Nuclear receptor co-repressor 2 explained

The nuclear receptor co-repressor 2 is a transcriptional coregulatory protein that contains several nuclear receptor-interacting domains. In addition, NCOR2 appears to recruit histone deacetylases to DNA promoter regions. Hence NCOR2 assists nuclear receptors in the down regulation of target gene expression.^{[1] [2]} NCOR2 is also referred to as a silencing mediator for retinoid or thyroid-hormone receptors (SMRT)^[1] or T₃ receptor-associating cofactor 1 (TRAC-1).^[2]

Function

NCOR2/SMRT is a transcriptional coregulatory protein that contains several modulatory functional domains including multiple autonomous repression domains as well as two or three C-terminal nuclear receptor-interacting domains.^[1] NCOR2/SMRT serves as a repressive coregulatory factor (corepressor) for multiple transcription factor pathways. In this regard, NCOR2/SMRT functions as a platform protein, facilitating the recruitment of histone deacetylases to the DNA promoters bound by its interacting transcription factors.^[3]

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 1.^[4]

Discovery

SMRT was initially cloned and characterized in the laboratory of Dr. Ronald M. Evans at the Salk Institute for Biological Studies.^[1] In another early investigation into this molecule, similar findings were reported in a variant referred to as TRAC-1.^[2]

Interactions

Nuclear receptor co-repressor 2 has been shown to interact with:

• AR,^{[5] [6] [7]}
• BCL6,^{[8] [9]}
• C-Fos,^[10]
• C-jun,^[10]
• HDAC1,^{[11] [12]}
• HDAC3,^{[12] [13]}
• HDAC4,^[14]
• HDAC5,
• HDAC10,^[11]
• MeCP2,^[15]
• NR4A1,^[16]
• POU2F1,^[17]
• PPARD,^[18]
• PGR,^[19]
• PML^{[20] [21]}
• RBPJ,^{[22] [23]}
• RELA,^{[10] [24]}
• RUNX1T1,^[25]
• RARA,^{[26] [27]}
• SIN3A,^{[28] [29]}
• SNW1,^{[30] [31]}
• SPEN,^[32]
• SRF,^[10]
• TBL1X,^{[28] [33] [34] [35]}
• THRB,^{[36] [37] [38]}
• VDR,^{[37] [39]} and
• ZBTB16.^{[40] [41] [27]}

Further reading

• 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 .
• Chen JD, Evans RM . A transcriptional co-repressor that interacts with nuclear hormone receptors . Nature . 377 . 6548 . 454–7 . October 1995 . 7566127 . 10.1038/377454a0 . 1995Natur.377..454C . 4361329 .
• Sande S, Privalsky ML . Identification of TRACs (T3 receptor-associating cofactors), a family of cofactors that associate with, and modulate the activity of, nuclear hormone receptors . Molecular Endocrinology . 10 . 7 . 813–25 . July 1996 . 10.1210/mend.10.7.8813722 . 8813722 . free .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . September 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Margolis RL, Abraham MR, Gatchell SB, Li SH, Kidwai AS, Breschel TS, Stine OC, Callahan C, McInnis MG, Ross CA . cDNAs with long CAG trinucleotide repeats from human brain . Human Genetics . 100 . 1 . 114–22 . July 1997 . 9225980 . 10.1007/s004390050476 . 25999127 .
• Hong SH, David G, Wong CW, Dejean A, Privalsky ML . SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor alpha (RARalpha) and PLZF-RARalpha oncoproteins associated with acute promyelocytic leukemia . Proceedings of the National Academy of Sciences of the United States of America . 94 . 17 . 9028–33 . August 1997 . 9256429 . 23013 . 10.1073/pnas.94.17.9028 . 1997PNAS...94.9028H . free .
• Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM . Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300 . Cell . 90 . 3 . 569–80 . August 1997 . 9267036 . 10.1016/S0092-8674(00)80516-4 . 15284825 . free .
• Lin RJ, Nagy L, Inoue S, Shao W, Miller WH, Evans RM . Role of the histone deacetylase complex in acute promyelocytic leukaemia . Nature . 391 . 6669 . 811–4 . February 1998 . 9486654 . 10.1038/35895 . 1998Natur.391..811L . 4383951 . free .
• 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 . Molecular Cell . 2 . 1 . 33–42 . July 1998 . 9702189 . 10.1016/S1097-2765(00)80111-2 . free .
• 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 . free .
• Wong CW, Privalsky ML . Components of the SMRT corepressor complex exhibit distinctive interactions with the POZ domain oncoproteins PLZF, PLZF-RARalpha, and BCL-6 . The Journal of Biological Chemistry . 273 . 42 . 27695–702 . October 1998 . 9765306 . 10.1074/jbc.273.42.27695 . free .
• Ordentlich P, Downes M, Xie W, Genin A, Spinner NB, Evans RM . Unique forms of human and mouse nuclear receptor corepressor SMRT . Proceedings of the National Academy of Sciences of the United States of America . 96 . 6 . 2639–44 . March 1999 . 10077563 . 15821 . 10.1073/pnas.96.6.2639 . 1999PNAS...96.2639O . free .
• Park EJ, Schroen DJ, Yang M, Li H, Li L, Chen JD . SMRTe, a silencing mediator for retinoid and thyroid hormone receptors-extended isoform that is more related to the nuclear receptor corepressor . Proceedings of the National Academy of Sciences of the United States of America . 96 . 7 . 3519–24 . March 1999 . 10097068 . 22325 . 10.1073/pnas.96.7.3519 . 1999PNAS...96.3519P . free .
• Nguyen TA, Hoivik D, Lee JE, Safe S . Interactions of nuclear receptor coactivator/corepressor proteins with the aryl hydrocarbon receptor complex . Archives of Biochemistry and Biophysics . 367 . 2 . 250–7 . July 1999 . 10395741 . 10.1006/abbi.1999.1282 .
• Bailey P, Downes M, Lau P, Harris J, Chen SL, Hamamori Y, Sartorelli V, Muscat GE . The nuclear receptor corepressor N-CoR regulates differentiation: N-CoR directly interacts with MyoD . Molecular Endocrinology . 13 . 7 . 1155–68 . July 1999 . 10406466 . 10.1210/mend.13.7.0305 . free .
• Kao HY, Downes M, Ordentlich P, Evans RM . Isolation of a novel histone deacetylase reveals that class I and class II deacetylases promote SMRT-mediated repression . Genes & Development . 14 . 1 . 55–66 . January 2000 . 10640276 . 316336 . 10.1101/gad.14.1.55 .
• Zhou S, Fujimuro M, Hsieh JJ, Chen L, Miyamoto A, Weinmaster G, Hayward SD . SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function . Molecular and Cellular Biology . 20 . 7 . 2400–10 . April 2000 . 10713164 . 85419 . 10.1128/MCB.20.7.2400-2410.2000 .
• Lee SK, Kim JH, Lee YC, Cheong J, Lee JW . Silencing mediator of retinoic acid and thyroid hormone receptors, as a novel transcriptional corepressor molecule of activating protein-1, nuclear factor-kappaB, and serum response factor . The Journal of Biological Chemistry . 275 . 17 . 12470–4 . April 2000 . 10777532 . 10.1074/jbc.275.17.12470 . free .
• 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 & Development . 14 . 9 . 1048–57 . May 2000 . 10809664 . 316569 . 10.1101/gad.14.9.1048 .
• Grozinger CM, Schreiber SL . Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization . Proceedings of the National Academy of Sciences of the United States of America . 97 . 14 . 7835–40 . July 2000 . 10869435 . 16631 . 10.1073/pnas.140199597 . 2000PNAS...97.7835G . free .

Notes and References

1. Chen JD, Evans RM . A transcriptional co-repressor that interacts with nuclear hormone receptors . Nature . 377 . 6548 . 454–7 . October 1995 . 7566127 . 10.1038/377454a0 . 1995Natur.377..454C . 4361329 .
2. Sande S, Privalsky ML . Identification of TRACs (T3 receptor-associating cofactors), a family of cofactors that associate with, and modulate the activity of, nuclear hormone receptors . Molecular Endocrinology . 10 . 7 . 813–25 . July 1996 . 10.1210/mend.10.7.8813722 . 8813722 . free .
3. Nagy L, Kao HY, Chakravarti D, Lin RJ, Hassig CA, Ayer DE, Schreiber SL, Evans RM . Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase . Cell . 89 . 3 . 373–80 . May 1997 . 9150137 . 10.1016/S0092-8674(00)80218-4 . 14686941 . free .
4. UniProt Nuclear receptor corepressors family Page accessed June 26, 2016
5. Liao G, Chen LY, Zhang A, Godavarthy A, Xia F, Ghosh JC, Li H, Chen JD . Regulation of androgen receptor activity by the nuclear receptor corepressor SMRT . The Journal of Biological Chemistry . 278 . 7 . 5052–61 . February 2003 . 12441355 . 10.1074/jbc.M206374200 . free .
6. Song LN, Coghlan M, Gelmann EP . Antiandrogen effects of mifepristone on coactivator and corepressor interactions with the androgen receptor . Molecular Endocrinology . 18 . 1 . 70–85 . January 2004 . 14593076 . 10.1210/me.2003-0189 . free .
7. Dotzlaw H, Moehren U, Mink S, Cato AC, Iñiguez Lluhí JA, Baniahmad A . The amino terminus of the human AR is target for corepressor action and antihormone agonism . Molecular Endocrinology . 16 . 4 . 661–73 . April 2002 . 11923464 . 10.1210/me.16.4.661 . free .
8. Huynh KD, Fischle W, Verdin E, Bardwell VJ . BCoR, a novel corepressor involved in BCL-6 repression . Genes & Development . 14 . 14 . 1810–23 . July 2000 . 10898795 . 316791 . 10.1101/gad.14.14.1810 .
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10. Lee SK, Kim JH, Lee YC, Cheong J, Lee JW . Silencing mediator of retinoic acid and thyroid hormone receptors, as a novel transcriptional corepressor molecule of activating protein-1, nuclear factor-kappaB, and serum response factor . The Journal of Biological Chemistry . 275 . 17 . 12470–4 . April 2000 . 10777532 . 10.1074/jbc.275.17.12470 . free .
11. Fischer DD, Cai R, Bhatia U, Asselbergs FA, Song C, Terry R, Trogani N, Widmer R, Atadja P, Cohen D . Isolation and characterization of a novel class II histone deacetylase, HDAC10 . The Journal of Biological Chemistry . 277 . 8 . 6656–66 . February 2002 . 11739383 . 10.1074/jbc.M108055200 . free .
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14. 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 . Molecular Cell . 9 . 1 . 45–57 . January 2002 . 11804585 . 10.1016/S1097-2765(01)00429-4 . 11858/00-001M-0000-002C-9FF9-9 . free .
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20. 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 . Molecular Cell . 7 . 6 . 1233–43 . June 2001 . 11430826 . 10.1016/S1097-2765(01)00257-X . free .
21. Hong SH, Yang Z, Privalsky ML . Arsenic trioxide is a potent inhibitor of the interaction of SMRT corepressor with Its transcription factor partners, including the PML-retinoic acid receptor alpha oncoprotein found in human acute promyelocytic leukemia . Molecular and Cellular Biology . 21 . 21 . 7172–82 . November 2001 . 11585900 . 99892 . 10.1128/MCB.21.21.7172-7182.2001 .
22. Beatus P, Lundkvist J, Oberg C, Pedersen K, Lendahl U . The origin of the ankyrin repeat region in Notch intracellular domains is critical for regulation of HES promoter activity . Mechanisms of Development . 104 . 1–2 . 3–20 . June 2001 . 11404076 . 10.1016/S0925-4773(01)00373-2 . 9526831 . free .
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24. Espinosa L, Inglés-Esteve J, Robert-Moreno A, Bigas A . IkappaBalpha and p65 regulate the cytoplasmic shuttling of nuclear corepressors: cross-talk between Notch and NFkappaB pathways . Molecular Biology of the Cell . 14 . 2 . 491–502 . February 2003 . 12589049 . 149987 . 10.1091/mbc.E02-07-0404 .
25. 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 . Molecular and Cellular Biology . 21 . 1 . 156–63 . January 2001 . 11113190 . 88789 . 10.1128/MCB.21.1.156-163.2001 .
26. Dong S, Tweardy DJ . Interactions of STAT5b-RARalpha, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways . Blood . 99 . 8 . 2637–46 . April 2002 . 11929748 . 10.1182/blood.V99.8.2637 . free .
27. Hong SH, David G, Wong CW, Dejean A, Privalsky ML . SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor alpha (RARalpha) and PLZF-RARalpha oncoproteins associated with acute promyelocytic leukemia . Proceedings of the National Academy of Sciences of the United States of America . 94 . 17 . 9028–33 . August 1997 . 9256429 . 23013 . 10.1073/pnas.94.17.9028 . 1997PNAS...94.9028H . free .
28. 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 . The EMBO Journal . 19 . 16 . 4342–50 . August 2000 . 10944117 . 302030 . 10.1093/emboj/19.16.4342 .
29. 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 & Development . 14 . 1 . 45–54 . January 2000 . 10.1101/gad.14.1.45 . 10640275 . 316335 .
30. Zhou S, Fujimuro M, Hsieh JJ, Chen L, Hayward SD . A role for SKIP in EBNA2 activation of CBF1-repressed promoters . Journal of Virology . 74 . 4 . 1939–47 . February 2000 . 10644367 . 111672 . 10.1128/JVI.74.4.1939-1947.2000 .
31. Zhou S, Fujimuro M, Hsieh JJ, Chen L, Miyamoto A, Weinmaster G, Hayward SD . SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function . Molecular and Cellular Biology . 20 . 7 . 2400–10 . April 2000 . 10713164 . 85419 . 10.1128/MCB.20.7.2400-2410.2000 .
32. Shi Y, Downes M, Xie W, Kao HY, Ordentlich P, Tsai CC, Hon M, Evans RM . Sharp, an inducible cofactor that integrates nuclear receptor repression and activation . Genes & Development . 15 . 9 . 1140–51 . May 2001 . 11331609 . 312688 . 10.1101/gad.871201 .
33. 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 . The EMBO Journal . 22 . 6 . 1336–46 . March 2003 . 12628926 . 151047 . 10.1093/emboj/cdg120 .
34. Guenther MG, Yu J, Kao GD, Yen TJ, Lazar MA . Assembly of the SMRT-histone deacetylase 3 repression complex requires the TCP-1 ring complex . Genes & Development . 16 . 24 . 3130–5 . December 2002 . 12502735 . 187500 . 10.1101/gad.1037502 .
35. 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 & Development . 14 . 9 . 1048–57 . May 2000 . 10809664 . 316569 . 10.1101/gad.14.9.1048 .
36. 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 . free .
37. Tagami T, Lutz WH, Kumar R, Jameson JL . The interaction of the vitamin D receptor with nuclear receptor corepressors and coactivators . Biochemical and Biophysical Research Communications . 253 . 2 . 358–63 . December 1998 . 9878542 . 10.1006/bbrc.1998.9799 .
38. 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 . Molecular Endocrinology . 15 . 9 . 1529–38 . September 2001 . 11518802 . 10.1210/mend.15.9.0687 . free .
39. 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 Research . 62 . 23 . 7050–8 . December 2002 . 12460926 .
40. Wong CW, Privalsky ML . Components of the SMRT corepressor complex exhibit distinctive interactions with the POZ domain oncoproteins PLZF, PLZF-RARalpha, and BCL-6 . The Journal of Biological Chemistry . 273 . 42 . 27695–702 . October 1998 . 9765306 . 10.1074/jbc.273.42.27695 . free .
41. Takahashi S, McConnell MJ, Harigae H, Kaku M, Sasaki T, Melnick AM, Licht JD . The Flt3 internal tandem duplication mutant inhibits the function of transcriptional repressors by blocking interactions with SMRT . Blood . 103 . 12 . 4650–8 . June 2004 . 14982881 . 10.1182/blood-2003-08-2759 . free .