From Wikipedia, the free encyclopedia
Protein-coding gene in the species Homo sapiens
NCOA3
Identifiers
Aliases
NCOA3 , ACTR, AIB-1, AIB1, CAGH16, CTG26, KAT13B, RAC3, SRC-3, SRC3, TNRC14, TNRC16, TRAM-1, bHLHe42, pCIP, nuclear receptor coactivator 3External IDs
OMIM :
601937
MGI :
1276535
HomoloGene :
4764
GeneCards :
NCOA3
Wikidata
The nuclear receptor coactivator 3 also known as NCOA3 is a
protein that, in humans, is encoded by the NCOA3
gene .
[5]
[6] 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.
[7]
[8]
Clinical significance
The ratio of
PAX2 to AIB-1 protein expression may be predictive of the effectiveness of
tamoxifen in
breast cancer treatment .
[9]
[10]
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,
[11] and in the other hand in the inhibition of the proteasome-dependent AIB1 turn-over and therefore, in AIB1 overexpression.
[12] 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.
[13] 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.
[14]
Mechanisms for AIB1-dependent anti-estrogen therapy resistance
Interactions
Nuclear receptor coactivator 3 has been shown to
interact with:
Androgen receptor ,
[15]
[16]
[17]
CHUK
[18] and
CREB-binding protein ,
[18]
[19]
DDX17 ,
[20]
DDX5 ,
[20]
Estrogen receptor alpha ,
[20]
[21]
[22]
Estrogen receptor beta ,
[21]
[23]
Glucocorticoid receptor ,
[24]
[25]
IKBKG ,
[18]
IKK2 ,
[18]
Peroxisome proliferator-activated receptor gamma ,
[26] and
Retinoid X receptor alpha .
[27]
[28]
References
^
a
b
c
GRCh38: Ensembl release 89: ENSG00000124151 –
Ensembl , May 2017
^
a
b
c
GRCm38: Ensembl release 89: ENSMUSG00000027678 –
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^
"Human PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^
"Mouse PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^ Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS (August 1997).
"AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer" . Science . 277 (5328): 965–8.
doi :
10.1126/science.277.5328.965 .
PMID
9252329 .
^ Takeshita A, Cardona GR, Koibuchi N, Suen CS, Chin WW (October 1997).
"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.
doi :
10.1074/jbc.272.44.27629 .
PMID
9346901 .
^ Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS (1997).
"AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer" . Science . 277 (5328): 965–8.
doi :
10.1126/science.277.5328.965 .
PMID
9252329 .
^ Takeshita A, Cardona GR, Koibuchi N, Suen CS, Chin WW (1997).
"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.
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10.1074/jbc.272.44.27629 .
PMID
9346901 .
^
"Study sheds new light on tamoxifen resistance" . Cordis News . Cordis. 2008-11-13. Archived from
the original on 2009-02-20. Retrieved 2008-11-14 .
^ Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, et al. (December 2008).
"Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen" . Nature . 456 (7222): 663–6.
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2008Natur.456..663H .
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^ Font de Mora J, Brown M (July 2000).
"AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor" . Molecular and Cellular Biology . 20 (14): 5041–7.
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^ Ferrero M, Avivar A, García-Macías MC, Font de Mora J (July 2008).
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^ Osborne CK, Bardou V, Hopp TA, Chamness GC,
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"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.
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PMID
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^ Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, et al. (December 2008).
"Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen" . Nature . 456 (7222): 663–6.
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2008Natur.456..663H .
doi :
10.1038/nature07483 .
PMC
2920208 .
PMID
19005469 .
^ Tan JA, Hall SH, Petrusz P, French FS (September 2000).
"Thyroid receptor activator molecule, TRAM-1, is an androgen receptor coactivator" . Endocrinology . 141 (9): 3440–50.
doi :
10.1210/endo.141.9.7680 .
PMID
10965917 .
^ Gnanapragasam VJ, Leung HY, Pulimood AS, Neal DE, Robson CN (December 2001).
"Expression of RAC 3, a steroid hormone receptor co-activator in prostate cancer" . Br. J. Cancer . 85 (12): 1928–36.
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PMC
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PMID
11747336 .
^ Wang Q, Udayakumar TS, Vasaitis TS, Brodie AM, Fondell JD (April 2004).
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PMID
14966121 .
^
a
b
c
d Wu RC, Qin J, Hashimoto Y, Wong J, Xu J, Tsai SY,
Tsai MJ , O'Malley BW (May 2002).
"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.
doi :
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PMC
133790 .
PMID
11971985 .
^ Naltner A, Wert S, Whitsett JA, Yan C (December 2000). "Temporal/spatial expression of nuclear receptor coactivators in the mouse lung". Am. J. Physiol. Lung Cell Mol. Physiol . 279 (6): L1066-74.
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PMID
11076796 .
S2CID
27872061 .
^
a
b
c Watanabe M, Yanagisawa J, Kitagawa H, Takeyama K, Ogawa S, Arao Y, Suzawa M, Kobayashi Y, Yano T, Yoshikawa H, Masuhiro Y, Kato S (March 2001).
"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.
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PMC
145523 .
PMID
11250900 .
^
a
b Wong CW, Komm B, Cheskis BJ (June 2001). "Structure-function evaluation of ER alpha and beta interplay with SRC family coactivators. ER selective ligands". Biochemistry . 40 (23): 6756–65.
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10.1021/bi010379h .
PMID
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^ Tikkanen MK, Carter DJ, Harris AM, Le HM, Azorsa DO, Meltzer PS, Murdoch FE (November 2000).
"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.
Bibcode :
2000PNAS...9712536T .
doi :
10.1073/pnas.220427297 .
PMC
18799 .
PMID
11050174 .
^ Leo C, Li H, Chen JD (February 2000).
"Differential mechanisms of nuclear receptor regulation by receptor-associated coactivator 3" . J. Biol. Chem . 275 (8): 5976–82.
doi :
10.1074/jbc.275.8.5976 .
PMID
10681591 .
^ Hsiao PW, Fryer CJ, Trotter KW, Wang W, Archer TK (September 2003).
"BAF60a mediates critical interactions between nuclear receptors and the BRG1 chromatin-remodeling complex for transactivation" . Mol. Cell. Biol . 23 (17): 6210–20.
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PMC
180928 .
PMID
12917342 .
^ Zilliacus J, Holter E, Wakui H, Tazawa H, Treuter E, Gustafsson JA (April 2001).
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PMID
11266503 .
^ Kodera Y, Takeyama K, Murayama A, Suzawa M, Masuhiro Y, Kato S (October 2000).
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PMID
10944516 .
^ Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM (August 1997).
"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.
doi :
10.1016/S0092-8674(00)80516-4 .
PMID
9267036 .
S2CID
15284825 .
^ Lee WY, Noy N (February 2002). "Interactions of RXR with coactivators are differentially mediated by helix 11 of the receptor's ligand binding domain". Biochemistry . 41 (8): 2500–8.
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PMID
11851396 .
External links
Further reading
Liao L, Kuang SQ, Yuan Y, Gonzalez SM, O'Malley BW, Xu J (2003). "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.
doi :
10.1016/S0960-0760(02)00254-6 .
PMID
12650696 .
S2CID
40981759 .
Liu F, Ventura F, Doody J, Massagué J (1995).
"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.
doi :
10.1128/mcb.15.7.3479 .
PMC
230584 .
PMID
7791754 .
Guan XY, Xu J, Anzick SL, Zhang H, Trent JM, Meltzer PS (1996). "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.
PMID
8758910 .
Bonaldo MF, Lennon G, Soares MB (1997).
"Normalization and subtraction: two approaches to facilitate gene discovery" . Genome Res . 6 (9): 791–806.
doi :
10.1101/gr.6.9.791 .
PMID
8889548 .
Margolis RL, Abraham MR, Gatchell SB, Li SH, Kidwai AS, Breschel TS, Stine OC, Callahan C, McInnis MG, Ross CA (1997). "cDNAs with long CAG trinucleotide repeats from human brain". Hum. Genet . 100 (1): 114–22.
doi :
10.1007/s004390050476 .
PMID
9225980 .
S2CID
25999127 .
Li H, Gomes PJ, Chen JD (1997).
"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.
Bibcode :
1997PNAS...94.8479L .
doi :
10.1073/pnas.94.16.8479 .
PMC
22964 .
PMID
9238002 .
Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS (1997).
"AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer" . Science . 277 (5328): 965–8.
doi :
10.1126/science.277.5328.965 .
PMID
9252329 .
Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM (1997).
"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.
doi :
10.1016/S0092-8674(00)80516-4 .
PMID
9267036 .
S2CID
15284825 .
Takeshita A, Cardona GR, Koibuchi N, Suen CS, Chin WW (1997).
"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.
doi :
10.1074/jbc.272.44.27629 .
PMID
9346901 .
Korzus E, Torchia J, Rose DW, Xu L, Kurokawa R, McInerney EM, Mullen TM, Glass CK, Rosenfeld MG (1998). "Transcription factor-specific requirements for coactivators and their acetyltransferase functions". Science . 279 (5351): 703–7.
Bibcode :
1998Sci...279..703K .
doi :
10.1126/science.279.5351.703 .
PMID
9445475 .
Shirazi SK, Bober MA, Coetzee GA (1998). "Polymorphic exonic CAG microsatellites in the gene amplified in breast cancer (AIB1 gene)". Clin. Genet . 54 (1): 102–3.
doi :
10.1111/j.1399-0004.1998.tb03704.x .
PMID
9727751 .
S2CID
1315265 .
Wang JC, Stafford JM, Granner DK (1998).
"SRC-1 and GRIP1 coactivate transcription with hepatocyte nuclear factor 4" . J. Biol. Chem . 273 (47): 30847–50.
doi :
10.1074/jbc.273.47.30847 .
PMC
3968904 .
PMID
9812974 .
Zwijsen RM, Buckle RS, Hijmans EM, Loomans CJ, Bernards R (1999).
"Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1" . Genes Dev . 12 (22): 3488–98.
doi :
10.1101/gad.12.22.3488 .
PMC
317237 .
PMID
9832502 .
Chen H, Lin RJ, Xie W, Wilpitz D, Evans RM (1999).
"Regulation of hormone-induced histone hyperacetylation and gene activation via acetylation of an acetylase" . Cell . 98 (5): 675–86.
doi :
10.1016/S0092-8674(00)80054-9 .
PMID
10490106 .
S2CID
14697597 .
Ebisawa T, Tada K, Kitajima I, Tojo K, Sampath TK, Kawabata M, Miyazono K, Imamura T (2000). "Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation". J. Cell Sci . 112 (20): 3519–27.
doi :
10.1242/jcs.112.20.3519 .
PMID
10504300 .
Xie W, Hong H, Yang NN, Lin RJ, Simon CM, Stallcup MR, Evans RM (2000).
"Constitutive activation of transcription and binding of coactivator by estrogen-related receptors 1 and 2" . Mol. Endocrinol . 13 (12): 2151–62.
doi :
10.1210/mend.13.12.0381 .
PMID
10598588 .
Pao GM, Janknecht R, Ruffner H, Hunter T, Verma IM (2000).
"CBP/p300 interact with and function as transcriptional coactivators of BRCA1" . Proc. Natl. Acad. Sci. U.S.A . 97 (3): 1020–5.
Bibcode :
2000PNAS...97.1020P .
doi :
10.1073/pnas.97.3.1020 .
PMC
15508 .
PMID
10655477 .
Leo C, Li H, Chen JD (2000).
"Differential mechanisms of nuclear receptor regulation by receptor-associated coactivator 3" . J. Biol. Chem . 275 (8): 5976–82.
doi :
10.1074/jbc.275.8.5976 .
PMID
10681591 .
Font de Mora J, Brown M (2000).
"AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor" . Mol. Cell. Biol . 20 (14): 5041–7.
doi :
10.1128/MCB.20.14.5041-5047.2000 .
PMC
85954 .
PMID
10866661 .
Tan JA, Hall SH, Petrusz P, French FS (2000).
"Thyroid receptor activator molecule, TRAM-1, is an androgen receptor coactivator" . Endocrinology . 141 (9): 3440–50.
doi :
10.1210/endo.141.9.7680 .
PMID
10965917 .