Nuclear receptor co-repressor 2

Nuclear receptor corepressor 2
PDB rendering based on 1xc5.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1KKQ​, 1R2B​, 1XC5​, 2GPV​, 2L5G​, 2LTP​, 2ODD​, 2RT5​, 3R29​, 3R2A​, 4A69​, 4OAR​
Identifiers
Symbols	NCOR2 ; CTG26; N-CoR2; SMAP270; SMRT; SMRTE; SMRTE-tau; TNRC14; TRAC; TRAC-1; TRAC1
External IDs	OMIM: 600848 MGI: 1337080 HomoloGene: 31370 ChEMBL: 5949 GeneCards: NCOR2 Gene
Gene ontology Molecular function • DNA binding • transcription corepressor activity • Notch binding • protein binding • transcription factor binding • ligand-dependent nuclear receptor binding • histone deacetylase binding • protein N-terminus binding Cellular component • histone deacetylase complex • nucleus • nucleoplasm • membrane • nuclear matrix • nuclear body • transcriptional repressor complex Biological process • negative regulation of transcription from RNA polymerase II promoter • chromatin organization • transcription, DNA-templated • transcription initiation from RNA polymerase II promoter • transforming growth factor beta receptor signaling pathway • Notch signaling pathway • gene expression • cellular lipid metabolic process • small molecule metabolic process • regulation of cellular ketone metabolic process by negative regulation of transcription from RNA polymerase II promoter Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	9612	20602
Ensembl	ENSG00000196498	ENSMUSG00000029478
UniProt	Q9Y618	Q9WU42
RefSeq (mRNA)	NM_001077261	NM_001253904
RefSeq (protein)	NP_001070729	NP_001240833
Location (UCSC)	Chr 12: 124.32 – 124.57 Mb	Chr 5: 125.02 – 125.18 Mb
PubMed search

The nuclear receptor co-repressor 2 (NCOR2) 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]

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,^[4][5][6]
• BCL6,^[7][8][9]
• C-Fos,^[10]
• C-jun,^[10]
• HDAC1,^[11][12]
• HDAC3,^{[12][13][14][15][16][17][18]}
• HDAC4,^[17][19]
• HDAC5,^[19]
• HDAC10,^[11]
• MeCP2,^[20]
• NR4A1,^[21]
• POU2F1,^[22]
• PPARD,^[23]
• PGR,^[24]
• PML^[25][26]
• RBPJ,^[27][28]
• RELA,^[10][29]
• RUNX1T1,^[30][31]
• RARA,^[32][33]
• SIN3A,^[13][19]
• SNW1,^[34][35]
• SPEN,^[36]
• SRF,^[10]
• TBL1X,^{[13][14][15][16]}
• THRB,^[37][38][39]
• VDR,^[38][40] and
• ZBTB16.^[7][30][33]

References

1. Chen JD, Evans RM (1995). "A transcriptional co-repressor that interacts with nuclear hormone receptors". Nature 377 (6548): 454–7. doi:10.1038/377454a0. PMID 7566127.
2. Sande S, Privalsky ML (1996). "Identification of TRACs (T3 receptor-associating cofactors), a family of cofactors that associate with, and modulate the activity of, nuclear hormone receptors". Mol Endocrinol 10 (7): 813–25. doi:10.1210/me.10.7.813. PMID 8813722.
3. Nagy L, Kao HY, Chakravarti D, Lin RJ, Hassig CA, Ayer DE, Schreiber SL, Evans RM (1997). "Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase". Cell 89 (3): 373–80. doi:10.1016/S0092-8674(00)80218-4. PMID 9150137.
4. Liao G, Chen LY, Zhang A, Godavarthy A, Xia F, Ghosh JC, Li H, Chen JD (2003). "Regulation of androgen receptor activity by the nuclear receptor corepressor SMRT". J. Biol. Chem. 278 (7): 5052–61. doi:10.1074/jbc.M206374200. PMID 12441355.
5. Song LN, Coghlan M, Gelmann EP (2004). "Antiandrogen effects of mifepristone on coactivator and corepressor interactions with the androgen receptor". Mol. Endocrinol. 18 (1): 70–85. doi:10.1210/me.2003-0189. PMID 14593076.
6. Dotzlaw H, Moehren U, Mink S, Cato AC, Iñiguez Lluhí JA, Baniahmad A (2002). "The amino terminus of the human AR is target for corepressor action and antihormone agonism". Mol. Endocrinol. 16 (4): 661–73. doi:10.1210/me.16.4.661. PMID 11923464.
7. Wong CW, Privalsky ML (1998). "Components of the SMRT corepressor complex exhibit distinctive interactions with the POZ domain oncoproteins PLZF, PLZF-RARalpha, and BCL-6". J. Biol. Chem. 273 (42): 27695–702. doi:10.1074/jbc.273.42.27695. PMID 9765306.
8. Huynh KD, Fischle W, Verdin E, Bardwell VJ (2000). "BCoR, a novel corepressor involved in BCL-6 repression". Genes Dev. 14 (14): 1810–23. doi:10.1101/gad.14.14.1810. PMC 316791. PMID 10898795.
9. Deltour S, Guerardel C, Leprince D (1999). "Recruitment of SMRT/N-CoR-mSin3A-HDAC-repressing complexes is not a general mechanism for BTB/POZ transcriptional repressors: the case of HIC-1 and gammaFBP-B". Proc. Natl. Acad. Sci. U.S.A. 96 (26): 14831–6. doi:10.1073/pnas.96.26.14831. PMC 24733. PMID 10611298.
10. Lee SK, Kim JH, Lee YC, Cheong J, Lee JW (2000). "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". J. Biol. Chem. 275 (17): 12470–4. doi:10.1074/jbc.275.17.12470. PMID 10777532.
11. Fischer DD, Cai R, Bhatia U, Asselbergs FA, Song C, Terry R, Trogani N, Widmer R, Atadja P, Cohen D (2002). "Isolation and characterization of a novel class II histone deacetylase, HDAC10". J. Biol. Chem. 277 (8): 6656–66. doi:10.1074/jbc.M108055200. PMID 11739383.
12. Underhill C, Qutob MS, Yee SP, Torchia J (2000). "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. doi:10.1074/jbc.M007864200. PMID 11013263.
13. Li J, Wang J, Wang J, Nawaz Z, Liu JM, Qin J, Wong J (2000). "Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3". EMBO J. 19 (16): 4342–50. doi:10.1093/emboj/19.16.4342. PMC 302030. PMID 10944117.
14. Yoon HG, Chan DW, Huang ZQ, Li J, Fondell JD, Qin J, Wong J (2003). "Purification and functional characterization of the human N-CoR complex: the roles of HDAC3, TBL1 and TBLR1". EMBO J. 22 (6): 1336–46. doi:10.1093/emboj/cdg120. PMC 151047. PMID 12628926.
15. Guenther MG, Yu J, Kao GD, Yen TJ, Lazar MA (2002). "Assembly of the SMRT-histone deacetylase 3 repression complex requires the TCP-1 ring complex". Genes Dev. 16 (24): 3130–5. doi:10.1101/gad.1037502. PMC 187500. PMID 12502735.
16. Guenther MG, Lane WS, Fischle W, Verdin E, Lazar MA, Shiekhattar R (2000). "A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness". Genes Dev. 14 (9): 1048–57. doi:10.1101/gad.14.9.1048. PMC 316569. PMID 10809664.
17. Fischle W, Dequiedt F, Hendzel MJ, Guenther MG, Lazar MA, Voelter W, Verdin E (2002). "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. doi:10.1016/S1097-2765(01)00429-4. PMID 11804585.
18. Yoon HG, Chan DW, Reynolds AB, Qin J, Wong J (2003). "N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso". Mol. Cell 12 (3): 723–34. doi:10.1016/j.molcel.2003.08.008. PMID 14527417.
19. Huang EY, Zhang J, Miska EA, Guenther MG, Kouzarides T, Lazar MA (2000). "Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway". Genes Dev. 14 (1): 45–54. PMC 316335. PMID 10640275.
20. Lyst MJ, Ekiert R, Ebert DH, Merusi C, Nowak J, Selfridge J, Guy J, Kastan NR, Robinson ND, de Lima Alves F, Rappsilber J, Greenberg ME, Bird A (July 2013). "Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor". Nat. Neurosci. 16 (7): 898–902. doi:10.1038/nn.3434. PMID 23770565.
21. Sohn YC, Kwak E, Na Y, Lee JW, Lee SK (2001). "Silencing mediator of retinoid and thyroid hormone receptors and activating signal cointegrator-2 as transcriptional coregulators of the orphan nuclear receptor Nur77". J. Biol. Chem. 276 (47): 43734–9. doi:10.1074/jbc.M107208200. PMID 11559707.
22. Kakizawa T, Miyamoto T, Ichikawa K, Takeda T, Suzuki S, Mori J, Kumagai M, Yamashita K, Hashizume K (2001). "Silencing mediator for retinoid and thyroid hormone receptors interacts with octamer transcription factor-1 and acts as a transcriptional repressor". J. Biol. Chem. 276 (13): 9720–5. doi:10.1074/jbc.M008531200. PMID 11134019.
23. Shi Y, Hon M, Evans RM (2002). "The peroxisome proliferator-activated receptor delta, an integrator of transcriptional repression and nuclear receptor signaling". Proc. Natl. Acad. Sci. U.S.A. 99 (5): 2613–8. doi:10.1073/pnas.052707099. PMC 122396. PMID 11867749.
24. Giangrande PH, Kimbrel EA, Edwards DP, McDonnell DP (2000). "The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding". Mol. Cell. Biol. 20 (9): 3102–15. doi:10.1128/MCB.20.9.3102-3115.2000. PMC 85605. PMID 10757795.
25. Khan MM, Nomura T, Kim H, Kaul SC, Wadhwa R, Shinagawa T, Ichikawa-Iwata E, Zhong S, Pandolfi PP, Ishii S (2001). "Role of PML and PML-RARalpha in Mad-mediated transcriptional repression". Mol. Cell 7 (6): 1233–43. doi:10.1016/S1097-2765(01)00257-X. PMID 11430826.
26. Hong SH, Yang Z, Privalsky ML (2001). "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". Mol. Cell. Biol. 21 (21): 7172–82. doi:10.1128/MCB.21.21.7172-7182.2001. PMC 99892. PMID 11585900.
27. Beatus P, Lundkvist J, Oberg C, Pedersen K, Lendahl U (2001). "The origin of the ankyrin repeat region in Notch intracellular domains is critical for regulation of HES promoter activity". Mech. Dev. 104 (1-2): 3–20. doi:10.1016/S0925-4773(01)00373-2. PMID 11404076.
28. Zhou S, Hayward SD (2001). "Nuclear localization of CBF1 is regulated by interactions with the SMRT corepressor complex". Mol. Cell. Biol. 21 (18): 6222–32. doi:10.1128/MCB.21.18.6222-6232.2001. PMC 87339. PMID 11509665.
29. Espinosa L, Inglés-Esteve J, Robert-Moreno A, Bigas A (2003). "IkappaBalpha and p65 regulate the cytoplasmic shuttling of nuclear corepressors: cross-talk between Notch and NFkappaB pathways". Mol. Biol. Cell 14 (2): 491–502. doi:10.1091/mbc.E02-07-0404. PMC 149987. PMID 12589049.
30. Takahashi S, McConnell MJ, Harigae H, Kaku M, Sasaki T, Melnick AM, Licht JD (2004). "The Flt3 internal tandem duplication mutant inhibits the function of transcriptional repressors by blocking interactions with SMRT". Blood 103 (12): 4650–8. doi:10.1182/blood-2003-08-2759. PMID 14982881.
31. Zhang J, Hug BA, Huang EY, Chen CW, Gelmetti V, Maccarana M, Minucci S, Pelicci PG, Lazar MA (2001). "Oligomerization of ETO is obligatory for corepressor interaction". Mol. Cell. Biol. 21 (1): 156–63. doi:10.1128/MCB.21.1.156-163.2001. PMC 88789. PMID 11113190.
32. Dong S, Tweardy DJ (2002). "Interactions of STAT5b-RARalpha, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways". Blood 99 (8): 2637–46. doi:10.1182/blood.V99.8.2637. PMID 11929748.
33. Hong SH, David G, Wong CW, Dejean A, Privalsky ML (1997). "SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor alpha (RARalpha) and PLZF-RARalpha oncoproteins associated with acute promyelocytic leukemia". Proc. Natl. Acad. Sci. U.S.A. 94 (17): 9028–33. doi:10.1073/pnas.94.17.9028. PMC 23013. PMID 9256429.
34. Zhou S, Fujimuro M, Hsieh JJ, Chen L, Hayward SD (2000). "A role for SKIP in EBNA2 activation of CBF1-repressed promoters". J. Virol. 74 (4): 1939–47. doi:10.1128/JVI.74.4.1939-1947.2000. PMC 111672. PMID 10644367.
35. Zhou S, Fujimuro M, Hsieh JJ, Chen L, Miyamoto A, Weinmaster G, Hayward SD (2000). "SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function". Mol. Cell. Biol. 20 (7): 2400–10. doi:10.1128/MCB.20.7.2400-2410.2000. PMC 85419. PMID 10713164.
36. Shi Y, Downes M, Xie W, Kao HY, Ordentlich P, Tsai CC, Hon M, Evans RM (2001). "Sharp, an inducible cofactor that integrates nuclear receptor repression and activation". Genes Dev. 15 (9): 1140–51. doi:10.1101/gad.871201. PMC 312688. PMID 11331609.
37. Liu Y, Takeshita A, Misiti S, Chin WW, Yen PM (1998). "Lack of coactivator interaction can be a mechanism for dominant negative activity by mutant thyroid hormone receptors". Endocrinology 139 (10): 4197–204. doi:10.1210/endo.139.10.6218. PMID 9751500.
38. Tagami T, Lutz WH, Kumar R, Jameson JL (1998). "The interaction of the vitamin D receptor with nuclear receptor corepressors and coactivators". Biochem. Biophys. Res. Commun. 253 (2): 358–63. doi:10.1006/bbrc.1998.9799. PMID 9878542.
39. Ando S, Sarlis NJ, Krishnan J, Feng X, Refetoff S, Zhang MQ, Oldfield EH, Yen PM (2001). "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. doi:10.1210/me.15.9.1529. PMID 11518802.
40. Puccetti E, Obradovic D, Beissert T, Bianchini A, Washburn B, Chiaradonna F, Boehrer S, Hoelzer D, Ottmann OG, Pelicci PG, Nervi C, Ruthardt M (2002). "AML-associated translocation products block vitamin D(3)-induced differentiation by sequestering the vitamin D(3) receptor". Cancer Res. 62 (23): 7050–8. PMID 12460926.

Further reading

• Hörlein AJ, Näär AM, Heinzel T, et al. (1995). "Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor". Nature 377 (6548): 397–404. doi:10.1038/377397a0. PMID 7566114.
• Chen JD, Evans RM (1995). "A transcriptional co-repressor that interacts with nuclear hormone receptors". Nature 377 (6548): 454–7. doi:10.1038/377454a0. PMID 7566127.
• Sande S, Privalsky ML (1997). "Identification of TRACs (T3 receptor-associating cofactors), a family of cofactors that associate with, and modulate the activity of, nuclear hormone receptors". Mol. Endocrinol. 10 (7): 813–25. doi:10.1210/me.10.7.813. PMID 8813722.
• Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• Margolis RL, Abraham MR, Gatchell SB, et al. (1997). "cDNAs with long CAG trinucleotide repeats from human brain". Hum. Genet. 100 (1): 114–22. doi:10.1007/s004390050476. PMID 9225980.
• Hong SH, David G, Wong CW, et al. (1997). "SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor α (RARα) and PLZF-RARα oncoproteins associated with acute promyelocytic leukemia". Proc. Natl. Acad. Sci. U.S.A. 94 (17): 9028–33. doi:10.1073/pnas.94.17.9028. PMC 23013. PMID 9256429.
• Chen H, Lin RJ, Schiltz RL, et al. (1997). "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. doi:10.1016/S0092-8674(00)80516-4. PMID 9267036.
• Lin RJ, Nagy L, Inoue S, et al. (1998). "Role of the histone deacetylase complex in acute promyelocytic leukaemia". Nature 391 (6669): 811–4. doi:10.1038/35895. PMID 9486654.
• Laherty CD, Billin AN, Lavinsky RM, et al. (1998). "SAP30, a component of the mSin3 corepressor complex involved in N-CoR-mediated repression by specific transcription factors". Mol. Cell 2 (1): 33–42. doi:10.1016/S1097-2765(00)80111-2. PMID 9702189.
• Liu Y, Takeshita A, Misiti S, et al. (1998). "Lack of coactivator interaction can be a mechanism for dominant negative activity by mutant thyroid hormone receptors". Endocrinology 139 (10): 4197–204. doi:10.1210/endo.139.10.6218. PMID 9751500.
• Wong CW, Privalsky ML (1998). "Components of the SMRT corepressor complex exhibit distinctive interactions with the POZ domain oncoproteins PLZF, PLZF-RARalpha, and BCL-6". J. Biol. Chem. 273 (42): 27695–702. doi:10.1074/jbc.273.42.27695. PMID 9765306.
• Ordentlich P, Downes M, Xie W, et al. (1999). "Unique forms of human and mouse nuclear receptor corepressor SMRT". Proc. Natl. Acad. Sci. U.S.A. 96 (6): 2639–44. doi:10.1073/pnas.96.6.2639. PMC 15821. PMID 10077563.
• Park EJ, Schroen DJ, Yang M, et al. (1999). "SMRTe, a silencing mediator for retinoid and thyroid hormone receptors-extended isoform that is more related to the nuclear receptor corepressor". Proc. Natl. Acad. Sci. U.S.A. 96 (7): 3519–24. doi:10.1073/pnas.96.7.3519. PMC 22325. PMID 10097068.
• Nguyen TA, Hoivik D, Lee JE, Safe S (1999). "Interactions of nuclear receptor coactivator/corepressor proteins with the aryl hydrocarbon receptor complex". Arch. Biochem. Biophys. 367 (2): 250–7. doi:10.1006/abbi.1999.1282. PMID 10395741.
• Bailey P, Downes M, Lau P, et al. (1999). "The nuclear receptor corepressor N-CoR regulates differentiation: N-CoR directly interacts with MyoD". Mol. Endocrinol. 13 (7): 1155–68. doi:10.1210/me.13.7.1155. PMID 10406466.
• Kao HY, Downes M, Ordentlich P, Evans RM (2000). "Isolation of a novel histone deacetylase reveals that class I and class II deacetylases promote SMRT-mediated repression". Genes Dev. 14 (1): 55–66. doi:10.1101/gad.14.1.55. PMC 316336. PMID 10640276.
• Zhou S, Fujimuro M, Hsieh JJ, et al. (2000). "SKIP, a CBF1-Associated Protein, Interacts with the Ankyrin Repeat Domain of NotchIC To Facilitate NotchIC Function". Mol. Cell. Biol. 20 (7): 2400–10. doi:10.1128/MCB.20.7.2400-2410.2000. PMC 85419. PMID 10713164.
• Lee SK, Kim JH, Lee YC, et al. (2000). "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". J. Biol. Chem. 275 (17): 12470–4. doi:10.1074/jbc.275.17.12470. PMID 10777532.
• Guenther MG, Lane WS, Fischle W, et al. (2000). "A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness". Genes Dev. 14 (9): 1048–57. doi:10.1101/gad.14.9.1048. PMC 316569. PMID 10809664.
• Grozinger CM, Schreiber SL (2000). "Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3- 3-dependent cellular localization". Proc. Natl. Acad. Sci. U.S.A. 97 (14): 7835–40. doi:10.1073/pnas.140199597. PMC 16631. PMID 10869435.

External links

• nuclear receptor corepressor 2 at the US National Library of Medicine Medical Subject Headings (MeSH)
• NURSA C98