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Gene Review

NCOR1  -  nuclear receptor corepressor 1

Homo sapiens

Synonyms: KIAA1047, MGC104216, N-CoR, N-CoR1, Nuclear receptor corepressor 1, ...
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Disease relevance of NCOR1


High impact information on NCOR1

  • This is based on an evolutionarily conserved receptor N-terminal L/HX7LL motif, selectively present in sex steroid receptors, that causes recruitment of TAB2 as a component of an N-CoR corepressor complex [6].
  • The fragment forms a complex with the adaptor TAB2 and the corepressor N-CoR and transits to the nucleus, where it represses transcription of genes that promote the formation of astrocytes [7].
  • The transcriptional corepressors SMRT and N-CoR function as silencing mediators for retinoid and thyroid hormone receptors [8].
  • Thus, hormonal activation by nuclear receptors involves the mutual recruitment of at least three classes of histone acetyltransferases that may act cooperatively as an enzymatic unit to reverse the effects of histone deacetylase shown to be part of the nuclear receptor corepressor complex [9].
  • Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor [10].

Chemical compound and disease context of NCOR1


Biological context of NCOR1

  • Here we demonstrate that, in addition to protein-protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation [16].
  • Treatment with proteasomal inhibitor or with small interfering RNA against Siah2 prevented the down-regulation of N-CoR by estrogen [17].
  • This effect is attributable to estrogen up-regulation of the ubiquitin ligase Siah2, which is a rapid and primary transcriptional response mediated by the ER, and precedes the loss of N-CoR [17].
  • Mutagenesis studies demonstrate that the N-terminal surface of the AR-mediating NCoR recruitment was distinct from tau5 and from the FXXLF motif that mediates agonist-induced N-C-terminal interaction [18].
  • Trichostatin A treatment significantly stimulated the activity of MyoD by approximately 10-fold and inhibited the ability of N-CoR to repress MyoD-mediated transactivation, consistent with the involvement of the corepressor and the recruitment of a histone deacteylase activity in the process [19].

Anatomical context of NCOR1

  • It was found that NCOR1 mRNA was expressed at significantly higher levels in patients over 50 years of age, without axillary lymph node involvement, with tumor size less than 2 cm, with low or intermediate histological grade, with ERalpha/PgR-positive and with HER2 negative tumors [20].
  • Nuclear receptor corepressors (N-CoR) and silencing mediator for retinoid and thyroid receptors (SMRT) have both been implicated in thyroid hormone receptor (TR)-mediated repression [21].
  • We observed that the mRNA encoding N-CoR was suppressed as proliferating myoblasts exited the cell cycle, and formed morphologically and biochemically differentiated myotubes [19].
  • 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].
  • NCoR appears to influence PPARalpha signaling pathways and, therefore, may modulate tissue responsiveness to peroxisome proliferators [23].

Associations of NCOR1 with chemical compounds


Physical interactions of NCOR1

  • The N-CoR domains that interact with HDAC3 are distinct from those that bind other HDACs [26].
  • It appears that N-CoR/histone deacetylase corepressor complex interacts directly in an ATRA-insensitive manner with the BTB/POZ-domain of the wild-type PLZF protein and is required, at least in part, for its function as a transcriptional repressor [4].
  • The RU486-liganded AR interacted with a C-terminal fragment of NCoR, and this interaction was mediated by the two most C-terminal nuclear receptor interacting domains (RIDs) present in NCoR [18].
  • One of the fusion proteins (CDE-RD1), containing the ER DNA-binding and ligand-binding domains linked to the NCoR repressor domain (RD1), was selected for detailed examination [27].
  • We discovered that the fusion partner ETO binds to the human homolog of the murine nuclear receptor corepressor (N-CoR) [28].

Enzymatic interactions of NCOR1


Regulatory relationships of NCOR1

  • Finally, AR transcriptional activity could be enhanced in vivo by sequestration of endogenous NCoR with unliganded thyroid hormone receptor [5].
  • These ER-NCoR fusion proteins provide a novel means for inhibiting ER-mediated cellular responses, and analogous strategies could be used to create dominant negative mutants of other transcription factors [27].
  • We found that mutations of the BTB domain that neutralize key charged pocket residues did not disrupt dimerization, yet abrogated the ability of PLZF to repress transcription and led to the loss of interaction with N-CoR, SMRT, and histone deacetylases (HDACs) [30].
  • The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3 [31].
  • The nuclear receptor corepressor can repress the TR and RAR in the absence of ligand through either a Sin3A-dependent or -independent manner by recruiting HDACs [32].

Other interactions of NCOR1

  • Surprisingly, however, numerous biochemical studies have not detected N-CoR or SMRT in mSin3- and HDAC1-containing complexes [2].
  • 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 [33].
  • This ATRA-insensitive interaction between N-CoR and PLZF-RARalpha was mediated by the N-terminal PLZF moiety of the chimera [4].
  • Full repression mediated by THAP7 is also dependent on NCoR expression [34].
  • Three chimeric NCoR-ER proteins were created and shown to lack transcriptional activity [27].

Analytical, diagnostic and therapeutic context of NCOR1


  1. Expression analysis of estrogen receptor alpha coregulators in breast carcinoma: evidence that NCOR1 expression is predictive of the response to tamoxifen. Girault, I., Lerebours, F., Amarir, S., Tozlu, S., Tubiana-Hulin, M., Lidereau, R., Bièche, I. Clin. Cancer Res. (2003) [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. Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Gelmetti, V., Zhang, J., Fanelli, M., Minucci, S., Pelicci, P.G., Lazar, M.A. Mol. Cell. Biol. (1998) [Pubmed]
  4. Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. Guidez, F., Ivins, S., Zhu, J., Söderström, M., Waxman, S., Zelent, A. Blood (1998) [Pubmed]
  5. Inhibition of the dihydrotestosterone-activated androgen receptor by nuclear receptor corepressor. Cheng, S., Brzostek, S., Lee, S.R., Hollenberg, A.N., Balk, S.P. Mol. Endocrinol. (2002) [Pubmed]
  6. Macrophage/cancer cell interactions mediate hormone resistance by a nuclear receptor derepression pathway. Zhu, P., Baek, S.H., Bourk, E.M., Ohgi, K.A., Garcia-Bassets, I., Sanjo, H., Akira, S., Kotol, P.F., Glass, C.K., Rosenfeld, M.G., Rose, D.W. Cell (2006) [Pubmed]
  7. Nuclear signaling by receptor tyrosine kinases: the first robin of spring. Schlessinger, J., Lemmon, M.A. Cell (2006) [Pubmed]
  8. 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]
  9. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Chen, H., Lin, R.J., Schiltz, R.L., Chakravarti, D., Nash, A., Nagy, L., Privalsky, M.L., Nakatani, Y., Evans, R.M. Cell (1997) [Pubmed]
  10. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Hörlein, A.J., Näär, A.M., Heinzel, T., Torchia, J., Gloss, B., Kurokawa, R., Ryan, A., Kamei, Y., Söderström, M., Glass, C.K. Nature (1995) [Pubmed]
  11. Epstein-Barr virus nuclear antigen 3C recruits histone deacetylase activity and associates with the corepressors mSin3A and NCoR in human B-cell lines. Knight, J.S., Lan, K., Subramanian, C., Robertson, E.S. J. Virol. (2003) [Pubmed]
  12. 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]
  13. 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]
  14. Triflusal versus oral anticoagulation for primary prevention of thromboembolism after bioprosthetic valve replacement (trac): prospective, randomized, co-operative trial. Aramendi, J.I., Mestres, C.A., Mestres, C.A., Martinez-León, J., Campos, V., Muñoz, G., Navas, C. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. (2005) [Pubmed]
  15. Staphylococci in human periodontal diseases. Rams, T.E., Feik, D., Slots, J. Oral Microbiol. Immunol. (1990) [Pubmed]
  16. 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]
  17. Estrogen down-regulation of the corepressor N-CoR: mechanism and implications for estrogen derepression of N-CoR-regulated genes. Frasor, J., Danes, J.M., Funk, C.C., Katzenellenbogen, B.S. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  18. 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. Hodgson, M.C., Astapova, I., Cheng, S., Lee, L.J., Verhoeven, M.C., Choi, E., Balk, S.P., Hollenberg, A.N. J. Biol. Chem. (2005) [Pubmed]
  19. The nuclear receptor corepressor N-CoR regulates differentiation: N-CoR directly interacts with MyoD. Bailey, P., Downes, M., Lau, P., Harris, J., Chen, S.L., Hamamori, Y., Sartorelli, V., Muscat, G.E. Mol. Endocrinol. (1999) [Pubmed]
  20. NCOR1 mRNA is an independent prognostic factor for breast cancer. Zhang, Z., Yamashita, H., Toyama, T., Sugiura, H., Ando, Y., Mita, K., Hamaguchi, M., Hara, Y., Kobayashi, S., Iwase, H. Cancer Lett. (2006) [Pubmed]
  21. The N-CoR/histone deacetylase 3 complex is required for repression by thyroid hormone receptor. Ishizuka, T., Lazar, M.A. Mol. Cell. Biol. (2003) [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. Identification of nuclear receptor corepressor as a peroxisome proliferator-activated receptor alpha interacting protein. Dowell, P., Ishmael, J.E., Avram, D., Peterson, V.J., Nevrivy, D.J., Leid, M. J. Biol. Chem. (1999) [Pubmed]
  24. Unique forms of human and mouse nuclear receptor corepressor SMRT. Ordentlich, P., Downes, M., Xie, W., Genin, A., Spinner, N.B., Evans, R.M. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  25. Silencing mediator for retinoid and thyroid hormone receptor and nuclear receptor corepressor attenuate transcriptional activation by the beta-catenin-TCF4 complex. Song, L.N., Gelmann, E.P. J. Biol. Chem. (2008) [Pubmed]
  26. The histone deacetylase-3 complex contains nuclear receptor corepressors. Wen, Y.D., Perissi, V., Staszewski, L.M., Yang, W.M., Krones, A., Glass, C.K., Rosenfeld, M.G., Seto, E. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  27. A fusion protein of the estrogen receptor (ER) and nuclear receptor corepressor (NCoR) strongly inhibits estrogen-dependent responses in breast cancer cells. Chien, P.Y., Ito, M., Park, Y., Tagami, T., Gehm, B.D., Jameson, J.L. Mol. Endocrinol. (1999) [Pubmed]
  28. ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex. Wang, J., Hoshino, T., Redner, R.L., Kajigaya, S., Liu, J.M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  29. Cleavage of misfolded nuclear receptor corepressor confers resistance to unfolded protein response-induced apoptosis. Ng, A.P., Howe Fong, J., Sijin Nin, D., Hirpara, J.L., Asou, N., Chen, C.S., Pervaiz, S., Khan, M. Cancer Res. (2006) [Pubmed]
  30. Critical residues within the BTB domain of PLZF and Bcl-6 modulate interaction with corepressors. Melnick, A., Carlile, G., Ahmad, K.F., Kiang, C.L., Corcoran, C., Bardwell, V., Prive, G.G., Licht, J.D. Mol. Cell. Biol. (2002) [Pubmed]
  31. 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]
  32. 5'TG3' interacting factor interacts with Sin3A and represses AR-mediated transcription. Sharma, M., Sun, Z. Mol. Endocrinol. (2001) [Pubmed]
  33. 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]
  34. Human THAP7 is a chromatin-associated, histone tail-binding protein that represses transcription via recruitment of HDAC3 and nuclear hormone receptor corepressor. Macfarlan, T., Kutney, S., Altman, B., Montross, R., Yu, J., Chakravarti, D. J. Biol. Chem. (2005) [Pubmed]
  35. 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]
  36. Associations and interactions between Ets-1 and Ets-2 and coregulatory proteins, SRC-1, AIB1, and NCoR in breast cancer. Myers, E., Hill, A.D., Kelly, G., McDermott, E.W., O'Higgins, N.J., Buggy, Y., Young, L.S. Clin. Cancer Res. (2005) [Pubmed]
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