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Gene Review

Ncoa2  -  nuclear receptor coactivator 2

Mus musculus

Synonyms: D1Ertd433e, GRIP-1, Glucocorticoid receptor-interacting protein 1, Grip1, KAT13C, ...
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Disease relevance of Ncoa2


High impact information on Ncoa2

  • These results reveal that the relative level of TIF2/SRC-1 can modulate energy metabolism [1].
  • Here we report the crystal structure of the human estrogen receptor alpha (hER alpha) ligand-binding domain (LBD) bound to both the agonist diethylstilbestrol (DES) and a peptide derived from the NR box II region of the coactivator GRIP1 and the crystal structure of the hER alpha LBD bound to the selective antagonist 4-hydroxytamoxifen (OHT) [5].
  • During skeletal muscle differentiation, GRIP-1 is localized to punctate nuclear structures and can apparently tether MEF2 to such structures [6].
  • Consistent with the absence of punctate nuclear GRIP-1 in proliferating myoblasts, we have found that ectopic cyclin D-cdk4 expression disrupts the localization of both GRIP-1 and MEF2C to these punctate subnuclear structures [6].
  • GRIP-1 also coactivates the synergistic transactivation of E box-dependent transcription by myogenin and MEF-2C [7].

Chemical compound and disease context of Ncoa2


Biological context of Ncoa2


Anatomical context of Ncoa2

  • Immunohistological analysis confirmed that AR and TIF2 coexist in mouse testicular Sertoli cell nuclei under normal conditions [9].
  • In this study we demonstrate that SRC-2 is essentially localized in the nucleus of proliferating myoblasts; however, weak (but notable) expression is observed in the cytoplasm [13].
  • In most brain structures where SRC-1 is expressed, SRC-2 is expressed at lower levels; however, SRC-3 mRNA is detectable only in the hippocampus [14].
  • In the case of the mammary gland, whole-mount and histological analysis disclosed the absence of significant ductal side branching and alveologenesis in the hormone-treated PR(Cre/+) SRC-2(flox/flox) mammary gland, reinforcing an important role for SRC-2 in cellular proliferative changes that require PR [15].
  • Female hypofertility is due to a placental hypoplasia that most probably reflects a requirement for maternal TIF2 in decidua stromal cells that face the developing placenta [16].

Associations of Ncoa2 with chemical compounds

  • A search for possible coactivators for steroid hormone receptors resulted in identification of glucocorticoid receptor interacting protein 1 (GRIP1) [17].
  • This study demonstrates that the molecular targets of SRC-2 regulation in the murine liver stimulate fatty acid degradation and glycolytic pathway, whereas fatty acid, cholesterol, and steroid biosynthetic pathways are down-regulated [10].
  • At the same time, TIF-2(-/-) mice display significantly lower basal corticosterone levels and a sluggish and blunted initial secretory response to brief emotional and prolonged physical stress [18].
  • The agonistic activities of CPA- and hydroxyflutamide-occupied T877A-AR were hardly affected by N-CoR, whereas TIF2 strongly enhanced their activities [19].
  • In addition, we show that the interaction domain of TIF2 can compete with other AF-2-dependent cofactors for binding to receptors [20].
  • Microarray analysis of RNA from uteri of wild-type and SRC-2(-/-) mice treated with vehicle or P4 showed that SRC-2 was involved in the ability of progesterone to repress specific genes [21].

Physical interactions of Ncoa2

  • The glucocorticoid receptor (GR) interacting protein 1 (GRIP-1) exhibits a half maximal time for fluorescent recovery (tau(R)) of 5 s, reflecting the same rapid exchange as observed for GR [22].

Other interactions of Ncoa2

  • The transcription-intermediary-factor-2 (TIF-2) is a coactivator of the glucocorticoid receptor (GR), and its disruption would be expected to influence glucocorticoid-mediated control of the hypothalamo-pituitary-adrenal (HPA) axis [18].
  • Moreover, there are direct interactions among MEF2C, GRIP-1, and CARM1 [23].
  • We defined the GRIP1:IRF3 interface and showed that endogenous GRIP1 and IRF3 interact in mammalian cells [12].
  • Interestingly, the agonist-mediated activation did not involve modulation of primary coactivators' (e.g. p300 and SRC-2/GRIP-1) activity and/or recruitment [24].
  • A yeast two-hybrid screen with the GRIP1 corepression domain (RD) yielded interferon (IFN) regulatory factor (IRF)3-a downstream effector of Toll-like receptors (TLR) 3/4 and an essential activator of several IFN and chemokine genes [12].

Analytical, diagnostic and therapeutic context of Ncoa2

  • A genomic approach using microarray analysis was employed to identify the subsets of genes that are altered in the livers of SRC-1(-/-), SRC-2(-/-), and SRC-3(-/-) mice [10].
  • Through fluorescence in situ hybridization, we have mapped the mouse SRC-1, SRC-2, and SRC-3 genes to chromosomal locations 12A2-A3, 1A3-A5, and 2H2-H4, respectively [25].
  • GST-pulldowns, mammalian two-hybrid analysis, and immunoprecipitation demonstrate that the mechanism involves direct interactions between MEF-2C and GRIP-1 and is associated with the ability of the SRC to interact with the MADS domain of MEF-2C [7].
  • GPR30 down-regulated the expression of cofactor transcription intermediary factor 2 (TIF2) analyzed using quantitative RT-PCR analysis, and also diminished the expression of TIF2 at protein level analyzed by Western blotting using nuclear extracts from mammary epithelial cells [26].


  1. SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Picard, F., Géhin, M., Annicotte, J., Rocchi, S., Champy, M.F., O'Malley, B.W., Chambon, P., Auwerx, J. Cell (2002) [Pubmed]
  2. A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Gregory, C.W., He, B., Johnson, R.T., Ford, O.H., Mohler, J.L., French, F.S., Wilson, E.M. Cancer Res. (2001) [Pubmed]
  3. Nuclear receptor coactivator p160 proteins enhance the HIV-1 long terminal repeat promoter by bridging promoter-bound factors and the Tat-P-TEFb complex. Kino, T., Slobodskaya, O., Pavlakis, G.N., Chrousos, G.P. J. Biol. Chem. (2002) [Pubmed]
  4. Two distinct tumor cell growth-inhibiting factors from a human rhabdomyosarcoma cell line. Fryling, C.M., Iwata, K.K., Johnson, P.A., Knott, W.B., Todaro, G.J. Cancer Res. (1985) [Pubmed]
  5. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Shiau, A.K., Barstad, D., Loria, P.M., Cheng, L., Kushner, P.J., Agard, D.A., Greene, G.L. Cell (1998) [Pubmed]
  6. Cyclin D-cdk4 activity modulates the subnuclear localization and interaction of MEF2 with SRC-family coactivators during skeletal muscle differentiation. Lazaro, J.B., Bailey, P.J., Lassar, A.B. Genes Dev. (2002) [Pubmed]
  7. The steroid receptor coactivator, GRIP-1, is necessary for MEF-2C-dependent gene expression and skeletal muscle differentiation. Chen, S.L., Dowhan, D.H., Hosking, B.M., Muscat, G.E. Genes Dev. (2000) [Pubmed]
  8. Rabbit antibodies to the cell wall polysaccharide of Streptococcus pneumoniae fail to protect mice from lethal challenge with encapsulated pneumococci. Szu, S.C., Schneerson, R., Robbins, J.B. Infect. Immun. (1986) [Pubmed]
  9. Roles of steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF) 2 in androgen receptor activity in mice. Ye, X., Han, S.J., Tsai, S.Y., DeMayo, F.J., Xu, J., Tsai, M.J., O'Malley, B.W. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  10. The genomic analysis of the impact of steroid receptor coactivators ablation on hepatic metabolism. Jeong, J.W., Kwak, I., Lee, K.Y., White, L.D., Wang, X.P., Brunicardi, F.C., O'malley, B.W., Demayo, F.J. Mol. Endocrinol. (2006) [Pubmed]
  11. Factor recruitment and TIF2/GRIP1 corepressor activity at a collagenase-3 response element that mediates regulation by phorbol esters and hormones. Rogatsky, I., Zarember, K.A., Yamamoto, K.R. EMBO J. (2001) [Pubmed]
  12. The GRIP1:IRF3 interaction as a target for glucocorticoid receptor-mediated immunosuppression. Reily, M.M., Pantoja, C., Hu, X., Chinenov, Y., Rogatsky, I. EMBO J. (2006) [Pubmed]
  13. Subcellular localization of the steroid receptor coactivators (SRCs) and MEF2 in muscle and rhabdomyosarcoma cells. Chen, S.L., Wang, S.C., Hosking, B., Muscat, G.E. Mol. Endocrinol. (2001) [Pubmed]
  14. SRC-1 null mice exhibit moderate motor dysfunction and delayed development of cerebellar Purkinje cells. Nishihara, E., Yoshida-Komiya, H., Chan, C.S., Liao, L., Davis, R.L., O'Malley, B.W., Xu, J. J. Neurosci. (2003) [Pubmed]
  15. Steroid receptor coactivator 2 is critical for progesterone-dependent uterine function and mammary morphogenesis in the mouse. Mukherjee, A., Soyal, S.M., Fernandez-Valdivia, R., Gehin, M., Chambon, P., Demayo, F.J., Lydon, J.P., O'Malley, B.W. Mol. Cell. Biol. (2006) [Pubmed]
  16. The function of TIF2/GRIP1 in mouse reproduction is distinct from those of SRC-1 and p/CIP. Gehin, M., Mark, M., Dennefeld, C., Dierich, A., Gronemeyer, H., Chambon, P. Mol. Cell. Biol. (2002) [Pubmed]
  17. GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors. Hong, H., Kohli, K., Garabedian, M.J., Stallcup, M.R. Mol. Cell. Biol. (1997) [Pubmed]
  18. Insidious adrenocortical insufficiency underlies neuroendocrine dysregulation in TIF-2 deficient mice. Patchev, A.V., Fischer, D., Wolf, S.S., Herkenham, M., G??tz, F., Gehin, M., Chambon, P., Patchev, V.K., Almeida, O.F. FASEB J. (2007) [Pubmed]
  19. Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR). Berrevoets, C.A., Umar, A., Trapman, J., Brinkmann, A.O. Biochem. J. (2004) [Pubmed]
  20. Mechanistic principles in NR box-dependent interaction between nuclear hormone receptors and the coactivator TIF2. Leers, J., Treuter, E., Gustafsson, J.A. Mol. Cell. Biol. (1998) [Pubmed]
  21. The p160 steroid receptor coactivator 2, SRC-2, regulates murine endometrial function and regulates progesterone-independent and -dependent gene expression. Jeong, J.W., Lee, K.Y., Han, S.J., Aronow, B.J., Lydon, J.P., O'Malley, B.W., DeMayo, F.J. Endocrinology (2007) [Pubmed]
  22. Dynamic behavior of transcription factors on a natural promoter in living cells. Becker, M., Baumann, C., John, S., Walker, D.A., Vigneron, M., McNally, J.G., Hager, G.L. EMBO Rep. (2002) [Pubmed]
  23. The coactivator-associated arginine methyltransferase is necessary for muscle differentiation: CARM1 coactivates myocyte enhancer factor-2. Chen, S.L., Loffler, K.A., Chen, D., Stallcup, M.R., Muscat, G.E. J. Biol. Chem. (2002) [Pubmed]
  24. TRAP220 is modulated by the antineoplastic agent 6-Mercaptopurine, and mediates the activation of the NR4A subgroup of nuclear receptors. Wansa, K.D., Muscat, G.E. J. Mol. Endocrinol. (2005) [Pubmed]
  25. Structure and chromosomal locations of mouse steroid receptor coactivator gene family. Ning, G., Jurecic, V., Baldini, A., Xu, J. In Vitro Cell. Dev. Biol. Anim. (1999) [Pubmed]
  26. G protein-coupled receptor 30 down-regulates cofactor expression and interferes with the transcriptional activity of glucocorticoid. Ylikomi, T., Vienonen, A., Ahola, T.M. Eur. J. Biochem. (2004) [Pubmed]
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