation by steroid receptor coactivator-1 of target-tissue responsiveness in resistance to thyroid hormone. Endocrinology. 2003;144:4144-53 pubmed..Thus, the present studies show that a coactivator such as SRC-1 could modulate the in vivo action of TR beta mutants in a tissue-dependent manner. ..
- Geistlinger T, Guy R. Novel selective inhibitors of the interaction of individual nuclear hormone receptors with a mutually shared steroid receptor coactivator 2. J Am Chem Soc. 2003;125:6852-3 pubmed..These compounds represent the first family-member-selective competitive inhibitors of the protein interactions of transcription factors. ..