Thyroid hormone receptor alpha explained

Thyroid hormone receptor alpha (TR-alpha) also known as nuclear receptor subfamily 1, group A, member 1 (NR1A1), is a nuclear receptor protein that in humans is encoded by the THRA gene.^{[1] [2] [3]}

Function

The protein encoded by this gene is a nuclear hormone receptor for triiodothyronine. 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. Alternatively spliced transcript variants encoding distinct isoforms have been reported.^[4]

Role in pathology

Mutations of the THRA gene may cause nongoitrous congenital hypothyroidism-6, a subtype of congenital hypothyroidism.

Interactions

THR1 has been shown to interact with:

• COPS2,^[5]
• EP300,
• ITGB3BP,^{[6] [7]}
• MED1,^[8]
• MED6,
• MED12,
• MED16,^[9]
• MEF2A,^[10]
• NCOA6,^{[11] [12]}
• TRIP11,^[13] and
• UBC.^[14]

Further reading

• Forrest D, Reh TA, Rüsch A . Neurodevelopmental control by thyroid hormone receptors . Current Opinion in Neurobiology . 12 . 1 . 49–56 . Feb 2002 . 11861164 . 10.1016/S0959-4388(02)00289-1 . 2884828 .
• Sakurai A, Bell GI, DeGroot LJ . Dinucleotide repeat polymorphism in the human thyroid hormone receptor alpha gene (THRA1) on chromosome 17 . Human Molecular Genetics . 1 . 7 . 553 . Oct 1992 . 1307263 . 10.1093/hmg/1.7.553-a .
• Berrodin TJ, Marks MS, Ozato K, Linney E, Lazar MA . Heterodimerization among thyroid hormone receptor, retinoic acid receptor, retinoid X receptor, chicken ovalbumin upstream promoter transcription factor, and an endogenous liver protein . Molecular Endocrinology . 6 . 9 . 1468–78 . Sep 1992 . 10.1210/mend.6.9.1331778 . 1331778 . 24291055 . free .
• 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 . The Journal of Endocrinology . 133 . 1 . 67–74 . Apr 1992 . 1517709 . 10.1677/joe.0.1330067 .
• Yen PM, Sunday ME, Darling DS, Chin WW . Isoform-specific thyroid hormone receptor antibodies detect multiple thyroid hormone receptors in rat and human pituitaries . Endocrinology . 130 . 3 . 1539–46 . Mar 1992 . 10.1210/endo.130.3.1537303 . 1537303 .
• Laudet V, Begue A, Henry-Duthoit C, Joubel A, Martin P, Stehelin D, Saule S . Genomic organization of the human thyroid hormone receptor alpha (c-erbA-1) gene . Nucleic Acids Research . 19 . 5 . 1105–12 . Mar 1991 . 1850510 . 333788 . 10.1093/nar/19.5.1105 .
• Nakai A, Sakurai A, Bell GI, DeGroot LJ . Characterization of a third human thyroid hormone receptor coexpressed with other thyroid hormone receptors in several tissues . Molecular Endocrinology . 2 . 11 . 1087–92 . Nov 1988 . 2464749 . 10.1210/mend-2-11-1087 . free .
• Miyajima N, Horiuchi R, Shibuya Y, Fukushige S, Matsubara K, Toyoshima K, Yamamoto T . Two erbA homologs encoding proteins with different T3 binding capacities are transcribed from opposite DNA strands of the same genetic locus . Cell . 57 . 1 . 31–9 . Apr 1989 . 2539258 . 10.1016/0092-8674(89)90169-4 . 19135678 .
• Sakurai A, Nakai A, DeGroot LJ . Expression of three forms of thyroid hormone receptor in human tissues . Molecular Endocrinology . 3 . 2 . 392–9 . Feb 1989 . 2710139 . 10.1210/mend-3-2-392 . free .
• Sap J, Muñoz A, Damm K, Goldberg Y, Ghysdael J, Leutz A, Beug H, Vennström B . The c-erb-A protein is a high-affinity receptor for thyroid hormone . Nature . 324 . 6098 . 635–40 . 1987 . 2879242 . 10.1038/324635a0 . 4353175 .
• Nakai A, Seino S, Sakurai A, Szilak I, Bell GI, DeGroot LJ . Characterization of a thyroid hormone receptor expressed in human kidney and other tissues . Proceedings of the National Academy of Sciences of the United States of America . 85 . 8 . 2781–5 . Apr 1988 . 3357890 . 280083 . 10.1073/pnas.85.8.2781 . 1988PNAS...85.2781N . free .
• Mitelman F, Manolov G, Manolova Y, Billström R, Heim S, Kristoffersson U, Mandahl N, Ferro MT, San Roman C . High resolution chromosome analysis of constitutional and acquired t(15;17) maps c-erbA to subband 17q11.2 . Cancer Genetics and Cytogenetics . 22 . 2 . 95–8 . Jun 1986 . 3458521 . 10.1016/0165-4608(86)90168-8 .
• Benbrook D, Pfahl M . A novel thyroid hormone receptor encoded by a cDNA clone from a human testis library . Science . 238 . 4828 . 788–91 . Nov 1987 . 3672126 . 10.1126/science.3672126 . 1987Sci...238..788B .
• Pfahl M, Benbrook D . Nucleotide sequence of cDNA encoding a novel human thyroid hormone receptor . Nucleic Acids Research . 15 . 22 . 9613 . Nov 1987 . 3684612 . 306505 . 10.1093/nar/15.22.9613 .
• Chen JD, Evans RM . A transcriptional co-repressor that interacts with nuclear hormone receptors . Nature . 377 . 6548 . 454–7 . Oct 1995 . 7566127 . 10.1038/377454a0 . 1995Natur.377..454C . 4361329 .
• Desai-Yajnik V, Hadzic E, Modlinger P, Malhotra S, Gechlik G, Samuels HH . Interactions of thyroid hormone receptor with the human immunodeficiency virus type 1 (HIV-1) long terminal repeat and the HIV-1 Tat transactivator . Journal of Virology . 69 . 8 . 5103–12 . Aug 1995 . 7609079 . 189328 . 10.1128/JVI.69.8.5103-5112.1995.
• Lee JW, Choi HS, Gyuris J, Brent R, Moore DD . Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor . Molecular Endocrinology . 9 . 2 . 243–54 . Feb 1995 . 10.1210/mend.9.2.7776974 . 7776974 . free .
• Desai-Yajnik V, Samuels HH . Regulation of the human immunodeficiency virus type 1 long terminal repeat: interactions of thyroid hormone receptor with retinoid-X receptor, nuclear factor kappa B, Sp1, and Tat . Transactions of the Association of American Physicians . 106 . 13–32 . 1994 . 8036737 .

Notes and References

1. Web site: Entrez Gene: THRA thyroid hormone receptor, alpha (erythroblastic leukemia viral (v-erb-a) oncogene homolog, avian).
2. Spurr NK, Solomon E, Jansson M, Sheer D, Goodfellow PN, Bodmer WF, Vennstrom B . Chromosomal localisation of the human homologues to the oncogenes erbA and B . The EMBO Journal . 3 . 1 . 159–63 . Jan 1984 . 6323162 . 557313 . 10.1002/j.1460-2075.1984.tb01777.x.
3. Dayton AI, Selden JR, Laws G, Dorney DJ, Finan J, Tripputi P, Emanuel BS, Rovera G, Nowell PC, Croce CM . A human c-erbA oncogene homologue is closely proximal to the chromosome 17 breakpoint in acute promyelocytic leukemia . Proceedings of the National Academy of Sciences of the United States of America . 81 . 14 . 4495–9 . Jul 1984 . 6589608 . 345617 . 10.1073/pnas.81.14.4495 . 1984PNAS...81.4495D . free .
4. Web site: Entrez Gene: THRA thyroid hormone receptor, alpha (erythroblastic leukemia viral (v-erb-a) oncogene homolog, avian).
5. Dressel U, Thormeyer D, Altincicek B, Paululat A, Eggert M, Schneider S, Tenbaum SP, Renkawitz R, Baniahmad A . Alien, a highly conserved protein with characteristics of a corepressor for members of the nuclear hormone receptor superfamily . Molecular and Cellular Biology . 19 . 5 . 3383–94 . May 1999 . 10207062 . 84131 . 10.1128/mcb.19.5.3383.
6. Li D, Wang F, Samuels HH . Domain structure of the NRIF3 family of coregulators suggests potential dual roles in transcriptional regulation . Molecular and Cellular Biology . 21 . 24 . 8371–84 . Dec 2001 . 11713274 . 100002 . 10.1128/MCB.21.24.8371-8384.2001 .
7. Li D, Desai-Yajnik V, Lo E, Schapira M, Abagyan R, Samuels HH . NRIF3 is a novel coactivator mediating functional specificity of nuclear hormone receptors . Molecular and Cellular Biology . 19 . 10 . 7191–202 . Oct 1999 . 10490654 . 84712 . 10.1128/mcb.19.10.7191.
8. Yuan CX, Ito M, Fondell JD, Fu ZY, Roeder RG . The TRAP220 component of a thyroid hormone receptor- associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion . Proceedings of the National Academy of Sciences of the United States of America . 95 . 14 . 7939–44 . Jul 1998 . 9653119 . 20908 . 10.1073/pnas.95.14.7939 . 1998PNAS...95.7939Y . free .
9. Ito M, Yuan CX, Malik S, Gu W, Fondell JD, Yamamura S, Fu ZY, Zhang X, Qin J, Roeder RG . Identity between TRAP and SMCC complexes indicates novel pathways for the function of nuclear receptors and diverse mammalian activators . Molecular Cell . 3 . 3 . 361–70 . Mar 1999 . 10198638 . 10.1016/S1097-2765(00)80463-3 . free .
10. De Luca A, Severino A, De Paolis P, Cottone G, De Luca L, De Falco M, Porcellini A, Volpe M, Condorelli G . p300/cAMP-response-element-binding-protein ('CREB')-binding protein (CBP) modulates co-operation between myocyte enhancer factor 2A (MEF2A) and thyroid hormone receptor-retinoid X receptor . The Biochemical Journal . 369 . Pt 3 . 477–84 . Feb 2003 . 12371907 . 1223100 . 10.1042/BJ20020057 .
11. 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 . The Journal of Biological Chemistry . 274 . 48 . 34283–93 . Nov 1999 . 10567404 . 10.1074/jbc.274.48.34283 . free .
12. Lee SK, Na SY, Jung SY, Choi JE, Jhun BH, Cheong J, Meltzer PS, Lee YC, Lee JW . Activating protein-1, nuclear factor-kappaB, and serum response factor as novel target molecules of the cancer-amplified transcription coactivator ASC-2 . Molecular Endocrinology . 14 . 6 . 915–25 . Jun 2000 . 10847592 . 10.1210/mend.14.6.0471 . free .
13. Chang KH, Chen Y, Chen TT, Chou WH, Chen PL, Ma YY, Yang-Feng TL, Leng X, Tsai MJ, O'Malley BW, Lee WH . Ming-Jer Tsai . A thyroid hormone receptor coactivator negatively regulated by the retinoblastoma protein . Proceedings of the National Academy of Sciences of the United States of America . 94 . 17 . 9040–5 . Aug 1997 . 9256431 . 23019 . 10.1073/pnas.94.17.9040 . 1997PNAS...94.9040C . free .
14. Tan F, Lu L, Cai Y, Wang J, Xie Y, Wang L, Gong Y, Xu BE, Wu J, Luo Y, Qiang B, Yuan J, Sun X, Peng X . Proteomic analysis of ubiquitinated proteins in normal hepatocyte cell line Chang liver cells . Proteomics . 8 . 14 . 2885–96 . Jul 2008 . 18655026 . 10.1002/pmic.200700887 . 25586938 .