Nuclear receptor co-repressor 1 explained

The nuclear receptor co-repressor 1 also known as thyroid-hormone- and retinoic-acid-receptor-associated co-repressor 1 (TRAC-1) is a protein that in humans is encoded by the NCOR1 gene.^{[1] [2]}

NCOR1 is a transcriptional coregulatory protein which contains several nuclear receptor interacting domains. In addition, NCOR1 appears to recruit histone deacetylases to DNA promoter regions. Hence NCOR1 assists nuclear receptors in the downregulation of gene expression.^{[1] [3]}

Loss of function of this protein significantly increases the strength and power of mouse muscles.^[4]

Family

It is a member of the family of nuclear receptor corepressors; the other human protein that is a member of that family is Nuclear receptor co-repressor 2.^[5]

Interactions

Nuclear receptor co-repressor 1 has been shown to interact with:

• Androgen receptor,^{[6] [7] [8] [9]}
• CHD1,^[10]
• Calcitriol receptor^{[11] [12]}
• GPS2,
• Glucocorticoid receptor,^{[13] [14]}
• HDAC3,^{[15] [16]}
• HDAC4,^[15]
• HDAC7A,^[17]
• HDAC9,^[18]
• HEY2,^[19]
• Histone deacetylase 5,^{[20] [21]}
• MAP3K7IP2,^[22]
• MECP2,^[23]
• Peroxisome proliferator-activated receptor alpha,^[24]
• Peroxisome proliferator-activated receptor gamma
• Promyelocytic leukemia protein,^[25]
• RUNX1T1,^{[26] [27]}
• Retinoic acid receptor alpha,^{[24] [28]}
• Retinoic acid receptor gamma,^[24]
• SAP30,^{[16] [29]}
• TBL1XR1,^{[20] [30] [31]}
• TBL1X,^{[20] [31] [32] [33]} and
• ZBTB33.^[30]

Further reading

• Minucci S, Pelicci PG . Retinoid receptors in health and disease: co-regulators and the chromatin connection. . Semin. Cell Dev. Biol. . 10 . 2 . 215–25 . 1999 . 10441075 . 10.1006/scdb.1999.0303 .
• Downes M, Burke LJ, Bailey PJ, Muscat GE . Two receptor interaction domains in the corepressor, N-CoR/RIP13, are required for an efficient interaction with Rev-erbA alpha and RVR: physical association is dependent on the E region of the orphan receptors. . Nucleic Acids Res. . 24 . 22 . 4379–86 . 1997 . 8948627 . 146280 . 10.1093/nar/24.22.4379 .
• Tagami T, Madison LD, Nagaya T, Jameson JL . Nuclear receptor corepressors activate rather than suppress basal transcription of genes that are negatively regulated by thyroid hormone. . Mol. Cell. Biol. . 17 . 5 . 2642–8 . 1997 . 9111334 . 232114 . 10.1128/mcb.17.5.2642.
• Zamir I, Dawson J, Lavinsky RM, Glass CK, Rosenfeld MG, Lazar MA . Cloning and characterization of a corepressor and potential component of the nuclear hormone receptor repression complex. . Proc. Natl. Acad. Sci. U.S.A. . 94 . 26 . 14400–5 . 1998 . 9405624 . 24996 . 10.1073/pnas.94.26.14400 . free .
• Burke LJ, Downes M, Laudet V, Muscat GE . Identification and characterization of a novel corepressor interaction region in RVR and Rev-erbA alpha. . Mol. Endocrinol. . 12 . 2 . 248–62 . 1998 . 10.1210/mend.12.2.0061 . 9482666 . free .
• Guidez F, Ivins S, Zhu J, Söderström M, Waxman S, Zelent A . Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. . Blood . 91 . 8 . 2634–42 . 1998 . 9531570 . 10.1182/blood.V91.8.2634.2634_2634_2642. free .
• Kao HY, Ordentlich P, Koyano-Nakagawa N, Tang Z, Downes M, Kintner CR, Evans RM, Kadesch T . A histone deacetylase corepressor complex regulates the Notch signal transduction pathway. . Genes Dev. . 12 . 15 . 2269–77 . 1998 . 9694793 . 317043 . 10.1101/gad.12.15.2269 .
• Laherty CD, Billin AN, Lavinsky RM, Yochum GS, Bush AC, Sun JM, Mullen TM, Davie JR, Rose DW, Glass CK, Rosenfeld MG, Ayer DE, Eisenman RN . SAP30, a component of the mSin3 corepressor complex involved in N-CoR-mediated repression by specific transcription factors. . Mol. Cell . 2 . 1 . 33–42 . 1998 . 9702189 . 10.1016/S1097-2765(00)80111-2 . free .
• Wang J, Hoshino T, Redner RL, Kajigaya S, Liu JM . ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex. . Proc. Natl. Acad. Sci. U.S.A. . 95 . 18 . 10860–5 . 1998 . 9724795 . 27986 . 10.1073/pnas.95.18.10860 . 1998PNAS...9510860W . free .
• Ordentlich P, Downes M, Xie W, Genin A, Spinner NB, Evans RM . Unique forms of human and mouse nuclear receptor corepressor SMRT. . Proc. Natl. Acad. Sci. U.S.A. . 96 . 6 . 2639–44 . 1999 . 10077563 . 15821 . 10.1073/pnas.96.6.2639 . 1999PNAS...96.2639O . free .
• Dowell P, Ishmael JE, Avram D, Peterson VJ, Nevrivy DJ, Leid M . Identification of nuclear receptor corepressor as a peroxisome proliferator-activated receptor alpha interacting protein. . J. Biol. Chem. . 274 . 22 . 15901–7 . 1999 . 10336495 . 10.1074/jbc.274.22.15901 . free .
• Boutell JM, Thomas P, Neal JW, Weston VJ, Duce J, Harper PS, Jones AL . Aberrant interactions of transcriptional repressor proteins with the Huntington's disease gene product, huntingtin. . Hum. Mol. Genet. . 8 . 9 . 1647–55 . 2000 . 10441327 . 10.1093/hmg/8.9.1647 . free .
• Nagaya T, Chen KS, Fujieda M, Ohmori S, Richer JK, Horwitz KB, Lupski JR, Seo H . Localization of the human nuclear receptor corepressor (hN-CoR) gene between the CMT1A and the SMS critical regions of chromosome 17p11.2. . Genomics . 59 . 3 . 339–41 . 1999 . 10444336 . 10.1006/geno.1998.5694 .
• Kikuno R, Nagase T, Ishikawa K, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. . DNA Res. . 6 . 3 . 197–205 . 1999 . 10470851 . 10.1093/dnares/6.3.197 . free .
• Hu X, Lazar MA . The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. . Nature . 402 . 6757 . 93–6 . 1999 . 10573424 . 10.1038/47069 . 1999Natur.402...93H . 4380362 .
• Huang EY, Zhang J, Miska EA, Guenther MG, Kouzarides T, Lazar MA . Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway. . Genes Dev. . 14 . 1 . 45–54 . 2000 . 10.1101/gad.14.1.45 . 10640275 . 316335 .
• Morohoshi F, Mitani S, Mitsuhashi N, Kitabayashi I, Takahashi E, Suzuki M, Munakata N, Ohki M . Structure and expression pattern of a human MTG8/ETO family gene, MTGR1. . Gene . 241 . 2 . 287–95 . 2000 . 10675041 . 10.1016/S0378-1119(99)00481-3 .
• Masselink H, Bernards R . The adenovirus E1A binding protein BS69 is a corepressor of transcription through recruitment of N-CoR. . Oncogene . 19 . 12 . 1538–46 . 2000 . 10734313 . 10.1038/sj.onc.1203421 . free .

Notes and References

1. Hörlein AJ, Näär AM, Heinzel T, Torchia J, Gloss B, Kurokawa R, Ryan A, Kamei Y, Söderström M, Glass CK . Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor . Nature . 377 . 6548 . 397–404 . October 1995 . 7566114 . 10.1038/377397a0 . 1995Natur.377..397H . 4230850 .
2. Wang J, Hoshino T, Redner RL, Kajigaya S, Liu JM . ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex . Proc. Natl. Acad. Sci. U.S.A. . 95 . 18 . 10860–5 . September 1998 . 9724795 . 27986 . 10.1073/pnas.95.18.10860 . 1998PNAS...9510860W . free .
3. Wang J, Hoshino T, Redner RL, Kajigaya S, Liu JM . ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex . Proc Natl Acad Sci USA . 95 . 18 . 10860–5 . 1998 . 9724795 . 27986 . 10.1073/pnas.95.18.10860 . 1998PNAS...9510860W . free .
4. Yamamoto H, Williams EG, Mouchiroud L, Cantó C, Fan W, Downes M, Héligon C, Barish GD, Desvergne B, Evans RM, Schoonjans K, Auwerx J . NCoR1 Is a Conserved Physiological Modulator of Muscle Mass and Oxidative Function . Cell . 147 . 4 . 827–839 . 2011 . 22078881 . 10.1016/j.cell.2011.10.017 . 3225739.
5. UniProt Nuclear receptor corepressors family Page accessed June 26, 2016
6. Masiello D, Chen SY, Xu Y, Verhoeven MC, Choi E, Hollenberg AN, Balk SP . Recruitment of beta-catenin by wild-type or mutant androgen receptors correlates with ligand-stimulated growth of prostate cancer cells . Mol. Endocrinol. . 18 . 10 . 2388–401 . October 2004 . 15256534 . 10.1210/me.2003-0436 . free .
7. Song LN, Coghlan M, Gelmann EP . Antiandrogen effects of mifepristone on coactivator and corepressor interactions with the androgen receptor . Mol. Endocrinol. . 18 . 1 . 70–85 . January 2004 . 14593076 . 10.1210/me.2003-0189 . free .
8. Cheng S, Brzostek S, Lee SR, Hollenberg AN, Balk SP . Inhibition of the dihydrotestosterone-activated androgen receptor by nuclear receptor corepressor . Mol. Endocrinol. . 16 . 7 . 1492–501 . July 2002 . 12089345 . 10.1210/mend.16.7.0870 . free .
9. Hodgson MC, Astapova I, Cheng S, Lee LJ, Verhoeven MC, Choi E, Balk SP, Hollenberg AN . The androgen receptor recruits nuclear receptor CoRepressor (N-CoR) in the presence of mifepristone via its N and C termini revealing a novel molecular mechanism for androgen receptor antagonists . J. Biol. Chem. . 280 . 8 . 6511–9 . February 2005 . 15598662 . 10.1074/jbc.M408972200 . free .
10. Tai HH, Geisterfer M, Bell JC, Moniwa M, Davie JR, Boucher L, McBurney MW . CHD1 associates with NCoR and histone deacetylase as well as with RNA splicing proteins . Biochem. Biophys. Res. Commun. . 308 . 1 . 170–6 . August 2003 . 12890497 . 10.1016/s0006-291x(03)01354-8 .
11. Puccetti E, Obradovic D, Beissert T, Bianchini A, Washburn B, Chiaradonna F, Boehrer S, Hoelzer D, Ottmann OG, Pelicci PG, Nervi C, Ruthardt M . AML-associated translocation products block vitamin D(3)-induced differentiation by sequestering the vitamin D(3) receptor . Cancer Res. . 62 . 23 . 7050–8 . December 2002 . 12460926 .
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. Stevens A, Garside H, Berry A, Waters C, White A, Ray D . Dissociation of steroid receptor coactivator 1 and nuclear receptor corepressor recruitment to the human glucocorticoid receptor by modification of the ligand-receptor interface: the role of tyrosine 735 . Mol. Endocrinol. . 17 . 5 . 845–59 . May 2003 . 12569182 . 10.1210/me.2002-0320 . free .
14. Schulz M, Eggert M, Baniahmad A, Dostert A, Heinzel T, Renkawitz R . RU486-induced glucocorticoid receptor agonism is controlled by the receptor N terminus and by corepressor binding . J. Biol. Chem. . 277 . 29 . 26238–43 . July 2002 . 12011091 . 10.1074/jbc.M203268200 . free .
15. Fischle W, Dequiedt F, Hendzel MJ, Guenther MG, Lazar MA, Voelter W, Verdin E . Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR . Mol. Cell . 9 . 1 . 45–57 . January 2002 . 11804585 . 10.1016/s1097-2765(01)00429-4 . 11858/00-001M-0000-002C-9FF9-9 . free .
16. Underhill C, Qutob MS, Yee SP, Torchia J . A novel nuclear receptor corepressor complex, N-CoR, contains components of the mammalian SWI/SNF complex and the corepressor KAP-1 . J. Biol. Chem. . 275 . 51 . 40463–70 . December 2000 . 11013263 . 10.1074/jbc.M007864200 . free .
17. Fischle W, Dequiedt F, Fillion M, Hendzel MJ, Voelter W, Verdin E . Human HDAC7 histone deacetylase activity is associated with HDAC3 in vivo . J. Biol. Chem. . 276 . 38 . 35826–35 . September 2001 . 11466315 . 10.1074/jbc.M104935200 . free .
18. Petrie K, Guidez F, Howell L, Healy L, Waxman S, Greaves M, Zelent A . The histone deacetylase 9 gene encodes multiple protein isoforms . J. Biol. Chem. . 278 . 18 . 16059–72 . May 2003 . 12590135 . 10.1074/jbc.M212935200 . free .
19. Iso T, Sartorelli V, Poizat C, Iezzi S, Wu HY, Chung G, Kedes L, Hamamori Y . HERP, a novel heterodimer partner of HES/E(spl) in Notch signaling . Mol. Cell. Biol. . 21 . 17 . 6080–9 . September 2001 . 11486045 . 87325 . 10.1128/mcb.21.17.6080-6089.2001 .
20. Zhang J, Kalkum M, Chait BT, Roeder RG . The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2 . Mol. Cell . 9 . 3 . 611–23 . March 2002 . 11931768 . 10.1016/s1097-2765(02)00468-9 . free .
21. Huang EY, Zhang J, Miska EA, Guenther MG, Kouzarides T, Lazar MA . Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway . Genes Dev. . 14 . 1 . 45–54 . January 2000 . 10.1101/gad.14.1.45 . 10640275 . 316335 .
22. Baek SH, Ohgi KA, Rose DW, Koo EH, Glass CK, Rosenfeld MG . Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and beta-amyloid precursor protein . Cell . 110 . 1 . 55–67 . July 2002 . 12150997 . 10.1016/S0092-8674(02)00809-7 . 17679498 . free .
23. Kokura K, Kaul SC, Wadhwa R, Nomura T, Khan MM, Shinagawa T, Yasukawa T, Colmenares C, Ishii S . The Ski protein family is required for MeCP2-mediated transcriptional repression . J. Biol. Chem. . 276 . 36 . 34115–21 . September 2001 . 11441023 . 10.1074/jbc.M105747200 . free .
24. Dowell P, Ishmael JE, Avram D, Peterson VJ, Nevrivy DJ, Leid M . Identification of nuclear receptor corepressor as a peroxisome proliferator-activated receptor alpha interacting protein . J. Biol. Chem. . 274 . 22 . 15901–7 . May 1999 . 10336495 . 10.1074/jbc.274.22.15901 . free .
25. Khan MM, Nomura T, Kim H, Kaul SC, Wadhwa R, Shinagawa T, Ichikawa-Iwata E, Zhong S, Pandolfi PP, Ishii S . Role of PML and PML-RARalpha in Mad-mediated transcriptional repression . Mol. Cell . 7 . 6 . 1233–43 . June 2001 . 11430826 . 10.1016/s1097-2765(01)00257-x . free .
26. Amann JM, Nip J, Strom DK, Lutterbach B, Harada H, Lenny N, Downing JR, Meyers S, Hiebert SW . ETO, a target of t(8;21) in acute leukemia, makes distinct contacts with multiple histone deacetylases and binds mSin3A through its oligomerization domain . Mol. Cell. Biol. . 21 . 19 . 6470–83 . October 2001 . 11533236 . 99794 . 10.1128/mcb.21.19.6470-6483.2001 .
27. Zhang J, Hug BA, Huang EY, Chen CW, Gelmetti V, Maccarana M, Minucci S, Pelicci PG, Lazar MA . Oligomerization of ETO is obligatory for corepressor interaction . Mol. Cell. Biol. . 21 . 1 . 156–63 . January 2001 . 11113190 . 88789 . 10.1128/MCB.21.1.156-163.2001 .
28. Guidez F, Ivins S, Zhu J, Söderström M, Waxman S, Zelent A . Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia . Blood . 91 . 8 . 2634–42 . April 1998 . 9531570 . 10.1182/blood.V91.8.2634.2634_2634_2642. free .
29. Laherty CD, Billin AN, Lavinsky RM, Yochum GS, Bush AC, Sun JM, Mullen TM, Davie JR, Rose DW, Glass CK, Rosenfeld MG, Ayer DE, Eisenman RN . SAP30, a component of the mSin3 corepressor complex involved in N-CoR-mediated repression by specific transcription factors . Mol. Cell . 2 . 1 . 33–42 . July 1998 . 9702189 . 10.1016/s1097-2765(00)80111-2 . free .
30. Yoon HG, Chan DW, Reynolds AB, Qin J, Wong J . N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso . Mol. Cell . 12 . 3 . 723–34 . September 2003 . 14527417 . 10.1016/j.molcel.2003.08.008 . free .
31. Yoon HG, Chan DW, Huang ZQ, Li J, Fondell JD, Qin J, Wong J . Purification and functional characterization of the human N-CoR complex: the roles of HDAC3, TBL1 and TBLR1 . EMBO J. . 22 . 6 . 1336–46 . March 2003 . 12628926 . 151047 . 10.1093/emboj/cdg120 .
32. Li J, Wang J, Wang J, Nawaz Z, Liu JM, Qin J, Wong J . Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3 . EMBO J. . 19 . 16 . 4342–50 . August 2000 . 10944117 . 302030 . 10.1093/emboj/19.16.4342 .
33. Guenther MG, Lane WS, Fischle W, Verdin E, Lazar MA, Shiekhattar R . A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness . Genes Dev. . 14 . 9 . 1048–57 . May 2000 . 10809664 . 316569 . 10.1101/gad.14.9.1048.