TABLE 2

TRβ

Receptor nomenclature NR1A2
Receptor code 4.10.1:TH:B1
Other names THRB, c-erbAβ
Molecular information Hs: 461aa, P10828, chr. 3p24.31
Rn: 461aa, P18113, chr. 15p162
Mm: 461aa, P37242, chr. 14 A33
DNA binding
   Structure Homodimer, heterodimer, RXR partner
   HRE core sequence AGGTCA (DR-4, palindrome)
Agonists TRIAC (20 pM), GC-1* (67 pM), T3 (81 pM), T4 (3 nM), reverse T3 (46 nM) [Kd]4–6
Antagonists NH3 (93 nM) [Kd]6
Coactivators NCOA1, NCOA2, NCOA3, PPARBP7–10
Corepressors NCOR1, NCOR211,12
Biologically important isoforms Trβ1 {Hs, Mm, Rn}: main isoform in most cases; Trβ2 {Hs, Mm, Rn}: alternative promoter usage, N-terminal variant13; Trβ3 {Rn}: alternative promoter usage and splicing14; TRδβ3 {Rn}: alternative promoter usage and splicing14
Tissue distribution Liver, heart, several brain areas {Hs, Mm, Rn} [Northern blot, Q-PCR]15
Functional assays Type 1 deiodinase expression in the liver {Mm}16
Main target genes Activated: Dio1 {Mm}16; repressed: Tshb {Mm}17
Mutant phenotype Deafness, color perception, elevated T3 level {Mm} [knockout]18–22; deafness, elevated T3 level, cerebellum development {Mm} [knockin]17,23,24; resistance to thyroid hormone {Mm} [point mutation]25
Human disease Resistance to thyroid hormones

  • aa, amino acids; chr., chromosome; Q-PCR, quantitative polymerase chain reaction; PPARBP, peroxisome proliferator-activated receptor binding protein

  • ↵* Radioligand

  • ↵1. Weinberger C, Thompson CC, Ong ES, Lebo R, Gruol DJ, and Evans RM (1986) The c-erb-A gene encodes a thyroid hormone receptor. Nature (Lond) 324: 641-646

  • ↵2. Thompson CC, Weinberger C, Lebo R, and Evans RM (1987) Identification of a novel thyroid hormone receptor expressed in the mammalian central nervous system. Science 237: 1610-1614

  • ↵3. Wood WM, Ocran KW, Gordon DF, and Ridgway EC (1991) Isolation and characterization of mouse complementary DNAs encoding alpha and beta thyroid hormone receptors from thyrotrope cells: the mouse pituitary-specific beta 2 isoform differs at the amino terminus from the corresponding species from rat pituitary tumor cells. Mol Endocrinol 5: 1049-1061

  • ↵4. Schueler PA, Schwartz HL, Strait KA, Mariash CN, and Oppenheimer JH (1990) Binding of 3,5,3′-triiodothyronine (T3) and its analogs to the in vitro translational products of c-erbA protooncogenes: differences in the affinity of the alpha- and beta-forms for the acetic acid analog and failure of the human testis and kidney alpha-2 products to bind T3. Mol Endocrinol 4: 227-234

  • ↵5. Sharma D and Fondell JD (2002) Ordered recruitment of histone acetyltransferases and the TRAP/Mediator complex to thyroid hormone-responsive promoters in vivo. Proc Natl Acad Sci USA 99: 7934-7939

  • ↵6. Nguyen NH, Apriletti JW, Cunha Lima ST, Webb P, Baxter JD, and Scanlan TS (2002) Rational design and synthesis of a novel thyroid hormone antagonist that blocks coactivator recruitment. J Med Chem 45: 3310-3320

  • ↵7. Nevado J, Tenbaum SP, and Aranda A (2004) hSrb7, an essential human Mediator component, acts as a coactivator for the thyroid hormone receptor. Mol Cell Endocrinol 222: 41-51

  • ↵8. Ma H, Hong H, Huang SM, Irvine RA, Webb P, Kushner PJ, Coetzee GA, and Stallcup MR (1999) Multiple signal input and output domains of the 160-kilodalton nuclear receptor coactivator proteins. Mol Cell Biol 19: 6164-6173

  • ↵9. Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, and Evans RM (1997) Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90: 569-580

  • ↵10. Ito M, Yuan CX, Okano HJ, Darnell RB, and Roeder RG (2000) Involvement of the TRAP220 component of the TRAP/SMCC coactivator complex in embryonic development and thyroid hormone action. Mol Cell 5: 683-693

  • ↵11. Chen JD and Evans RM (1995) A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature (Lond) 377: 454-457

  • ↵12. Horlein AJ, Naar AM, Heinzel T, Torchia J, Gloss B, Kurokawa R, Ryan A, Kamei Y, Soderstrom M, Glass CK, et al. (1995) Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature (Lond) 377: 397-404

  • ↵13. Lazar MA and Chin WW (1990) Nuclear thyroid hormone receptors. J Clin Investig 86: 1777-1782

  • ↵14. Williams GR (2000) Cloning and characterization of two novel thyroid hormone receptor beta isoforms. Mol Cell Biol 20: 8329-8342

  • ↵15. Iskaros J, Pickard M, Evans I, Sinha A, Hardiman P, and Ekins R (2000) Thyroid hormone receptor gene expression in first trimester human fetal brain. J Clin Endocrinol Metab 85: 2620-2623

  • ↵16. Zavacki AM, Ying H, Christoffolete MA, Aerts G, So E, Harney JW, Cheng SY, Larsen PR, and Bianco AC (2005) Type 1 iodothyronine deiodinase is a sensitive marker of peripheral thyroid status in the mouse. Endocrinology 146: 1568-1575

  • ↵17. Shibusawa N, Hollenberg AN, and Wondisford FE (2003) Thyroid hormone receptor DNA binding is required for both positive and negative gene regulation. J Biol Chem 278: 732-738

  • ↵18. Forrest D, Erway LC, Ng L, Altschuler R, and Curran T (1996) Thyroid hormone receptor beta is essential for development of auditory function. Nat Genet 13: 354-357

  • ↵19. Forrest D, Hanebuth E, Smeyne RJ, Everds N, Stewart CL, Wehner JM, and Curran T (1996) Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor beta: evidence for tissue-specific modulation of receptor function. EMBO (Eur Mol Biol Org) J 15: 3006-3015

  • ↵20. Gauthier K, Chassande O, Plateroti M, Roux JP, Legrand C, Pain B, Rousset B, Weiss R, Trouillas J, and Samarut J (1999) Different functions for the thyroid hormone receptors TRalpha and TRbeta in the control of thyroid hormone production and post-natal development. EMBO (Eur Mol Biol Org) J 18: 623-631

  • ↵21. Abel ED, Boers ME, Pazos-Moura C, Moura E, Kaulbach H, Zakaria M, Lowell B, Radovick S, Liberman MC, and Wondisford F (1999) Divergent roles for thyroid hormone receptor beta isoforms in the endocrine axis and auditory system. J Clin Investig 104: 291-300

  • ↵22. Ng L, Hurley JB, Dierks B, Srinivas M, Salto C, Vennstrom B, Reh TA, and Forrest D (2001) A thyroid hormone receptor that is required for the development of green cone photoreceptors. Nat Genet 27: 94-98

  • ↵23. Hashimoto K, Curty FH, Borges PP, Lee CE, Abel ED, Elmquist JK, Cohen RN, and Wondisford FE (2001) An unliganded thyroid hormone receptor causes severe neurological dysfunction. Proc Natl Acad Sci USA 98: 3998-4003

  • ↵24. Kaneshige M, Kaneshige K, Zhu X, Dace A, Garrett L, Carter TA, Kazlauskaite R, Pankratz DG, Wynshaw-Boris A, Refetoff S, et al. (2000) Mice with a targeted mutation in the thyroid hormone beta receptor gene exhibit impaired growth and resistance to thyroid hormone. Proc Natl Acad Sci USA 97: 13209-13214

  • ↵25. Weiss RE and Refetoff S (2000) Resistance to thyroid hormone. Rev Endocr Metab Disord 1: 97-108