Nuclear receptor coactivator 3 explained

The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the NCOA3 gene.^{[1] [2]} NCOA3 is also frequently called 'amplified in breast 1' (AIB1), steroid receptor coactivator-3 (SRC-3), or thyroid hormone receptor activator molecule 1 (TRAM-1).

Function

NCOA3 is a transcriptional coactivator protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA3 is recruited to DNA promotion sites by ligand-activated nuclear receptors. NCOA3, in turn, acylates histones, which makes downstream DNA more accessible to transcription. Hence, NCOA3 assists nuclear receptors in the upregulation of gene expression.^{[3] [4]}

Clinical significance

The ratio of PAX2 to AIB-1 protein expression may be predictive of the effectiveness of tamoxifen in breast cancer treatment.^{[5] [6]}

Several molecular mechanisms implicate NCOA3 (AIB1) in the endocrine therapy resistance (depicted in the figure). Signaling pathways or mutations (i.e. HER2/neu overexpression, activating mutations in PIK3CA (PI3K), activating mutations in the proto-oncogene tyrosine-protein kinase Src, etc.) that lead to persistent activation of ERK and/or PIK3CA/AKT kinase pathways result, in one hand in an enhanced AIB1 transcriptional coactivation capacity,^[7] and in the other hand in the inhibition of the proteasome-dependent AIB1 turn-over and therefore, in AIB1 overexpression.^[8] In both conditions, the equilibrium of estrogen receptor (ER) complex formation is displaced towards a transcriptionally active complex and thus, counteracting the inhibition caused by anti-estrogenic drugs such as tamoxifen or fulvestrant (selective estrogen receptor modulators). The result is the restoration of estrogen-sensitive gene transcription and the promotion of cancer progression and/or relapse.

Notably, tumors diagnosed with concomitant overexpression of AIB1 and HER2/neu have worse outcome with tamoxifen therapy than all other patients combined.^[9] In addition, dormant tumor cells of luminal breast cancers treated with endocrine therapy may acquire with time, mutations that alter kinase signalling pathways and ultimately enhance AIB1 oncogenic functions. Also, estrogen receptor-PAX2 complexes repress HER2/neu expression, but loss of PAX2 expression may result in de novo HER2/neu expression and initiate endocrine therapy resistance and relapse.^[10]

Interactions

Nuclear receptor coactivator 3 has been shown to interact with:

• Androgen receptor,^{[11] [12] [13]}
• CHUK and
• CREB-binding protein,^[14]
• DDX17,^[15]
• DDX5,^[15]
• Estrogen receptor alpha,^{[15] [16] [17]}
• Estrogen receptor beta,^{[16] [18]}
• Glucocorticoid receptor,^{[19] [20]}
• IKBKG,
• IKK2,^[21]
• Peroxisome proliferator-activated receptor gamma,^[22] and
• Retinoid X receptor alpha.^{[23] [24]}

Further reading

• Liao L, Kuang SQ, Yuan Y, Gonzalez SM, O'Malley BW, Xu J . Molecular structure and biological function of the cancer-amplified nuclear receptor coactivator SRC-3/AIB1 . J. Steroid Biochem. Mol. Biol. . 83 . 1–5 . 3–14 . 2003 . 12650696 . 10.1016/S0960-0760(02)00254-6 . 40981759 .
• Liu F, Ventura F, Doody J, Massagué J . Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs . Mol. Cell. Biol. . 15 . 7 . 3479–86 . 1995 . 7791754 . 230584 . 10.1128/mcb.15.7.3479.
• Guan XY, Xu J, Anzick SL, Zhang H, Trent JM, Meltzer PS . Hybrid selection of transcribed sequences from microdissected DNA: isolation of genes within amplified region at 20q11-q13.2 in breast cancer . Cancer Res. . 56 . 15 . 3446–50 . 1996 . 8758910 .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Res. . 6 . 9 . 791–806 . 1997 . 8889548 . 10.1101/gr.6.9.791 . free .
• Margolis RL, Abraham MR, Gatchell SB, Li SH, Kidwai AS, Breschel TS, Stine OC, Callahan C, McInnis MG, Ross CA . cDNAs with long CAG trinucleotide repeats from human brain . Hum. Genet. . 100 . 1 . 114–22 . 1997 . 9225980 . 10.1007/s004390050476 . 25999127 .
• Li H, Gomes PJ, Chen JD . RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2 . Proc. Natl. Acad. Sci. U.S.A. . 94 . 16 . 8479–84 . 1997 . 9238002 . 22964 . 10.1073/pnas.94.16.8479 . 1997PNAS...94.8479L . free .
• Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS . AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer . Science . 277 . 5328 . 965–8 . 1997 . 9252329 . 10.1126/science.277.5328.965 .
• Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM . Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300 . Cell . 90 . 3 . 569–80 . 1997 . 9267036 . 10.1016/S0092-8674(00)80516-4 . 15284825 . free .
• Takeshita A, Cardona GR, Koibuchi N, Suen CS, Chin WW . TRAM-1, A novel 160-kDa thyroid hormone receptor activator molecule, exhibits distinct properties from steroid receptor coactivator-1 . J. Biol. Chem. . 272 . 44 . 27629–34 . 1997 . 9346901 . 10.1074/jbc.272.44.27629 . free .
• Korzus E, Torchia J, Rose DW, Xu L, Kurokawa R, McInerney EM, Mullen TM, Glass CK, Rosenfeld MG . Transcription factor-specific requirements for coactivators and their acetyltransferase functions . Science . 279 . 5351 . 703–7 . 1998 . 9445475 . 10.1126/science.279.5351.703 . 1998Sci...279..703K .
• Shirazi SK, Bober MA, Coetzee GA . Polymorphic exonic CAG microsatellites in the gene amplified in breast cancer (AIB1 gene) . Clin. Genet. . 54 . 1 . 102–3 . 1998 . 9727751 . 10.1111/j.1399-0004.1998.tb03704.x . 1315265 .
• Wang JC, Stafford JM, Granner DK . SRC-1 and GRIP1 coactivate transcription with hepatocyte nuclear factor 4 . J. Biol. Chem. . 273 . 47 . 30847–50 . 1998 . 9812974 . 10.1074/jbc.273.47.30847 . 3968904 . free .
• Zwijsen RM, Buckle RS, Hijmans EM, Loomans CJ, Bernards R . Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1 . Genes Dev. . 12 . 22 . 3488–98 . 1999 . 9832502 . 317237 . 10.1101/gad.12.22.3488 .
• Chen H, Lin RJ, Xie W, Wilpitz D, Evans RM . Regulation of hormone-induced histone hyperacetylation and gene activation via acetylation of an acetylase . Cell . 98 . 5 . 675–86 . 1999 . 10490106 . 10.1016/S0092-8674(00)80054-9 . 14697597 . free .
• Ebisawa T, Tada K, Kitajima I, Tojo K, Sampath TK, Kawabata M, Miyazono K, Imamura T . Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation . J. Cell Sci. . 112 . 20 . 3519–27 . 2000 . 10.1242/jcs.112.20.3519 . 10504300 .
• Xie W, Hong H, Yang NN, Lin RJ, Simon CM, Stallcup MR, Evans RM . Constitutive activation of transcription and binding of coactivator by estrogen-related receptors 1 and 2 . Mol. Endocrinol. . 13 . 12 . 2151–62 . 2000 . 10598588 . 10.1210/mend.13.12.0381 . free .
• Pao GM, Janknecht R, Ruffner H, Hunter T, Verma IM . CBP/p300 interact with and function as transcriptional coactivators of BRCA1 . Proc. Natl. Acad. Sci. U.S.A. . 97 . 3 . 1020–5 . 2000 . 10655477 . 15508 . 10.1073/pnas.97.3.1020 . 2000PNAS...97.1020P . free .
• Leo C, Li H, Chen JD . Differential mechanisms of nuclear receptor regulation by receptor-associated coactivator 3 . J. Biol. Chem. . 275 . 8 . 5976–82 . 2000 . 10681591 . 10.1074/jbc.275.8.5976 . free .
• Font de Mora J, Brown M . AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor . Mol. Cell. Biol. . 20 . 14 . 5041–7 . 2000 . 10866661 . 85954 . 10.1128/MCB.20.14.5041-5047.2000 .
• Tan JA, Hall SH, Petrusz P, French FS . Thyroid receptor activator molecule, TRAM-1, is an androgen receptor coactivator . Endocrinology . 141 . 9 . 3440–50 . 2000 . 10965917 . 10.1210/endo.141.9.7680 . free .

Notes and References

1. Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS . AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer . Science . 277 . 5328 . 965–8 . August 1997 . 9252329 . 10.1126/science.277.5328.965 .
2. Takeshita A, Cardona GR, Koibuchi N, Suen CS, Chin WW . TRAM-1, A novel 160-kDa thyroid hormone receptor activator molecule, exhibits distinct properties from steroid receptor coactivator-1 . J. Biol. Chem. . 272 . 44 . 27629–34 . October 1997 . 9346901 . 10.1074/jbc.272.44.27629 . free .
3. Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS . AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer . Science . 277 . 5328 . 965–8 . 1997 . 9252329 . 10.1126/science.277.5328.965 .
4. Takeshita A, Cardona GR, Koibuchi N, Suen CS, Chin WW . TRAM-1, A novel 160-kDa thyroid hormone receptor activator molecule, exhibits distinct properties from steroid receptor coactivator-1 . J Biol Chem . 272 . 44 . 27629–34 . 1997 . 9346901 . 10.1074/jbc.272.44.27629 . free .
5. Web site: Study sheds new light on tamoxifen resistance . 2008-11-13 . Cordis News . Cordis . 2008-11-14 . 2009-02-20 . https://web.archive.org/web/20090220060249/http://cordis.europa.eu/fetch?CALLER=EN_NEWS&ACTION=D&SESSION=&RCN=30093 . dead .
6. Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, Jiang J, Howat WJ, Ali S, Carroll JS . 6 . Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen . Nature . 456 . 7222 . 663–6 . December 2008 . 19005469 . 2920208 . 10.1038/nature07483 . 2008Natur.456..663H .
7. Font de Mora J, Brown M . AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor . Molecular and Cellular Biology . 20 . 14 . 5041–7 . July 2000 . 10866661 . 85954 . 10.1128/MCB.20.14.5041-5047.2000 .
8. Ferrero M, Avivar A, García-Macías MC, Font de Mora J . Phosphoinositide 3-kinase/AKT signaling can promote AIB1 stability independently of GSK3 phosphorylation . Cancer Research . 68 . 13 . 5450–9 . July 2008 . 18593948 . 10.1158/0008-5472.CAN-07-6433 . free .
9. Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, Fuqua SA, Wong J, Allred DC, Clark GM, Schiff R . 6 . Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer . Journal of the National Cancer Institute . 95 . 5 . 353–61 . March 2003 . 12618500 . 10.1093/jnci/95.5.353 . free .
10. Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, Jiang J, Howat WJ, Ali S, Carroll JS . 6 . Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen . Nature . 456 . 7222 . 663–6 . December 2008 . 19005469 . 2920208 . 10.1038/nature07483 . 2008Natur.456..663H .
11. Tan JA, Hall SH, Petrusz P, French FS . Thyroid receptor activator molecule, TRAM-1, is an androgen receptor coactivator . Endocrinology . 141 . 9 . 3440–50 . September 2000 . 10965917 . 10.1210/endo.141.9.7680 . free .
12. Gnanapragasam VJ, Leung HY, Pulimood AS, Neal DE, Robson CN . Expression of RAC 3, a steroid hormone receptor co-activator in prostate cancer . Br. J. Cancer . 85 . 12 . 1928–36 . December 2001 . 11747336 . 2364015 . 10.1054/bjoc.2001.2179 .
13. Wang Q, Udayakumar TS, Vasaitis TS, Brodie AM, Fondell JD . Mechanistic relationship between androgen receptor polyglutamine tract truncation and androgen-dependent transcriptional hyperactivity in prostate cancer cells . J. Biol. Chem. . 279 . 17 . 17319–28 . April 2004 . 14966121 . 10.1074/jbc.M400970200 . free .
14. Naltner A, Wert S, Whitsett JA, Yan C . Temporal/spatial expression of nuclear receptor coactivators in the mouse lung . Am. J. Physiol. Lung Cell Mol. Physiol. . 279 . 6 . L1066-74 . December 2000 . 11076796 . 10.1152/ajplung.2000.279.6.l1066. 27872061 .
15. Watanabe M, Yanagisawa J, Kitagawa H, Takeyama K, Ogawa S, Arao Y, Suzawa M, Kobayashi Y, Yano T, Yoshikawa H, Masuhiro Y, Kato S . 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 . EMBO J. . 20 . 6 . 1341–52 . March 2001 . 11250900 . 145523 . 10.1093/emboj/20.6.1341 .
16. Wong CW, Komm B, Cheskis BJ . Structure-function evaluation of ER alpha and beta interplay with SRC family coactivators. ER selective ligands . Biochemistry . 40 . 23 . 6756–65 . June 2001 . 11389589 . 10.1021/bi010379h .
17. Tikkanen MK, Carter DJ, Harris AM, Le HM, Azorsa DO, Meltzer PS, Murdoch FE . Endogenously expressed estrogen receptor and coactivator AIB1 interact in MCF-7 human breast cancer cells . Proc. Natl. Acad. Sci. U.S.A. . 97 . 23 . 12536–40 . November 2000 . 11050174 . 18799 . 10.1073/pnas.220427297 . 2000PNAS...9712536T . free .
18. Leo C, Li H, Chen JD . Differential mechanisms of nuclear receptor regulation by receptor-associated coactivator 3 . J. Biol. Chem. . 275 . 8 . 5976–82 . February 2000 . 10681591 . 10.1074/jbc.275.8.5976 . free .
19. Hsiao PW, Fryer CJ, Trotter KW, Wang W, Archer TK . BAF60a mediates critical interactions between nuclear receptors and the BRG1 chromatin-remodeling complex for transactivation . Mol. Cell. Biol. . 23 . 17 . 6210–20 . September 2003 . 12917342 . 180928 . 10.1128/MCB.23.17.6210-6220.2003 .
20. Zilliacus J, Holter E, Wakui H, Tazawa H, Treuter E, Gustafsson JA . Regulation of glucocorticoid receptor activity by 14--3-3-dependent intracellular relocalization of the corepressor RIP140 . Mol. Endocrinol. . 15 . 4 . 501–11 . April 2001 . 11266503 . 10.1210/mend.15.4.0624 . free .
21. Ming-Jer Tsai . Wu RC, Qin J, Hashimoto Y, Wong J, Xu J, Tsai SY, Tsai MJ, O'Malley BW . Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator activity by I kappa B kinase . Mol. Cell. Biol. . 22 . 10 . 3549–61 . May 2002 . 11971985 . 133790 . 10.1128/MCB.22.10.3549-3561.2002 .
22. Kodera Y, Takeyama K, Murayama A, Suzawa M, Masuhiro Y, Kato S . Ligand type-specific interactions of peroxisome proliferator-activated receptor gamma with transcriptional coactivators . J. Biol. Chem. . 275 . 43 . 33201–4 . October 2000 . 10944516 . 10.1074/jbc.C000517200 . free .
23. Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM . Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300 . Cell . 90 . 3 . 569–80 . August 1997 . 9267036 . 10.1016/S0092-8674(00)80516-4 . 15284825 . free .
24. Lee WY, Noy N . Interactions of RXR with coactivators are differentially mediated by helix 11 of the receptor's ligand binding domain . Biochemistry . 41 . 8 . 2500–8 . February 2002 . 11851396 . 10.1021/bi011764+.