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Gene Review

NCOA2  -  nuclear receptor coactivator 2

Homo sapiens

Synonyms: BHLHE75, Class E basic helix-loop-helix protein 75, GRIP1, KAT13C, NCoA-2, ...
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Disease relevance of NCOA2


Psychiatry related information on NCOA2


High impact information on NCOA2

  • Here, we report the crystal structure of the human GR ligand binding domain (LBD) bound to dexamethasone and a coactivator motif derived from the transcriptional intermediary factor 2 [8].
  • Biochemical and crystallographic analyses revealed that hormone binding leads to the formation of a hydrophobic groove within the ligand binding domain (LBD) of the thyroid hormone receptor that interacts with an LxxLL motif-containing alpha-helix from GRIP1, a coactivator [9].
  • Our study demonstrates that ERalpha is a TNFalpha-induced coactivator that becomes a repressor in the presence of estradiol by recruiting GRIP1 [10].
  • LCoR binding to estrogen receptor alpha depends in part on residues in the coactivator binding pocket distinct from those bound by TIF-2 [11].
  • TIF2 exhibits partial sequence homology with the recently isolated steroid receptor coactivator SRC-1, indicating the existence of a novel gene family of nuclear receptor transcriptional mediators [12].

Chemical compound and disease context of NCOA2


Biological context of NCOA2

  • As seen in the previous cases, the inv(8)(p11q13) molecular characterization showed that the alteration results in a MOZ-NCOA2 gene fusion [1].
  • In a transient expression assay, a combination of p72/p68 with SRA and one TIF2 brought an ultimate synergism to the estrogen-induced transactivation of hER alpha [14].
  • The reciprocal TIF2-MOZ fusion gene is not expressed, perhaps as a result of a deletion near the chromosome 8 centromere [15].
  • Here we have shown that MOZ-TIF2 associates with the RARbeta2 promoter in vivo, resulting in altered recruitment of CBP/p300, aberrant histone modification, and down-regulation of the RARbeta2 gene [16].
  • This likely reflects a direct interaction between these proteins because mutation of a conserved residue within the major coactivator binding site on AR (K720A) inhibits AR-dependent dissociation of GRIP-1 from foci [17].

Anatomical context of NCOA2

  • The CBP-binding domain is also required for the ability of MOZ-TIF2 to extend the proliferative potential of murine bone marrow lineage-negative cells in vitro [18].
  • Compared with both fertile and infertile controls, PCOS women exhibited elevated levels of AIB1 and transcriptional intermediary factor-2 expression in both epithelial and stromal cells [19].
  • The enhanced ability of ERbeta (over ERalpha) to recruit coactivators in the presence of xenoestrogens was consistent with a greater ability of ERbeta to potentiate reporter gene activity in transiently transfected HeLa cells expressing SRC-1e and TIF2 [20].
  • Compared with the interaction of VDR with RXR or GRIP-1, the differentiation dose-response most closely correlated to the ligand-dependent recruitment of the DRIP coactivator complex to VDR and to the ability of the receptor to activate transcription in a cell-free system [21].
  • SRC-1 and GRIP1 coactivate transcription with hepatocyte nuclear factor 4 [5].

Associations of NCOA2 with chemical compounds


Physical interactions of NCOA2

  • We observe that TIF2 is capable of interacting simultaneously with both the isolated N- and C-terminus of ER alpha in transfected mammalian cells and in vitro, indicating that TIF2 can bridge both receptor domains [25].
  • For the Glu897 substitutions, the decrease in ligand-dependent transactivation could partially be reversed by overexpression of GRIP1 (GR-interacting protein 1) or CBP, putative coactivators for AR [26].
  • We propose that TIF2 provides a nuclear compartment that allows the assembly of multi-protein complexes required for GR-mediated gene activation [27].
  • SHP specifically targets the ligand-regulated activation domain AF-2 and competes for binding of coactivators such as TIF2 [28].

Other interactions of NCOA2

  • The MOZ-TIF2 fusion is one of a new family of chromosomal rearrangements that associate HAT activity, transcriptional coactivation, and acute leukemia [15].
  • ERbeta and GRIP1/TIF2 are shown to interact in vitro in a ligand-dependent manner and thus may form functional transcription complexes in NSCLC cells [29].
  • We therefore developed antisense oligodeoxynucleotides (asODNs) to SRA, SRC-1, and TIF2 mRNAs, which rapidly and specifically reduced the expression of each of these coactivators [30].
  • Significantly, the effects of TIF2 and SMRT were mutually antagonistic [31].
  • In contrast, seven normal brain specimens were positive for TIF2 and SRC-1 but negative for AIB1 [22].

Analytical, diagnostic and therapeutic context of NCOA2

  • Co-immunoprecipitation experiments demonstrate that PPAR alpha and GRIP1/TIF2 physically interact in vivo in human liver [32].
  • Using mammalian two-hybrid assays, hAR amino/carboxyl (N/C)-terminal interactions of the mutant receptors were analyzed in the presence and absence of the hAR coactivator transcription intermediary factor 2 (TIF2) [33].
  • Moreover, surface plasmon resonance analysis revealed reduced interaction of the V320G ERbeta variant with the NR box I and II modules of TIF2 [34].
  • Among co-activators such as SRC-1, TIF-2, and p300, PPARdelta had more strong binding with SRC-1 in an ELISA system [35].
  • Rearrangements were detected by Southern blotting with a TIF2 probe that was close to the breakpoint in the original inv(8) case and with a MOZ probe corresponding to the breakpoint cluster region in the t(8;16) (p11;p13) [36].


  1. A further case of acute myelomonocytic leukemia with inv(8) chromosomal rearrangement and MOZ-NCOA2 gene fusion. Murati, A., Adélaïde, J., Popovici, C., Mozziconacci, M.J., Arnoulet, C., Lafage-Pochitaloff, M., Sainty, D., Birnbaum, D., Chaffanet, M. Int. J. Mol. Med. (2003) [Pubmed]
  2. Expression levels of estrogen receptor-alpha, estrogen receptor-beta, coactivators, and corepressors in breast cancer. Kurebayashi, J., Otsuki, T., Kunisue, H., Tanaka, K., Yamamoto, S., Sonoo, H. Clin. Cancer Res. (2000) [Pubmed]
  3. Expression and function of androgen receptor coactivators in prostate cancer. Culig, Z., Comuzzi, B., Steiner, H., Bartsch, G., Hobisch, A. J. Steroid Biochem. Mol. Biol. (2004) [Pubmed]
  4. Estrogen response elements alter coactivator recruitment through allosteric modulation of estrogen receptor beta conformation. Loven, M.A., Likhite, V.S., Choi, I., Nardulli, A.M. J. Biol. Chem. (2001) [Pubmed]
  5. SRC-1 and GRIP1 coactivate transcription with hepatocyte nuclear factor 4. Wang, J.C., Stafford, J.M., Granner, D.K. J. Biol. Chem. (1998) [Pubmed]
  6. Differential expression of phosphorylated translation initiation factor 2 alpha in Alzheimer's disease and Creutzfeldt-Jakob's disease. Ferrer, I. Neuropathol. Appl. Neurobiol. (2002) [Pubmed]
  7. Hand function in patients on maintenance hemodialysis. Branz, N.R., Newton, R.A. Physical therapy. (1988) [Pubmed]
  8. Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Bledsoe, R.K., Montana, V.G., Stanley, T.B., Delves, C.J., Apolito, C.J., McKee, D.D., Consler, T.G., Parks, D.J., Stewart, E.L., Willson, T.M., Lambert, M.H., Moore, J.T., Pearce, K.H., Xu, H.E. Cell (2002) [Pubmed]
  9. Structure and specificity of nuclear receptor-coactivator interactions. Darimont, B.D., Wagner, R.L., Apriletti, J.W., Stallcup, M.R., Kushner, P.J., Baxter, J.D., Fletterick, R.J., Yamamoto, K.R. Genes Dev. (1998) [Pubmed]
  10. Distinct roles of unliganded and liganded estrogen receptors in transcriptional repression. Cvoro, A., Tzagarakis-Foster, C., Tatomer, D., Paruthiyil, S., Fox, M.S., Leitman, D.C. Mol. Cell (2006) [Pubmed]
  11. Ligand-dependent nuclear receptor corepressor LCoR functions by histone deacetylase-dependent and -independent mechanisms. Fernandes, I., Bastien, Y., Wai, T., Nygard, K., Lin, R., Cormier, O., Lee, H.S., Eng, F., Bertos, N.R., Pelletier, N., Mader, S., Han, V.K., Yang, X.J., White, J.H. Mol. Cell (2003) [Pubmed]
  12. TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. Voegel, J.J., Heine, M.J., Zechel, C., Chambon, P., Gronemeyer, H. EMBO J. (1996) [Pubmed]
  13. Molecular mechanisms involved in the growth stimulation of breast cancer cells by leptin. Yin, N., Wang, D., Zhang, H., Yi, X., Sun, X., Shi, B., Wu, H., Wu, G., Wang, X., Shang, Y. Cancer Res. (2004) [Pubmed]
  14. A subfamily of RNA-binding DEAD-box proteins acts as an estrogen receptor alpha coactivator through the N-terminal activation domain (AF-1) with an RNA coactivator, SRA. Watanabe, M., Yanagisawa, J., Kitagawa, H., Takeyama , K., Ogawa, S., Arao, Y., Suzawa, M., Kobayashi, Y., Yano, T., Yoshikawa, H., Masuhiro, Y., Kato, S. EMBO J. (2001) [Pubmed]
  15. Acute mixed lineage leukemia with an inv(8)(p11q13) resulting in fusion of the genes for MOZ and TIF2. Liang, J., Prouty, L., Williams, B.J., Dayton, M.A., Blanchard, K.L. Blood (1998) [Pubmed]
  16. MOZ-TIF2 alters cofactor recruitment and histone modification at the RARbeta2 promoter: differential effects of MOZ fusion proteins on CBP- and MOZ-dependent activators. Collins, H.M., Kindle, K.B., Matsuda, S., Ryan, C., Troke, P.J., Kalkhoven, E., Heery, D.M. J. Biol. Chem. (2006) [Pubmed]
  17. Transient, ligand-dependent arrest of the androgen receptor in subnuclear foci alters phosphorylation and coactivator interactions. Black, B.E., Vitto, M.J., Gioeli, D., Spencer, A., Afshar, N., Conaway, M.R., Weber, M.J., Paschal, B.M. Mol. Endocrinol. (2004) [Pubmed]
  18. MOZ-TIF2 inhibits transcription by nuclear receptors and p53 by impairment of CBP function. Kindle, K.B., Troke, P.J., Collins, H.M., Matsuda, S., Bossi, D., Bellodi, C., Kalkhoven, E., Salomoni, P., Pelicci, P.G., Minucci, S., Heery, D.M. Mol. Cell. Biol. (2005) [Pubmed]
  19. Steroid receptor coactivator expression throughout the menstrual cycle in normal and abnormal endometrium. Gregory, C.W., Wilson, E.M., Apparao, K.B., Lininger, R.A., Meyer, W.R., Kowalik, A., Fritz, M.A., Lessey, B.A. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  20. Differential effects of xenoestrogens on coactivator recruitment by estrogen receptor (ER) alpha and ERbeta. Routledge, E.J., White, R., Parker, M.G., Sumpter, J.P. J. Biol. Chem. (2000) [Pubmed]
  21. 20-Epi analogues of 1,25-dihydroxyvitamin D3 are highly potent inducers of DRIP coactivator complex binding to the vitamin D3 receptor. Yang, W., Freedman, L.P. J. Biol. Chem. (1999) [Pubmed]
  22. Expression of a subset of steroid receptor cofactors is associated with progesterone receptor expression in meningiomas. Carroll, R.S., Brown, M., Zhang, J., DiRenzo, J., Font De Mora, J., Black, P.M. Clin. Cancer Res. (2000) [Pubmed]
  23. Functional analysis of a novel androgen receptor mutation, Q902K, in an individual with partial androgen insensitivity. Umar, A., Berrevoets, C.A., Van, N.M., van Leeuwen, M., Verbiest, M., Kleijer, W.J., Dooijes, D., Grootegoed, J.A., Drop, S.L., Brinkmann, A.O. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  24. Lack of significant estrogenic or antiestrogenic activity of pyrethroid insecticides in three in vitro assays based on classic estrogen receptor alpha-mediated mechanisms. Saito, K., Tomigahara, Y., Ohe, N., Isobe, N., Nakatsuka, I., Kaneko, H. Toxicol. Sci. (2000) [Pubmed]
  25. Synergy between estrogen receptor alpha activation functions AF1 and AF2 mediated by transcription intermediary factor TIF2. Benecke, A., Chambon, P., Gronemeyer, H. EMBO Rep. (2000) [Pubmed]
  26. Mutational analysis of the androgen receptor AF-2 (activation function 2) core domain reveals functional and mechanistic differences of conserved residues compared with other nuclear receptors. Slagsvold, T., Kraus, I., Bentzen, T., Palvimo, J., Saatcioglu, F. Mol. Endocrinol. (2000) [Pubmed]
  27. Nuclear structure-associated TIF2 recruits glucocorticoid receptor and its target DNA. Ogawa, H., Yu, R.T., Haraguchi, T., Hiraoka, Y., Nakatani, Y., Morohashi, K., Umesono, K. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  28. The orphan nuclear receptor SHP inhibits agonist-dependent transcriptional activity of estrogen receptors ERalpha and ERbeta. Johansson, L., Thomsen, J.S., Damdimopoulos, A.E., Spyrou, G., Gustafsson, J.A., Treuter, E. J. Biol. Chem. (1999) [Pubmed]
  29. Regulation of endogenous gene expression in human non-small cell lung cancer cells by estrogen receptor ligands. Hershberger, P.A., Vasquez, A.C., Kanterewicz, B., Land, S., Siegfried, J.M., Nichols, M. Cancer Res. (2005) [Pubmed]
  30. Reduction of coactivator expression by antisense oligodeoxynucleotides inhibits ERalpha transcriptional activity and MCF-7 proliferation. Cavarretta, I.T., Mukopadhyay, R., Lonard, D.M., Cowsert, L.M., Bennett, C.F., O'Malley, B.W., Smith, C.L. Mol. Endocrinol. (2002) [Pubmed]
  31. Opposing effects of corepressor and coactivators in determining the dose-response curve of agonists, and residual agonist activity of antagonists, for glucocorticoid receptor-regulated gene expression. Szapary, D., Huang, Y., Simons, S.S. Mol. Endocrinol. (1999) [Pubmed]
  32. Negative regulation of human fibrinogen gene expression by peroxisome proliferator-activated receptor alpha agonists via inhibition of CCAAT box/enhancer-binding protein beta. Gervois, P., Vu-Dac, N., Kleemann, R., Kockx, M., Dubois, G., Laine, B., Kosykh, V., Fruchart, J.C., Kooistra, T., Staels, B. J. Biol. Chem. (2001) [Pubmed]
  33. The use of androgen receptor amino/carboxyl-terminal interaction assays to investigate androgen receptor gene mutations in subjects with varying degrees of androgen insensitivity. Ghali, S.A., Gottlieb, B., Lumbroso, R., Beitel, L.K., Elhaji, Y., Wu, J., Pinsky, L., Trifiro, M.A. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  34. Identification of a functional variant of estrogen receptor beta in an African population. Zhao, C., Xu, L., Otsuki, M., Toresson, G., Koehler, K., Pan-Hammarström, Q., Hammarström, L., Nilsson, S., Gustafsson, J.A., Dahlman-Wright, K. Carcinogenesis (2004) [Pubmed]
  35. A simple method to screen ligands of peroxisome proliferator-activated receptor delta. Cho, M.C., Yoon, H.E., Kang, J.W., Park, S.W., Yang, Y., Hong, J.T., Song, E.Y., Paik, S.G., Kim, S.H., Yoon, D.Y. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (2006) [Pubmed]
  36. Consistent fusion of MOZ and TIF2 in AML with inv(8)(p11q13). Carapeti, M., Aguiar, R.C., Watmore, A.E., Goldman, J.M., Cross, N.C. Cancer Genet. Cytogenet. (1999) [Pubmed]
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