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Gene Review

NCOA1  -  nuclear receptor coactivator 1

Homo sapiens

Synonyms: BHLHE74, Class E basic helix-loop-helix protein 74, F-SRC-1, KAT13A, NCoA-1, ...
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Disease relevance of NCOA1


High impact information on NCOA1

  • Biochemical fractionation shows that SRA exists in distinct ribonucleoprotein complexes, one of which contains the nuclear receptor coactivator steroid receptor coactivator 1 [6].
  • These results, together with the observation that two consecutive LXXLL motifs of SRC-1 make identical contacts with both subunits of a PPAR-gamma homodimer, suggest a general mechanism for the assembly of nuclear receptors with co-activators [7].
  • Transcriptional activation by nuclear receptors requires a carboxy-terminal helical region, termed activation function-2 (AF-2), that forms part of the ligand-binding pocket and undergoes a conformational change required for the recruitment of co-activator proteins, including NCoA-1/SRC-1 [8].
  • Glutamate and lysine residues that are highly conserved in LBDs of nuclear receptors form a 'charge clamp' that contacts backbone atoms of the LXXLL helices of SRC-1 [7].
  • Steroid receptor coactivator-1 is a histone acetyltransferase [9].

Chemical compound and disease context of NCOA1


Biological context of NCOA1


Anatomical context of NCOA1

  • Although the PR(Cre/+)SRC-2(flox/flox) uterus could mount a partial decidual response, removal of SRC-1 in the PR(Cre/+)SRC-2(flox/flox) uterus resulted in a complete block in decidualization, confirming that uterine SRC-2 and -1 are both required for P-initiated transcriptional programs which lead to full decidualization [18].
  • Finally, overexpression of GRIP1 or SRC-1 does not convert COUP-TFI from a transcriptional repressor into a transcriptional activator in HeLa cells [19].
  • Previously, our lab has shown that SRC-1 and CBP modulate estrogen receptor (ER)-mediated induction of progestin receptor (PR) gene expression in the ventromedial nucleus of the hypothalamus (VMN) and hormone-dependent sexual receptivity in female rats [14].
  • The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-dependent transcription factor that is important in adipocyte differentiation and glucose homeostasis and which depends on interactions with co-activators, including steroid receptor co-activating factor-1 (SRC-1) [7].
  • Epithelial cells facilitated interactions of AR with SRC-1 in an androgen-dependent manner [20].

Associations of NCOA1 with chemical compounds


Physical interactions of NCOA1

  • To define the mechanism of coactivator recognition, we determined the crystal structure of the NCoA-1 PAS-B domain in complex with the STAT6 LXXLL motif [26].
  • Nuclear receptor coactivator SRC-1 interacts with the Q-rich subdomain of the AhR and modulates its transactivation potential [27].
  • FRET data also demonstrate that, in contrast to ERalpha, ERbeta interacts with all three SRC RIDs in a ligand-independent manner [28].
  • We show here that cyclin D1 also interacts in a ligand-independent fashion with coactivators of the SRC-1 family through a motif that resembles the leucine-rich coactivator binding motif of nuclear receptors [29].
  • We report the x-ray crystal structure of the ligand binding domain of PPAR alpha (NR1C1) as a complex with the agonist ligand GW409544 and a coactivator motif from the steroid receptor coactivator 1 [30].

Regulatory relationships of NCOA1


Other interactions of NCOA1


Analytical, diagnostic and therapeutic context of NCOA1


  1. Gene expression signatures identify rhabdomyosarcoma subtypes and detect a novel t(2;2)(q35;p23) translocation fusing PAX3 to NCOA1. Wachtel, M., Dettling, M., Koscielniak, E., Stegmaier, S., Treuner, J., Simon-Klingenstein, K., Bühlmann, P., Niggli, F.K., Schäfer, B.W. Cancer Res. (2004) [Pubmed]
  2. Review of the in vivo functions of the p160 steroid receptor coactivator family. Xu, J., Li, Q. Mol. Endocrinol. (2003) [Pubmed]
  3. Steroid receptor coactivator AIB1 in endometrial carcinoma, hyperplasia and normal endometrium: correlation with clinicopathologic parameters and biomarkers. Balmer, N.N., Richer, J.K., Spoelstra, N.S., Torkko, K.C., Lyle, P.L., Singh, M. Mod. Pathol. (2006) [Pubmed]
  4. Expression of steroid receptor coactivators in cultured cells from paired myometrial and fibroid tissues. Hussein-Fikret, S., Fuller, P.J., Gargett, C.E. J. Soc. Gynecol. Investig. (2005) [Pubmed]
  5. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Anzick, S.L., Kononen, J., Walker, R.L., Azorsa, D.O., Tanner, M.M., Guan, X.Y., Sauter, G., Kallioniemi, O.P., Trent, J.M., Meltzer, P.S. Science (1997) [Pubmed]
  6. A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex. Lanz, R.B., McKenna, N.J., Onate, S.A., Albrecht, U., Wong, J., Tsai, S.Y., Tsai, M.J., O'Malley, B.W. Cell (1999) [Pubmed]
  7. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nolte, R.T., Wisely, G.B., Westin, S., Cobb, J.E., Lambert, M.H., Kurokawa, R., Rosenfeld, M.G., Willson, T.M., Glass, C.K., Milburn, M.V. Nature (1998) [Pubmed]
  8. Interactions controlling the assembly of nuclear-receptor heterodimers and co-activators. Westin, S., Kurokawa, R., Nolte, R.T., Wisely, G.B., McInerney, E.M., Rose, D.W., Milburn, M.V., Rosenfeld, M.G., Glass, C.K. Nature (1998) [Pubmed]
  9. Steroid receptor coactivator-1 is a histone acetyltransferase. Spencer, T.E., Jenster, G., Burcin, M.M., Allis, C.D., Zhou, J., Mizzen, C.A., McKenna, N.J., Onate, S.A., Tsai, S.Y., Tsai, M.J., O'Malley, B.W. Nature (1997) [Pubmed]
  10. 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]
  11. 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]
  12. Loss of coordinated androgen regulation in nonmalignant ovarian epithelial cells with BRCA1/2 mutations and ovarian cancer cells. Evangelou, A., Letarte, M., Jurisica, I., Sultan, M., Murphy, K.J., Rosen, B., Brown, T.J. Cancer Res. (2003) [Pubmed]
  13. Inhibiting proteasomal proteolysis sustains estrogen receptor-alpha activation. Fan, M., Nakshatri, H., Nephew, K.P. Mol. Endocrinol. (2004) [Pubmed]
  14. Nuclear receptor coactivators function in estrogen receptor- and progestin receptor-dependent aspects of sexual behavior in female rats. Molenda-Figueira, H.A., Williams, C.A., Griffin, A.L., Rutledge, E.M., Blaustein, J.D., Tetel, M.J. Hormones and behavior. (2006) [Pubmed]
  15. Variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in the Framingham Heart Study. Peter, I., Shearman, A.M., Zucker, D.R., Schmid, C.H., Demissie, S., Cupples, L.A., Larson, M.G., Vasan, R.S., D'Agostino, R.B., Karas, R.H., Mendelsohn, M.E., Housman, D.E., Levy, D. J. Hypertens. (2005) [Pubmed]
  16. Recruitment of the NCoA/SRC-1/p160 family of transcriptional coactivators by the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator complex. Beischlag, T.V., Wang, S., Rose, D.W., Torchia, J., Reisz-Porszasz, S., Muhammad, K., Nelson, W.E., Probst, M.R., Rosenfeld, M.G., Hankinson, O. Mol. Cell. Biol. (2002) [Pubmed]
  17. An LXXLL motif in the transactivation domain of STAT6 mediates recruitment of NCoA-1/SRC-1. Litterst, C.M., Pfitzner, E. J. Biol. Chem. (2002) [Pubmed]
  18. Steroid receptor coactivator 2 is essential for progesterone-dependent uterine function and mammary morphogenesis: Insights from the mouse-implications for the human. Mukherjee, A., Amato, P., Allred, D.C., Fernandez-Valdivia, R., Nguyen, J., O'malley, B.W., Demayo, F.J., Lydon, J.P. J. Steroid Biochem. Mol. Biol. (2006) [Pubmed]
  19. Transcription activation by the orphan nuclear receptor, chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI). Definition of the domain involved in the glucocorticoid response of the phosphoenolpyruvate carboxykinase gene. Sugiyama, T., Wang, J.C., Scott, D.K., Granner, D.K. J. Biol. Chem. (2000) [Pubmed]
  20. Stromal-epithelial cell interactions and androgen receptor-coregulator recruitment is altered in the tissue microenvironment of prostate cancer. Cano, P., Godoy, A., Escamilla, R., Dhir, R., Onate, S.A. Cancer Res. (2007) [Pubmed]
  21. CREB binding protein acts synergistically with steroid receptor coactivator-1 to enhance steroid receptor-dependent transcription. Smith, C.L., Oñate, S.A., Tsai, M.J., O'Malley, B.W. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  22. Multiple signal input and output domains of the 160-kilodalton nuclear receptor coactivator proteins. Ma, H., Hong, H., Huang, S.M., Irvine, R.A., Webb, P., Kushner, P.J., Coetzee, G.A., Stallcup, M.R. Mol. Cell. Biol. (1999) [Pubmed]
  23. Distinct roles of the steroid receptor coactivator 1 and of MED1 in retinoid-induced transcription and cellular differentiation. Flajollet, S., Lefebvre, B., Rachez, C., Lefebvre, P. J. Biol. Chem. (2006) [Pubmed]
  24. Interaction between the amino- and carboxyl-terminal regions of the rat androgen receptor modulates transcriptional activity and is influenced by nuclear receptor coactivators. Ikonen, T., Palvimo, J.J., Jänne, O.A. J. Biol. Chem. (1997) [Pubmed]
  25. The Src kinase pathway promotes tamoxifen agonist action in Ishikawa endometrial cells through phosphorylation-dependent stabilization of estrogen receptor (alpha) promoter interaction and elevated steroid receptor coactivator 1 activity. Shah, Y.M., Rowan, B.G. Mol. Endocrinol. (2005) [Pubmed]
  26. Structure of the NCoA-1/SRC-1 PAS-B domain bound to the LXXLL motif of the STAT6 transactivation domain. Razeto, A., Ramakrishnan, V., Litterst, C.M., Giller, K., Griesinger, C., Carlomagno, T., Lakomek, N., Heimburg, T., Lodrini, M., Pfitzner, E., Becker, S. J. Mol. Biol. (2004) [Pubmed]
  27. Nuclear receptor coactivator SRC-1 interacts with the Q-rich subdomain of the AhR and modulates its transactivation potential. Kumar, M.B., Perdew, G.H. Gene Expr. (1999) [Pubmed]
  28. Isoform-selective interactions between estrogen receptors and steroid receptor coactivators promoted by estradiol and ErbB-2 signaling in living cells. Bai, Y., Giguére, V. Mol. Endocrinol. (2003) [Pubmed]
  29. Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1. Zwijsen, R.M., Buckle, R.S., Hijmans, E.M., Loomans, C.J., Bernards, R. Genes Dev. (1998) [Pubmed]
  30. Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Xu, H.E., Lambert, M.H., Montana, V.G., Plunket, K.D., Moore, L.B., Collins, J.L., Oplinger, J.A., Kliewer, S.A., Gampe, R.T., McKee, D.D., Moore, J.T., Willson, T.M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  31. Synthetic 19-nortestosterone derivatives as estrogen receptor alpha subtype-selective ligands induce similar receptor conformational changes and steroid receptor coactivator recruitment than natural estrogens. García-Becerra, R., Borja-Cacho, E., Cooney, A.J., Smith, C.L., Lemus, A.E., Pérez-Palacios, G., Larrea, F. J. Steroid Biochem. Mol. Biol. (2006) [Pubmed]
  32. Steroid receptor coactivator-1 and its family members differentially regulate transactivation by the tumor suppressor protein p53. Lee, S.K., Kim, H.J., Kim, J.W., Lee, J.W. Mol. Endocrinol. (1999) [Pubmed]
  33. Transcriptional Activation of CYP2C9, CYP1A1, and CYP1A2 by Hepatocyte Nuclear Factor 4{alpha} Requires Coactivators Peroxisomal Proliferator Activated Receptor-{gamma} Coactivator 1{alpha} and Steroid Receptor Coactivator 1. Mart??nez-Jim??nez, C.P., Castell, J.V., G??mez-Lech??n, M.J., Jover, R. Mol. Pharmacol. (2006) [Pubmed]
  34. Bcl3, an IkappaB protein, as a novel transcription coactivator of the retinoid X receptor. Na, S.Y., Choi, H.S., Kim, J.W., Na, D.S., Lee, J.W. J. Biol. Chem. (1998) [Pubmed]
  35. Ligand-dependent interactions of coactivators steroid receptor coactivator-1 and peroxisome proliferator-activated receptor binding protein with nuclear hormone receptors can be imaged in live cells and are required for transcription. Llopis, J., Westin, S., Ricote, M., Wang, Z., Cho, C.Y., Kurokawa, R., Mullen, T.M., Rose, D.W., Rosenfeld, M.G., Tsien, R.Y., Glass, C.K., Wang, J. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  36. Sumoylation of the progesterone receptor and of the steroid receptor coactivator SRC-1. Chauchereau, A., Amazit, L., Quesne, M., Guiochon-Mantel, A., Milgrom, E. J. Biol. Chem. (2003) [Pubmed]
  37. Ligand-controlled interaction of histone acetyltransferase binding to ORC-1 (HBO1) with the N-terminal transactivating domain of progesterone receptor induces steroid receptor coactivator 1-dependent coactivation of transcription. Georgiakaki, M., Chabbert-Buffet, N., Dasen, B., Meduri, G., Wenk, S., Rajhi, L., Amazit, L., Chauchereau, A., Burger, C.W., Blok, L.J., Milgrom, E., Lombès, M., Guiochon-Mantel, A., Loosfelt, H. Mol. Endocrinol. (2006) [Pubmed]
  38. Inverse relationship between ER-beta and SRC-1 predicts outcome in endocrine-resistant breast cancer. Myers, E., Fleming, F.J., Crotty, T.B., Kelly, G., McDermott, E.W., O'higgins, N.J., Hill, A.D., Young, L.S. Br. J. Cancer (2004) [Pubmed]
  39. Crystallization and preliminary crystallographic studies of the NCoA-1/SRC-1 PAS-B domain bound to the LXXLL motif of the STAT6 transactivation domain. Razeto, A., Pfitzner, E., Becker, S. Acta Crystallogr. D Biol. Crystallogr. (2004) [Pubmed]
  40. Mifepristone alters expression of endometrial steroid receptors and their cofactors in new users of medroxyprogesterone acetate. Jain, J.K., Li, A., Yang, W., Minoo, P., Felix, J.C. Fertil. Steril. (2007) [Pubmed]
  41. Dissection of the LXXLL nuclear receptor-coactivator interaction motif using combinatorial peptide libraries: discovery of peptide antagonists of estrogen receptors alpha and beta. Chang, C., Norris, J.D., Grøn, H., Paige, L.A., Hamilton, P.T., Kenan, D.J., Fowlkes, D., McDonnell, D.P. Mol. Cell. Biol. (1999) [Pubmed]
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