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Gene Review

NCOA3  -  nuclear receptor coactivator 3

Homo sapiens

Synonyms: ACTR, AIB-1, AIB1, Amplified in breast cancer 1 protein, BHLHE42, ...
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Disease relevance of NCOA3

  • In contrast, NCOA3 deficiency suppresses v-Ha-ras-induced breast cancer initiation and progression in mice [1].
  • The NCOA3 mRNA encodes a nuclear receptor co-activator that is amplified and over-expressed in a high proportion of breast and ovarian cancers [2].
  • At 13 months of age, mammary ductal ectasia was found in CMV-AIB1/ACTR-Delta3 mice, but secondary and tertiary branching patterns were normal [3].
  • To determine the role of AIB1-Delta3 in breast cancer pathogenesis, we generated transgenic mice with human cytomegalovirus immediate early gene 1 (hCMVIE1) promoter-driven over-expression of human AIB1/ACTR-Delta3 (CMVAIB1/ACTR-Delta3 mice) [3].
  • AIB1 expression correlates with older age (P=0.003), peri- or postmenopausal status (P=0.002) and a higher grade of carcinomas (P=0.04) [4].

Psychiatry related information on NCOA3

  • Like earlier cognitive models such as SOAR, ACT-R, 3CAPS, and EPIC, the proposed cognitive model is implemented in a computer simulation that predicts observable variables such as human response times and error patterns [5].
  • ACT-R/PM can model simple dual tasks such as the psychological refractory period (PRP), including subtle results previously explained with executive process interactive control (EPIC, D. E. Meyer & D. E. Kieras, 1997a) [6].
  • METHOD: An integrated driver model developed in the ACT-R (Adaptive Control of Thought-Rational) cognitive architecture is described that focuses on the component processes of control, monitoring, and decision making in a multilane highway environment [7].

High impact information on NCOA3

  • Cellular levels of REGgamma expression affect estrogen-receptor target-gene expression and cell growth as a result of its ability to promote degradation of the SRC-3 protein [8].
  • Steroid receptor coactivator-3 (SRC-3/AIB1) is an oncogene frequently amplified and overexpressed in breast cancers [8].
  • In exploring the underlying mechanism, we found that the acetylase ACTR can be acetylated by p300/CBP [9].
  • In addition, and unexpectedly, we show that purified ACTR is a potent histone acetyltransferase and appears to define a distinct evolutionary branch to this recently described family [10].
  • A critical component of the innate immune system, TLRs utilize leucine-rich-repeat motifs for ligand binding and a shared cytoplasmic domain to recruit the adaptors MyD88, TRIF, TIRAP, and/or TRAM for downstream signaling [11].

Chemical compound and disease context of NCOA3


Biological context of NCOA3


Anatomical context of NCOA3


Associations of NCOA3 with chemical compounds

  • Both E2-dependent and -independent SRC-3/ERalpha-binding sites were identified [13].
  • Here, we show that overexpression of ACTR not only enhances estrogen-stimulated cell proliferation but also, more strikingly, completely negates the cell cycle arrest effect by tamoxifen and pure antiestrogens [18].
  • Mutations of the ERalpha DNA binding domain did not block this rapid E2-dependent SRC-3 phosphorylation [19].
  • In response to serum stimulation, AR and ACTR are recruited to the corresponding target gene promoters to activate their expression in androgen-independent manner [20].
  • AIB1 expression correlated with ER (r=0.30, P=0.006) [4].

Physical interactions of NCOA3

  • Rapid estrogen-induced phosphorylation of the SRC-3 coactivator occurs in an extranuclear complex containing estrogen receptor [19].
  • Consistent with this finding, we demonstrated that methylation promotes dissociation of the SRC-3/CARM1 coactivator complex [21].
  • Here we show that the receptor-associated coactivator 3 (RAC3) uses two separate LXXLL motifs to bind RAR and RXR [22].
  • These results suggest a mechanism for formation of the complex where the unfolded ACTR domain interacts with the partly folded CBP domain in a rapid and specific manner to form the final stable complex [23].
  • Binding to DRIP occurs in the undifferentiated keratinocyte, but, as the cell differentiates, DRIP(205) levels fall and p160/SRC binding takes over as SRC3 expression increases [24].

Enzymatic interactions of NCOA3


Co-localisations of NCOA3

  • In human testis, immunostaining of SRC-3 colocalized with AR in nuclei of Sertoli cells and peritubular myoid cells, indicating it could function as an AR coactivator in these cells [26].

Regulatory relationships of NCOA3

  • Elevation of ACTR in quiescent cells strongly stimulates the transcription of a subset of E2F-responsive genes that are associated with the G(1)/S transition [18].
  • Using phosphospecific antibodies for six phosphorylation sites, we investigated the mechanisms involved in estradiol (E2)-induced SRC-3 phosphorylation and found that this occurs only when either activated estrogen receptor alpha (ERalpha) or activated ERbeta is present [19].
  • Signaling through the HER-2 receptor pathway activates AIB1 by phosphorylation [27].
  • SRC3 overexpression failed to enhance estrogen-dependent transcription of any ER combination in OBs [28].
  • Furthermore, the receptor tyrosine kinase HER2/Neu, an oncoprotein particularly found overexpressed in breast tumors, cooperates with both ACTR and p300 to stimulate ER81-mediated transcription [29].

Other interactions of NCOA3


Analytical, diagnostic and therapeutic context of NCOA3


  1. Association of NCOA3 polymorphisms with breast cancer risk. Burwinkel, B., Wirtenberger, M., Klaes, R., Schmutzler, R.K., Grzybowska, E., Försti, A., Frank, B., Bermejo, J.L., Bugert, P., Wappenschmidt, B., Butkiewicz, D., Pamula, J., Pekala, W., Zientek, H., Mielzynska, D., Siwinska, E., Bartram, C.R., Hemminki, K. Clin. Cancer Res. (2005) [Pubmed]
  2. Detection of antisense and ribozyme accessible sites on native mRNAs: application to NCOA3 mRNA. Scherr, M., LeBon, J., Castanotto, D., Cunliffe, H.E., Meltzer, P.S., Ganser, A., Riggs, A.D., Rossi, J.J. Mol. Ther. (2001) [Pubmed]
  3. Overexpression of an N-terminally truncated isoform of the nuclear receptor coactivator amplified in breast cancer 1 leads to altered proliferation of mammary epithelial cells in transgenic mice. Tilli, M.T., Reiter, R., Oh, A.S., Henke, R.T., McDonnell, K., Gallicano, G.I., Furth, P.A., Riegel, A.T. Mol. Endocrinol. (2005) [Pubmed]
  4. 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]
  5. Computational modeling of high-level cognition and brain function. Just, M.A., Carpenter, P.A., Varma, S. Human brain mapping. (1999) [Pubmed]
  6. Serial modules in parallel: the psychological refractory period and perfect time-sharing. Byrne, M.D., Anderson, J.R. Psychological review. (2001) [Pubmed]
  7. Modeling driver behavior in a cognitive architecture. Salvucci, D.D. Human factors. (2006) [Pubmed]
  8. The SRC-3/AIB1 coactivator is degraded in a ubiquitin- and ATP-independent manner by the REGgamma proteasome. Li, X., Lonard, D.M., Jung, S.Y., Malovannaya, A., Feng, Q., Qin, J., Tsai, S.Y., Tsai, M.J., O'Malley, B.W. Cell (2006) [Pubmed]
  9. Regulation of hormone-induced histone hyperacetylation and gene activation via acetylation of an acetylase. Chen, H., Lin, R.J., Xie, W., Wilpitz, D., Evans, R.M. Cell (1999) [Pubmed]
  10. 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]
  11. Recognition and signaling by toll-like receptors. West, A.P., Koblansky, A.A., Ghosh, S. Annu. Rev. Cell Dev. Biol. (2006) [Pubmed]
  12. Elevated expression levels of NCOA3, TOP1, and TFAP2C in breast tumors as predictors of poor prognosis. Zhao, C., Yasui, K., Lee, C.J., Kurioka, H., Hosokawa, Y., Oka, T., Inazawa, J. Cancer (2003) [Pubmed]
  13. Identification of target genes in breast cancer cells directly regulated by the SRC-3/AIB1 coactivator. Labhart, P., Karmakar, S., Salicru, E.M., Egan, B.S., Alexiadis, V., O'Malley, B.W., Smith, C.L. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  14. SRC-3 is required for prostate cancer cell proliferation and survival. Zhou, H.J., Yan, J., Luo, W., Ayala, G., Lin, S.H., Erdem, H., Ittmann, M., Tsai, S.Y., Tsai, M.J. Cancer Res. (2005) [Pubmed]
  15. Nuclear receptor coactivator-3 alleles are associated with serum bioavailable testosterone, insulin-like growth factor-1, and vertebral bone mass in men. Sheu, Y.T., Zmuda, J.M., Cauley, J.A., Moffett, S.P., Rosen, C.J., Ishwad, C., Ferrell, R.E. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  16. Expression of sex steroid receptors and their co-factors in normal and malignant breast tissue: AIB1 is a carcinoma-specific co-activator. Hudelist, G., Czerwenka, K., Kubista, E., Marton, E., Pischinger, K., Singer, C.F. Breast Cancer Res. Treat. (2003) [Pubmed]
  17. 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]
  18. ACTR/AIB1 functions as an E2F1 coactivator to promote breast cancer cell proliferation and antiestrogen resistance. Louie, M.C., Zou, J.X., Rabinovich, A., Chen, H.W. Mol. Cell. Biol. (2004) [Pubmed]
  19. Rapid estrogen-induced phosphorylation of the SRC-3 coactivator occurs in an extranuclear complex containing estrogen receptor. Zheng, F.F., Wu, R.C., Smith, C.L., O'Malley, B.W. Mol. Cell. Biol. (2005) [Pubmed]
  20. ACTR/AIB1/SRC-3 and androgen receptor control prostate cancer cell proliferation and tumor growth through direct control of cell cycle genes. Zou, J.X., Zhong, Z., Shi, X.B., Tepper, C.G., Devere White, R.W., Kung, H.J., Chen, H. Prostate (2006) [Pubmed]
  21. Signaling within a Coactivator Complex: Methylation of SRC-3/AIB1 Is a Molecular Switch for Complex Disassembly. Feng, Q., Yi, P., Wong, J., O'malley, B.W. Mol. Cell. Biol. (2006) [Pubmed]
  22. Role of retinoid receptor coactivator pockets in cofactor recruitment and transcriptional regulation. Leo, C., Yang, X., Liu, J., Li, H., Chen, J.D. J. Biol. Chem. (2001) [Pubmed]
  23. Packing, specificity, and mutability at the binding interface between the p160 coactivator and CREB-binding protein. Demarest, S.J., Deechongkit, S., Dyson, H.J., Evans, R.M., Wright, P.E. Protein Sci. (2004) [Pubmed]
  24. Vitamin D and skin cancer. Bikle, D.D. J. Nutr. (2004) [Pubmed]
  25. Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator activity by I kappa B kinase. Wu, R.C., Qin, J., Hashimoto, Y., Wong, J., Xu, J., Tsai, S.Y., Tsai, M.J., O'Malley, B.W. Mol. Cell. Biol. (2002) [Pubmed]
  26. Thyroid receptor activator molecule, TRAM-1, is an androgen receptor coactivator. Tan, J.A., Hall, S.H., Petrusz, P., French, F.S. Endocrinology (2000) [Pubmed]
  27. Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. Osborne, C.K., Bardou, V., Hopp, T.A., Chamness, G.C., Hilsenbeck, S.G., Fuqua, S.A., Wong, J., Allred, D.C., Clark, G.M., Schiff, R. J. Natl. Cancer Inst. (2003) [Pubmed]
  28. Mutual antagonism of estrogen receptors alpha and beta and their preferred interactions with steroid receptor coactivators in human osteoblastic cell lines. Monroe, D.G., Johnsen, S.A., Subramaniam, M., Getz, B.J., Khosla, S., Riggs, B.L., Spelsberg, T.C. J. Endocrinol. (2003) [Pubmed]
  29. Concerted activation of ETS protein ER81 by p160 coactivators, the acetyltransferase p300 and the receptor tyrosine kinase HER2/Neu. Goel, A., Janknecht, R. J. Biol. Chem. (2004) [Pubmed]
  30. Review of the in vivo functions of the p160 steroid receptor coactivator family. Xu, J., Li, Q. Mol. Endocrinol. (2003) [Pubmed]
  31. SUG-1 plays proteolytic and non-proteolytic roles in the control of retinoic acid target genes via its interaction with SRC-3. Ferry, C., Gianni, M., Lalevée, S., Bruck, N., Plassat, J.L., Raska, I., Garattini, E., Rochette-Egly, C. J. Biol. Chem. (2009) [Pubmed]
  32. Molecular structure and biological function of the cancer-amplified nuclear receptor coactivator SRC-3/AIB1. Liao, L., Kuang, S.Q., Yuan, Y., Gonzalez, S.M., O'Malley, B.W., Xu, J. J. Steroid Biochem. Mol. Biol. (2002) [Pubmed]
  33. Endogenously expressed estrogen receptor and coactivator AIB1 interact in MCF-7 human breast cancer cells. Tikkanen, M.K., Carter, D.J., Harris, A.M., Le, H.M., Azorsa, D.O., Meltzer, P.S., Murdoch, F.E. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  34. Molecular cloning of xSRC-3, a novel transcription coactivator from Xenopus, that is related to AIB1, p/CIP, and TIF2. Kim, H.J., Lee, S.K., Na, S.Y., Choi, H.S., Lee, J.W. Mol. Endocrinol. (1998) [Pubmed]
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