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Gene Review

NCOR2  -  nuclear receptor corepressor 2

Homo sapiens

Synonyms: CTG repeat protein 26, CTG26, N-CoR2, Nuclear receptor corepressor 2, SMAP270, ...
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Disease relevance of NCOR2

  • In contrast to the results obtained with differentiating osteoclasts, addition of 17beta-estradiol (0.001-10 nM) to mature osteoclasts did not affect bone resorption or TRACP activity [1].
  • Transcriptional repression mediated by corepressors N-CoR and SMRT is a critical function of nuclear hormone receptors, and is dysregulated in human myeloid leukemias [2].
  • Two SMRT fragments bind symmetrically to the BCL6 BTB homodimer and, in combination with biochemical and in vivo data, the structure provides insight into the basis of transcriptional repression by this critical B cell lymphoma protein [3].
  • Here we show the effects of reducing N-CoR and SMRT levels on the actions of estrogen and tamoxifen in breast cancer cells [4].
  • These data demonstrate that elevated SMRT levels are common in prostate cancer cells, resulting in suppression of target genes associated with antiproliferative action and apparent 1alpha,25(OH)2D3-insensitivity [5].

Psychiatry related information on NCOR2


High impact information on NCOR2


Chemical compound and disease context of NCOR2


Biological context of NCOR2

  • A SANT motif in the SMRT corepressor interprets the histone code and promotes histone deacetylation [17].
  • Here we show that SMRTe inhibits MEF2C transcriptional activation by targeting selective HDACs to unique subnuclear domains [18].
  • Transient cotransfections of mammalian cells (Hepa1c1c7, MCF-7, and BG-1) with SMRT and a TCDD-inducible luciferase reporter containing the dioxin-responsive domain from the mouse CYP1A1 regulatory region revealed that SMRT does not repress, but enhances, AhR signaling [19].
  • Using a nonphosphorylatable SMRT protein, we demonstrate that IKKalpha-induced phosphorylation is required to recruit 14-3-3epsilon and Ubc5 for SMRT derepression [20].
  • Failure of IKKalpha to stimulate the removal of SMRT from chromatin inhibits the recruitment of NF-kappaB to promoters, blocking transcription and sensitizing cells to apoptosis [20].

Anatomical context of NCOR2

  • 4- Hydroxy-tamoxifen (4-OHT) increased ER-alpha and silencing mediator for retinoid and thyroid receptors (SMRT) expression and increased ER-ERE binding [21].
  • It attaches to the nuclear matrix and associates with histone deacetylases and the co-repressors N-CoR, SMRT, and mSin3A, and may act as a co-repressor for site-specific transcriptions factors [22].
  • Addition of 0.1-10 nM 17beta-estradiol to differentiating osteoclasts resulted in a dose-dependent reduction in tartrate resistant acid phosphatase (TRACP) activity reaching 60% at 0.1 nM [1].
  • Here we report the isolation of a novel SMRT-containing complex from HeLa cells [23].
  • For example, PC-3 and DU-145 prostate cancer cell lines had 1.8-fold and twofold increases in SMRT mRNA relative to normal PrEC cells (P<0.05) [5].

Associations of NCOR2 with chemical compounds


Physical interactions of NCOR2

  • Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR [29].
  • Unexpectedly, the PLZF moiety itself can interact with SMRT corepressor [30].
  • We found that AR possesses an intrinsic transcriptional repression activity, and AR interacts directly with SMRT [26].
  • Conversely, in cells treated with 4-OHT, ER-alpha and ER-beta bound SMRT [21].
  • Here we report that HDAC3 interacts with SMRT only after priming by cellular chaperones including the TCP-1 ring complex (TRiC), which is required for proper folding of HDAC3 in an ATP-dependent process [31].

Co-localisations of NCOR2

  • RIP140 foci do not correspond to PML bodies but partly colocalize with domains harboring the corepressor SMRT [32].

Regulatory relationships of NCOR2


Other interactions of NCOR2

  • We present evidence that both corepressors SMRT and N-CoR exist in large protein complexes with estimated sizes of 1.5-2 MDa in HeLa nuclear extracts [24].
  • SMRT was released from STAT5b-RARalpha/SMRT complexes by ATRA at 10(-6) M, whereas TRAM-1 became associated with STAT5b-RARalpha at 10(-7) M [38].
  • In contrast, N-CoR-2 contained predominantly HDAC1 and HDAC2 as well as several other subunits that are found in the Sin3A.HDAC complex [39].
  • Our data establish a significant role of SMRT in modulating AR transcriptional activity [26].
  • We show that SMRT and DAX-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases [40].

Analytical, diagnostic and therapeutic context of NCOR2


  1. Estrogen directly attenuates human osteoclastogenesis, but has no effect on resorption by mature osteoclasts. Sørensen, M.G., Henriksen, K., Dziegiel, M.H., Tankó, L.B., Karsdal, M.A. DNA Cell Biol. (2006) [Pubmed]
  2. Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway. Huang, E.Y., Zhang, J., Miska, E.A., Guenther, M.G., Kouzarides, T., Lazar, M.A. Genes Dev. (2000) [Pubmed]
  3. Mechanism of SMRT corepressor recruitment by the BCL6 BTB domain. Ahmad, K.F., Melnick, A., Lax, S., Bouchard, D., Liu, J., Kiang, C.L., Mayer, S., Takahashi, S., Licht, J.D., Privé, G.G. Mol. Cell (2003) [Pubmed]
  4. Cell cycle progression stimulated by tamoxifen-bound estrogen receptor-alpha and promoter-specific effects in breast cancer cells deficient in N-CoR and SMRT. Keeton, E.K., Brown, M. Mol. Endocrinol. (2005) [Pubmed]
  5. Altered SMRT levels disrupt vitamin D3 receptor signalling in prostate cancer cells. Khanim, F.L., Gommersall, L.M., Wood, V.H., Smith, K.L., Montalvo, L., O'Neill, L.P., Xu, Y., Peehl, D.M., Stewart, P.M., Turner, B.M., Campbell, M.J. Oncogene (2004) [Pubmed]
  6. Methylation gets SMRT. Functional insights into Rett syndrome. Vetter, M.L. Dev. Cell (2003) [Pubmed]
  7. Exclusion of non-synonymous SNPs and a polyglutamine tract in SMRT/N-CoR2 as common deleterious mutation for bipolar disorder in the Sagnenay-Lac-St-Jean population. Shink, E., Harvey, M., Tremblay, M., Raymond, C., Labbé, M., Gagné, B., Barden, N. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2005) [Pubmed]
  8. Flow cytoenzymology of intracellular tartrate-resistant acid phosphatase. Janckila, A.J., Yang, W.K., Lin, R.J., Tseng, C.J., Chang, H.Y., Chang, J.M., Yam, L.T. J. Histochem. Cytochem. (2003) [Pubmed]
  9. Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Nagy, L., Kao, H.Y., Chakravarti, D., Lin, R.J., Hassig, C.A., Ayer, D.E., Schreiber, S.L., Evans, R.M. Cell (1997) [Pubmed]
  10. Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha. Xu, H.E., Stanley, T.B., Montana, V.G., Lambert, M.H., Shearer, B.G., Cobb, J.E., McKee, D.D., Galardi, C.M., Plunket, K.D., Nolte, R.T., Parks, D.J., Moore, J.T., Kliewer, S.A., Willson, T.M., Stimmel, J.B. Nature (2002) [Pubmed]
  11. A transcriptional co-repressor that interacts with nuclear hormone receptors. Chen, J.D., Evans, R.M. Nature (1995) [Pubmed]
  12. Histone deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4. Zhang, X., Ozawa, Y., Lee, H., Wen, Y.D., Tan, T.H., Wadzinski, B.E., Seto, E. Genes Dev. (2005) [Pubmed]
  13. Decreased Chicken Ovalbumin Upstream Promoter Transcription Factor II Expression in Tamoxifen-Resistant Breast Cancer Cells. Riggs, K.A., Wickramasinghe, N.S., Cochrum, R.K., Watts, M.B., Klinge, C.M. Cancer Res. (2006) [Pubmed]
  14. Differential expression of an orphan receptor COUP-TFI and corepressors in adrenal tumors. Shibata, H., Ando, T., Suzuki, T., Kurihara, I., Hayashi, K., Hayashi, M., Saito, I., Kawabe, H., Tsujioka, M., Mural, M., Saruta, T. Endocr. Res. (1998) [Pubmed]
  15. Nuclear IKK activity leads to dysregulated Notch-dependent gene expression in colorectal cancer. Fern??ndez-Majada, V., Aguilera, C., Villanueva, A., Vilardell, F., Robert-Moreno, A., Ayt??s, A., Real, F.X., Capella, G., Mayo, M.W., Espinosa, L., Bigas, A. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  16. Alteration of SMRT tumor suppressor function in transformed non-Hodgkin lymphomas. Song, L., Zlobin, A., Ghoshal, P., Zhang, Q., Houde, C., Weijzen, S., Jiang, Q., Nacheva, E., Yagan, D., Davis, E., Galiegue-Zouitina, S., Catovsky, D., Grogan, T., Fisher, R.I., Miele, L., Coignet, L.J. Cancer Res. (2005) [Pubmed]
  17. A SANT motif in the SMRT corepressor interprets the histone code and promotes histone deacetylation. Yu, J., Li, Y., Ishizuka, T., Guenther, M.G., Lazar, M.A. EMBO J. (2003) [Pubmed]
  18. SMRTE inhibits MEF2C transcriptional activation by targeting HDAC4 and 5 to nuclear domains. Wu, X., Li, H., Park, E.J., Chen, J.D. J. Biol. Chem. (2001) [Pubmed]
  19. The silencing mediator of retinoic acid and thyroid hormone receptors can interact with the aryl hydrocarbon (Ah) receptor but fails to repress Ah receptor-dependent gene expression. Rushing, S.R., Denison, M.S. Arch. Biochem. Biophys. (2002) [Pubmed]
  20. SMRT derepression by the IkappaB kinase alpha: a prerequisite to NF-kappaB transcription and survival. Hoberg, J.E., Yeung, F., Mayo, M.W. Mol. Cell (2004) [Pubmed]
  21. Differential recruitment of coregulator proteins steroid receptor coactivator-1 and silencing mediator for retinoid and thyroid receptors to the estrogen receptor-estrogen response element by beta-estradiol and 4-hydroxytamoxifen in human breast cancer. Fleming, F.J., Hill, A.D., McDermott, E.W., O'Higgins, N.J., Young, L.S. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  22. Gfi-1 attaches to the nuclear matrix, associates with ETO (MTG8) and histone deacetylase proteins, and represses transcription using a TSA-sensitive mechanism. McGhee, L., Bryan, J., Elliott, L., Grimes, H.L., Kazanjian, A., Davis, J.N., Meyers, S. J. Cell. Biochem. (2003) [Pubmed]
  23. A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness. Guenther, M.G., Lane, W.S., Fischle, W., Verdin, E., Lazar, M.A., Shiekhattar, R. Genes Dev. (2000) [Pubmed]
  24. Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. Li, J., Wang, J., Wang, J., Nawaz, Z., Liu, J.M., Qin, J., Wong, J. EMBO J. (2000) [Pubmed]
  25. Isolation and characterization of a novel class II histone deacetylase, HDAC10. Fischer, D.D., Cai, R., Bhatia, U., Asselbergs, F.A., Song, C., Terry, R., Trogani, N., Widmer, R., Atadja, P., Cohen, D. J. Biol. Chem. (2002) [Pubmed]
  26. Regulation of androgen receptor activity by the nuclear receptor corepressor SMRT. Liao, G., Chen, L.Y., Zhang, A., Godavarthy, A., Xia, F., Ghosh, J.C., Li, H., Chen, J.D. J. Biol. Chem. (2003) [Pubmed]
  27. The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT. Jackson, T.A., Richer, J.K., Bain, D.L., Takimoto, G.S., Tung, L., Horwitz, K.B. Mol. Endocrinol. (1997) [Pubmed]
  28. Functional interaction of STAT5 and nuclear receptor co-repressor SMRT: implications in negative regulation of STAT5-dependent transcription. Nakajima, H., Brindle, P.K., Handa, M., Ihle, J.N. EMBO J. (2001) [Pubmed]
  29. Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR. Fischle, W., Dequiedt, F., Hendzel, M.J., Guenther, M.G., Lazar, M.A., Voelter, W., Verdin, E. Mol. Cell (2002) [Pubmed]
  30. SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor alpha (RARalpha) and PLZF-RARalpha oncoproteins associated with acute promyelocytic leukemia. Hong, S.H., David, G., Wong, C.W., Dejean, A., Privalsky, M.L. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  31. Assembly of the SMRT-histone deacetylase 3 repression complex requires the TCP-1 ring complex. Guenther, M.G., Yu, J., Kao, G.D., Yen, T.J., Lazar, M.A. Genes Dev. (2002) [Pubmed]
  32. Regulation of subnuclear localization is associated with a mechanism for nuclear receptor corepression by RIP140. Tazawa, H., Osman, W., Shoji, Y., Treuter, E., Gustafsson, J.A., Zilliacus, J. Mol. Cell. Biol. (2003) [Pubmed]
  33. Silencing mediator of retinoid and thyroid hormone receptors and activating signal cointegrator-2 as transcriptional coregulators of the orphan nuclear receptor Nur77. Sohn, Y.C., Kwak, E., Na, Y., Lee, J.W., Lee, S.K. J. Biol. Chem. (2001) [Pubmed]
  34. The nuclear corepressors NCoR and SMRT are key regulators of both ligand- and 8-bromo-cyclic AMP-dependent transcriptional activity of the human progesterone receptor. Wagner, B.L., Norris, J.D., Knotts, T.A., Weigel, N.L., McDonnell, D.P. Mol. Cell. Biol. (1998) [Pubmed]
  35. The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Guenther, M.G., Barak, O., Lazar, M.A. Mol. Cell. Biol. (2001) [Pubmed]
  36. The SMRT corepressor is regulated by a MEK-1 kinase pathway: inhibition of corepressor function is associated with SMRT phosphorylation and nuclear export. Hong, S.H., Privalsky, M.L. Mol. Cell. Biol. (2000) [Pubmed]
  37. Silencing mediator for retinoid and thyroid hormone receptors interacts with octamer transcription factor-1 and acts as a transcriptional repressor. Kakizawa, T., Miyamoto, T., Ichikawa, K., Takeda, T., Suzuki, S., Mori , J., Kumagai, M., Yamashita, K., Hashizume, K. J. Biol. Chem. (2001) [Pubmed]
  38. Interactions of STAT5b-RARalpha, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways. Dong, S., Tweardy, D.J. Blood (2002) [Pubmed]
  39. A novel nuclear receptor corepressor complex, N-CoR, contains components of the mammalian SWI/SNF complex and the corepressor KAP-1. Underhill, C., Qutob, M.S., Yee, S.P., Torchia, J. J. Biol. Chem. (2000) [Pubmed]
  40. Repressors of androgen and progesterone receptor action. Agoulnik, I.U., Krause, W.C., Bingman, W.E., Rahman, H.T., Amrikachi, M., Ayala, G.E., Weigel, N.L. J. Biol. Chem. (2003) [Pubmed]
  41. Nuclear localization of CBF1 is regulated by interactions with the SMRT corepressor complex. Zhou, S., Hayward, S.D. Mol. Cell. Biol. (2001) [Pubmed]
  42. Dynamic inhibition of nuclear receptor activation by corepressor binding. Sohn, Y.C., Kim, S.W., Lee, S., Kong, Y.Y., Na, D.S., Lee, S.K., Lee, J.W. Mol. Endocrinol. (2003) [Pubmed]
  43. Thoughts on tamoxifen resistant breast cancer. Are coregulators the answer or just a red herring? Graham, J.D., Bain, D.L., Richer, J.K., Jackson, T.A., Tung, L., Horwitz, K.B. J. Steroid Biochem. Mol. Biol. (2000) [Pubmed]
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