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Gene Review

NCOA4  -  nuclear receptor coactivator 4

Homo sapiens

Synonyms: 70 kDa AR-activator, 70 kDa androgen receptor coactivator, ARA70, Androgen receptor coactivator 70 kDa protein, Androgen receptor-associated protein of 70 kDa, ...
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Disease relevance of NCOA4


Psychiatry related information on NCOA4


High impact information on NCOA4

  • The significance of this newly described E2-induced AR transcriptional activity in DU145 human prostate cancer cells was further strengthened by finding patients with Reifenstein partial-androgen-insensitive syndrome that fail in the E2-AR-ARA70 pathway [8].
  • Promotion of agonist activity of antiandrogens by the androgen receptor coactivator, ARA70, in human prostate cancer DU145 cells [9].
  • Using mammalian two-hybrid assay, we report that antiandrogens, hydroxyflutamide, bicalutamide (casodex), cyproterone acetate, and RU58841, and other compounds such as genistein and RU486, can promote the interaction between AR and its coactivator, ARA70, in a dose-dependent manner [9].
  • The chloramphenicol acetyltransferase assay further demonstrates that these antiandrogens and related compounds significantly enhance the AR transcriptional activity by cotransfection of AR and ARA70 in a 1:3 ratio into human prostate cancer DU145 cells [9].
  • Three forms of the ret/PTC oncogene have been identified; the two most common forms, ret/PTC-1 and ret/PTC-3, both result from a paracentric inversion, of the long arm of chromosome 10 [10].

Chemical compound and disease context of NCOA4

  • Taken together, these findings indicate that ARA70 may contribute to the acquired agonist activity of antiandrogens and plays an important role in making prostate cancer cells resistant to androgen ablation and/or antiandrogen therapy [11].
  • Because ARA70 can promote the antiandrogen hydroxyflutamide (HF)-enhanced AR transactivation, the increased ARA70 expression in hormone-refractory prostate tumors may confer the development of HF withdrawal syndrome, commonly diagnosed in patients with the later stages of prostate cancer [12].
  • We examined the expression of ret/PTC in 99 German papillary thyroid carcinomas, including two recently described new variants of ret/PTC3 and identified eight ret/PTC-positive tumours (8%) but none with the new variants [13].

Biological context of NCOA4


Anatomical context of NCOA4

  • Genetic evidence to exclude the androgen receptor co-factor, ARA70 (NCOA4) as a candidate gene for the causation of undermasculinised genitalia [18].
  • Finally, we show that AR can squelch PPARgamma-ARA70 transactivation, which suggests that cross-talk may occur between PPARgamma- and AR-mediated responses in adipocytes [14].
  • Here we describe the cloning of the cDNA for ELE1/ARA70 by RT-PCR from RNA derived from different cell lines (HeLa, DU-145, and LNCaP) [19].
  • Overexpression of either ELE1 isoform in DU-145, HeLa, or COS cells had only minor effects on the transcriptional activity of the human AR [19].
  • Thus, ARA70 is a coactivator for ERalpha and may represent a functional link between ERalpha/AR modulating their cross-talk in models of estrogen signaling in MCF-7 and HeLa cells [20].

Associations of NCOA4 with chemical compounds

  • PPARgamma and ARA70 interact in the absence of the PPARgamma ligand 15-deoxy-Delta12,14-prostaglandin J2, although the addition of exogenous ligand enhances this interaction [14].
  • Interaction of the putative androgen receptor-specific coactivator ARA70/ELE1alpha with multiple steroid receptors and identification of an internally deleted ELE1beta isoform [19].
  • Together, these data suggest that AR may need a specific coactivator(s) such as ARA70 for optimal androgen activity [1].
  • Transcriptional activity of hAR(M745I) was stimulated by 1 or 10nM R1881 and activity was further enhanced by co-expression of ARA70 similar to that of the hAR(wt) [21].
  • In contrast to this finding, an active metabolite of dehydroepiandrosterone, 7-oxo-dehydroepiandrosterone, does not activate AR target gene in the absence or presence of ARA70 [22].

Physical interactions of NCOA4

  • Taken together, we have identified two isoforms of the putative coactivator ARA70/ELE1 that may act as a bridging factor between steroid receptors and components of the transcription initiation complex but which lack some fundamental properties of a classic nuclear receptor coactivator [19].
  • Endogenous coactivator ARA70 interacts with estrogen receptor alpha (ERalpha) and modulates the functional ERalpha/androgen receptor interplay in MCF-7 cells [20].

Regulatory relationships of NCOA4


Other interactions of NCOA4

  • Thus, while our findings are in agreement with published reports which indicate that RFG interacts with AR-HBD in a ligand-dependent fashion, in our assays RFG does not exert major effects on the activity of the hAR in response to androgen or to other steroid hormones [15].
  • In an effort to understand transcriptional regulation by the peroxisome proliferator-activated receptor gamma (PPARgamma), we have investigated its potential interaction with coregulators and have identified ARA70 as a ligand-enhanced coactivator [14].
  • Sequence analysis of this clone revealed that it encoded a portion of a protein that had been previously characterized as RFG (RET Fused Gene) [15].
  • RFG/ELE1alpha/ARA70 mRNA levels in PC-3 cells, which express both estrogen receptor subtypes, were upregulated by 17beta-estradiol and inhibited by the antiestrogen ICI-182780 [17].
  • The LXXLL motif of ARA70 is essential for interaction with VDR and partially responsible for its function as a coactivator of VDR [25].

Analytical, diagnostic and therapeutic context of NCOA4


  1. Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells. Yeh, S., Chang, C. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  2. Expression of androgen receptor coactivator ARA70/ELE1 in androgenic alopecia. Lee, P., Zhu, C.C., Sadick, N.S., Diwan, A.H., Zhang, P.S., Liu, J.S., Prieto, V.G. J. Cutan. Pathol. (2005) [Pubmed]
  3. Molecular characterization of RET/PTC3; a novel rearranged version of the RETproto-oncogene in a human thyroid papillary carcinoma. Santoro, M., Dathan, N.A., Berlingieri, M.T., Bongarzone, I., Paulin, C., Grieco, M., Pierotti, M.A., Vecchio, G., Fusco, A. Oncogene (1994) [Pubmed]
  4. Quantitation of androgen receptor gene expression in sporadic breast tumors by real-time RT-PCR: evidence that MYC is an AR-regulated gene. Bièche, I., Parfait, B., Tozlu, S., Lidereau, R., Vidaud, M. Carcinogenesis (2001) [Pubmed]
  5. Activation of androgen receptor-associated protein 70 (ARA70) mRNA expression in ovarian cancer. Shaw, P.A., Rittenberg, P.V., Brown, T.J. Gynecol. Oncol. (2001) [Pubmed]
  6. Stimulation of prostate cancer cellular proliferation and invasion by the androgen receptor co-activator ARA70. Peng, Y., Li, C.X., Chen, F., Wang, Z., Ligr, M., Melamed, J., Wei, J., Gerald, W., Pagano, M., Garabedian, M.J., Lee, P. Am. J. Pathol. (2008) [Pubmed]
  7. Human papilloma virus 16 E7 oncogene does not cooperate with RET/PTC 3 oncogene in the neoplastic transformation of thyroid cells in transgenic mice. Portella, G., Borselli, C., Santoro, M., Gerbasio, D., D'Armiento, M.R., Dumont, J.E., Ledent, C., Rothstein, J.L., Vecchio, G., Fusco, A. Oncol. Res. (2000) [Pubmed]
  8. From estrogen to androgen receptor: a new pathway for sex hormones in prostate. Yeh, S., Miyamoto, H., Shima, H., Chang, C. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  9. Promotion of agonist activity of antiandrogens by the androgen receptor coactivator, ARA70, in human prostate cancer DU145 cells. Miyamoto, H., Yeh, S., Wilding, G., Chang, C. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  10. Breakpoint characterization of the ret/PTC oncogene in human papillary thyroid carcinoma. Smanik, P.A., Furminger, T.L., Mazzaferri, E.L., Jhiang, S.M. Hum. Mol. Genet. (1995) [Pubmed]
  11. Reducing the agonist activity of antiandrogens by a dominant-negative androgen receptor coregulator ARA70 in prostate cancer cells. Rahman, M.M., Miyamoto, H., Takatera, H., Yeh, S., Altuwaijri, S., Chang, C. J. Biol. Chem. (2003) [Pubmed]
  12. Functional domain and motif analyses of androgen receptor coregulator ARA70 and its differential expression in prostate cancer. Hu, Y.C., Yeh, S., Yeh, S.D., Sampson, E.R., Huang, J., Li, P., Hsu, C.L., Ting, H.J., Lin, H.K., Wang, L., Kim, E., Ni, J., Chang, C. J. Biol. Chem. (2004) [Pubmed]
  13. Expression of Ret/PTC1, -2, -3, -delta3 and -4 in German papillary thyroid carcinoma. Mayr, B., Pötter, E., Goretzki, P., Rüschoff, J., Dietmaier, W., Hoang-Vu, C., Dralle, H., Brabant, G. Br. J. Cancer (1998) [Pubmed]
  14. Identification of ARA70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma. Heinlein, C.A., Ting, H.J., Yeh, S., Chang, C. J. Biol. Chem. (1999) [Pubmed]
  15. RFG (ARA70, ELE1) interacts with the human androgen receptor in a ligand-dependent fashion, but functions only weakly as a coactivator in cotransfection assays. Gao, T., Brantley, K., Bolu, E., McPhaul, M.J. Mol. Endocrinol. (1999) [Pubmed]
  16. Heterogeneous expression and functions of androgen receptor co-factors in primary prostate cancer. Li, P., Yu, X., Ge, K., Melamed, J., Roeder, R.G., Wang, Z. Am. J. Pathol. (2002) [Pubmed]
  17. Expression of RFG/ELE1alpha/ARA70 in normal and malignant prostatic epithelial cell cultures and lines: regulation by methylation and sex steroids. Tekur, S., Lau, K.M., Long, J., Burnstein, K., Ho, S.M. Mol. Carcinog. (2001) [Pubmed]
  18. Genetic evidence to exclude the androgen receptor co-factor, ARA70 (NCOA4) as a candidate gene for the causation of undermasculinised genitalia. Lim, H.N., Hawkins, J.R., Hughes, I.A. Clin. Genet. (2001) [Pubmed]
  19. Interaction of the putative androgen receptor-specific coactivator ARA70/ELE1alpha with multiple steroid receptors and identification of an internally deleted ELE1beta isoform. Alen, P., Claessens, F., Schoenmakers, E., Swinnen, J.V., Verhoeven, G., Rombauts, W., Peeters, B. Mol. Endocrinol. (1999) [Pubmed]
  20. Endogenous coactivator ARA70 interacts with estrogen receptor alpha (ERalpha) and modulates the functional ERalpha/androgen receptor interplay in MCF-7 cells. Lanzino, M., De Amicis, F., McPhaul, M.J., Marsico, S., Panno, M.L., Andò, S. J. Biol. Chem. (2005) [Pubmed]
  21. A naturally occurring mutation in the human androgen receptor of a subject with complete androgen insensitivity confers binding and transactivation by estradiol. Bonagura, T.W., Deng, M., Brown, T.R. Mol. Cell. Endocrinol. (2007) [Pubmed]
  22. Delta5-androstenediol is a natural hormone with androgenic activity in human prostate cancer cells. Miyamoto, H., Yeh, S., Lardy, H., Messing, E., Chang, C. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  23. Functional analysis of androgen receptor N-terminal and ligand binding domain interacting coregulators in prostate cancer. Yeh, S., Sampson, E.R., Lee, D.K., Kim, E., Hsu, C.L., Chen, Y.L., Chang, H.C., Altuwaijri, S., Huang, K.E., Chang, C. J. Formos. Med. Assoc. (2000) [Pubmed]
  24. An Orally Administered Multitarget Tyrosine Kinase Inhibitor, SU11248, Is a Novel Potent Inhibitor of Thyroid Oncogenic RET/Papillary Thyroid Cancer Kinases. Kim, D.W., Jo, Y.S., Jung, H.S., Chung, H.K., Song, J.H., Park, K.C., Park, S.H., Hwang, J.H., Rha, S.Y., Kweon, G.R., Lee, S.J., Jo, K.W., Shong, M. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  25. Androgen-receptor coregulators mediate the suppressive effect of androgen signals on vitamin D receptor activity. Ting, H.J., Bao, B.Y., Hsu, C.L., Lee, Y.F. Endocrine (2005) [Pubmed]
  26. The two genes generating RET/PTC3 are localized in chromosomal band 10q11.2. Minoletti, F., Butti, M.G., Coronelli, S., Miozzo, M., Sozzi, G., Pilotti, S., Tunnacliffe, A., Pierotti, M.A., Bongarzone, I. Genes Chromosomes Cancer (1994) [Pubmed]
  27. Myostatin negatively regulates the expression of the steroid receptor co-factor ARA70. Siriett, V., Nicholas, G., Berry, C., Watson, T., Hennebry, A., Thomas, M., Ling, N., Sharma, M., Kambadur, R. J. Cell. Physiol. (2006) [Pubmed]
  28. Loss of androgen receptor associated protein 70 (ARA70) expression in a subset of HER2-positive breast cancers. Kollara, A., Kahn, H.J., Marks, A., Brown, T.J. Breast Cancer Res. Treat. (2001) [Pubmed]
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