Thyroid hormone receptor beta explained

Thyroid hormone receptor beta (TR-beta) also known as nuclear receptor subfamily 1, group A, member 2 (NR1A2), is a nuclear receptor protein that in humans is encoded by the THRB gene.^{[1] [2]}

Function

The protein encoded by this gene is a nuclear hormone receptor for triiodothyronine (T₃). It is one of the several receptors for thyroid hormone, and has been shown to mediate the biological activities of thyroid hormone. Knockout studies in mice suggest that the different receptors, while having certain extent of redundancy, may mediate different functions of thyroid hormone. Defects in this gene are known to be a cause of generalized thyroid hormone resistance (GTHR), a syndrome characterized by goiter and high levels of circulating thyroid hormone (T₃-T₄), with normal or slightly elevated thyroid stimulating hormone (TSH). Several transcript variants have been observed for this gene, but the full-length nature of only one has been observed so far.^[3]

Interactions

Thyroid hormone receptor beta has been shown to interact with:

• BRD8,^[4]
• CCND1,^[5]
• NCOA1,^{[6] [7]}
• NCOA6,^{[8] [9] [10] [11]}
• NCOR2,^{[6] [12] [13]}
• NR2F6,^[14]
• PPARGC1A,^[15] and
• RXRA.^{[4] [7]}

Further reading

• Lazar MA, Chin WW . Nuclear thyroid hormone receptors . J. Clin. Invest. . 86 . 6 . 1777–82 . 1990 . 2254444 . 329808 . 10.1172/JCI114906 .
• Forrest D, Reh TA, Rüsch A . Neurodevelopmental control by thyroid hormone receptors . Curr. Opin. Neurobiol. . 12 . 1 . 49–56 . 2002 . 11861164 . 10.1016/S0959-4388(02)00289-1 . 2884828 .
• González-Sancho JM, García V, Bonilla F, Muñoz A . Thyroid hormone receptors/THR genes in human cancer . Cancer Lett. . 192 . 2 . 121–32 . 2003 . 12668276 . 10.1016/S0304-3835(02)00614-6 .
• Cugini CD, Leidy JW, Chertow BS, Bérard J, Bradley WE, Menke JB, Hao EH, Usala SJ . An arginine to histidine mutation in codon 315 of the c-erbA beta thyroid hormone receptor in a kindred with generalized resistance to thyroid hormones results in a receptor with significant 3,5,3'-triiodothyronine binding activity . J. Clin. Endocrinol. Metab. . 74 . 5 . 1164–70 . 1992 . 10.1210/jcem.74.5.1314846 . 1314846 .
• Behr M, Loos U . A point mutation (Ala229 to Thr) in the hinge domain of the c-erbA beta thyroid hormone receptor gene in a family with generalized thyroid hormone resistance . Mol. Endocrinol. . 6 . 7 . 1119–26 . 1992 . 10.1210/mend.6.7.1324420 . 1324420 . free .
• Falcone M, Miyamoto T, Fierro-Renoy F, Macchia E, DeGroot LJ . Antipeptide polyclonal antibodies specifically recognize each human thyroid hormone receptor isoform . Endocrinology . 131 . 5 . 2419–29 . 1992 . 1425440 . 10.1210/endo.131.5.1425440 .
• Schmidt ED, Schmidt ED, van der Gaag R, Ganpat R, Broersma L, de Boer PA, Moorman AF, Lamers WH, Wiersinga WM, Koornneef L . Distribution of the nuclear thyroid-hormone receptor in extraocular and skeletal muscles . J. Endocrinol. . 133 . 1 . 67–74 . 1992 . 1517709 . 10.1677/joe.0.1330067 .
• Adams M, Nagaya T, Tone Y, Jameson JL, Chatterjee VK . Functional properties of a novel mutant thyroid hormone receptor in a family with generalized thyroid hormone resistance syndrome . Clin. Endocrinol. . 36 . 3 . 281–9 . 1992 . 1563081 . 10.1111/j.1365-2265.1992.tb01444.x . 25897422 .
• Sasaki S, Nakamura H, Tagami T, Miyoshi Y, Tanaka K, Imura H . A point mutation of the T3 receptor beta 1 gene in a kindred of generalized resistance to thyroid hormone . Mol. Cell. Endocrinol. . 84 . 3 . 159–66 . 1992 . 1587388 . 10.1016/0303-7207(92)90026-3 . 24853283 .
• Nagaya T, Madison LD, Jameson JL . Thyroid hormone receptor mutants that cause resistance to thyroid hormone. Evidence for receptor competition for DNA sequences in target genes . J. Biol. Chem. . 267 . 18 . 13014–9 . 1992 . 10.1016/S0021-9258(18)42375-7 . 1618799 . free .
• Shuto Y, Wakabayashi I, Amuro N, Minami S, Okazaki T . A point mutation in the 3,5,3'-triiodothyronine-binding domain of thyroid hormone receptor-beta associated with a family with generalized resistance to thyroid hormone . J. Clin. Endocrinol. Metab. . 75 . 1 . 213–7 . 1992 . 10.1210/jcem.75.1.1619012 . 1619012 .
• Näär AM, Boutin JM, Lipkin SM, Yu VC, Holloway JM, Glass CK, Rosenfeld MG . The orientation and spacing of core DNA-binding motifs dictate selective transcriptional responses to three nuclear receptors . Cell . 65 . 7 . 1267–79 . 1991 . 1648451 . 10.1016/0092-8674(91)90021-P . 22572347 .
• Usala SJ, Menke JB, Watson TL, Wondisford FE, Weintraub BD, Bérard J, Bradley WE, Ono S, Mueller OT, Bercu BB . A homozygous deletion in the c-erbA beta thyroid hormone receptor gene in a patient with generalized thyroid hormone resistance: isolation and characterization of the mutant receptor . Mol. Endocrinol. . 5 . 3 . 327–35 . 1991 . 1653889 . 10.1210/mend-5-3-327 . free .
• Bodenner DL, Mroczynski MA, Weintraub BD, Radovick S, Wondisford FE . A detailed functional and structural analysis of a major thyroid hormone inhibitory element in the human thyrotropin beta-subunit gene . J. Biol. Chem. . 266 . 32 . 21666–73 . 1991 . 10.1016/S0021-9258(18)54688-3 . 1657975 . free .
• Parrilla R, Mixson AJ, McPherson JA, McClaskey JH, Weintraub BD . Characterization of seven novel mutations of the c-erbA beta gene in unrelated kindreds with generalized thyroid hormone resistance. Evidence for two "hot spot" regions of the ligand binding domain . J. Clin. Invest. . 88 . 6 . 2123–30 . 1991 . 1661299 . 295818 . 10.1172/JCI115542 .
• Usala SJ, Menke JB, Watson TL, Bérard WE, Bradley C, Bale AE, Lash RW, Weintraub BD . A new point mutation in the 3,5,3'-triiodothyronine-binding domain of the c-erbA beta thyroid hormone receptor is tightly linked to generalized thyroid hormone resistance . J. Clin. Endocrinol. Metab. . 72 . 1 . 32–8 . 1991 . 1846005 . 10.1210/jcem-72-1-32 .
• Usala SJ, Tennyson GE, Bale AE, Lash RW, Gesundheit N, Wondisford FE, Accili D, Hauser P, Weintraub BD . A base mutation of the C-erbA beta thyroid hormone receptor in a kindred with generalized thyroid hormone resistance. Molecular heterogeneity in two other kindreds . J. Clin. Invest. . 85 . 1 . 93–100 . 1990 . 2153155 . 296391 . 10.1172/JCI114438 .
• Sakurai A, Takeda K, Ain K, Ceccarelli P, Nakai A, Seino S, Bell GI, Refetoff S, DeGroot LJ . Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor beta . Proc. Natl. Acad. Sci. U.S.A. . 86 . 22 . 8977–81 . 1989 . 2510172 . 298414 . 10.1073/pnas.86.22.8977 . 1989PNAS...86.8977S . free .

Notes and References

1. Web site: Entrez Gene: THRA thyroid hormone receptor, alpha (erythroblastic leukemia viral (v-erb-a) oncogene homolog, avian).
2. Sakurai A, Nakai A, DeGroot LJ . Structural analysis of human thyroid hormone receptor beta gene . Mol. Cell. Endocrinol. . 71 . 2 . 83–91 . June 1990 . 1973914 . 10.1016/0303-7207(90)90245-4 . 54389426 .
3. Web site: Entrez Gene: THRB thyroid hormone receptor, beta (erythroblastic leukemia viral (v-erb-a) oncogene homolog 2, avian).
4. Monden T, Wondisford FE, Hollenberg AN . Isolation and characterization of a novel ligand-dependent thyroid hormone receptor-coactivating protein . J. Biol. Chem. . 272 . 47 . 29834–41 . November 1997 . 9368056 . 10.1074/jbc.272.47.29834 . free .
5. Lin HM, Zhao L, Cheng SY . Cyclin D1 Is a Ligand-independent Co-repressor for Thyroid Hormone Receptors . J. Biol. Chem. . 277 . 32 . 28733–41 . August 2002 . 12048199 . 10.1074/jbc.M203380200 . free .
6. Liu Y, Takeshita A, Misiti S, Chin WW, Yen PM . Lack of coactivator interaction can be a mechanism for dominant negative activity by mutant thyroid hormone receptors . Endocrinology . 139 . 10 . 4197–204 . October 1998 . 9751500 . 10.1210/endo.139.10.6218 .
7. Jeyakumar M, Tanen MR, Bagchi MK . Analysis of the functional role of steroid receptor coactivator-1 in ligand-induced transactivation by thyroid hormone receptor . Mol. Endocrinol. . 11 . 6 . 755–67 . June 1997 . 9171239 . 10.1210/mend.11.6.0003 . free .
8. Lee SK, Jung SY, Kim YS, Na SY, Lee YC, Lee JW . Two distinct nuclear receptor-interaction domains and CREB-binding protein-dependent transactivation function of activating signal cointegrator-2 . Mol. Endocrinol. . 15 . 2 . 241–54 . February 2001 . 11158331 . 10.1210/mend.15.2.0595 . free .
9. Lee SK, Anzick SL, Choi JE, Bubendorf L, Guan XY, Jung YK, Kallioniemi OP, Kononen J, Trent JM, Azorsa D, Jhun BH, Cheong JH, Lee YC, Meltzer PS, Lee JW . A nuclear factor, ASC-2, as a cancer-amplified transcriptional coactivator essential for ligand-dependent transactivation by nuclear receptors in vivo . J. Biol. Chem. . 274 . 48 . 34283–93 . November 1999 . 10567404 . 10.1074/jbc.274.48.34283 . free .
10. Ko L, Cardona GR, Chin WW . Thyroid hormone receptor-binding protein, an LXXLL motif-containing protein, functions as a general coactivator . Proc. Natl. Acad. Sci. U.S.A. . 97 . 11 . 6212–7 . May 2000 . 10823961 . 18584 . 10.1073/pnas.97.11.6212 . 2000PNAS...97.6212K . free .
11. Ko L, Cardona GR, Iwasaki T, Bramlett KS, Burris TP, Chin WW . Ser-884 adjacent to the LXXLL motif of coactivator TRBP defines selectivity for ERs and TRs . Mol. Endocrinol. . 16 . 1 . 128–40 . January 2002 . 11773444 . 10.1210/mend.16.1.0755 . free .
12. Tagami T, Lutz WH, Kumar R, Jameson JL . The interaction of the vitamin D receptor with nuclear receptor corepressors and coactivators . Biochem. Biophys. Res. Commun. . 253 . 2 . 358–63 . December 1998 . 9878542 . 10.1006/bbrc.1998.9799 .
13. Ando S, Sarlis NJ, Krishnan J, Feng X, Refetoff S, Zhang MQ, Oldfield EH, Yen PM . Aberrant alternative splicing of thyroid hormone receptor in a TSH-secreting pituitary tumor is a mechanism for hormone resistance . Mol. Endocrinol. . 15 . 9 . 1529–38 . September 2001 . 11518802 . 10.1210/mend.15.9.0687 . free .
14. Zhu XG, Park KS, Kaneshige M, Bhat MK, Zhu Q, Mariash CN, McPhie P, Cheng SY . The orphan nuclear receptor Ear-2 is a negative coregulator for thyroid hormone nuclear receptor function . Mol. Cell. Biol. . 20 . 7 . 2604–18 . April 2000 . 10713182 . 85476 . 10.1128/MCB.20.7.2604-2618.2000 .
15. Wu Y, Delerive P, Chin WW, Burris TP . Requirement of helix 1 and the AF-2 domain of the thyroid hormone receptor for coactivation by PGC-1 . J. Biol. Chem. . 277 . 11 . 8898–905 . March 2002 . 11751919 . 10.1074/jbc.M110761200 . free .