NCOA3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNCOA3, ACTR, AIB-1, AIB1, CAGH16, CTG26, KAT13B, RAC3, SRC-3, SRC3, TNRC14, TNRC16, TRAM-1, bHLHe42, pCIP, nuclear receptor coactivator 3
External IDsOMIM: 601937 MGI: 1276535 HomoloGene: 4764 GeneCards: NCOA3
Orthologs
SpeciesHumanMouse
Entrez

8202

17979

Ensembl

ENSG00000124151

ENSMUSG00000027678

UniProt

Q9Y6Q9

O09000

RefSeq (mRNA)

NM_181659
NM_001174087
NM_001174088
NM_006534

NM_008679
NM_001374779

RefSeq (protein)

NP_001167558
NP_001167559
NP_006525
NP_858045

n/a

Location (UCSC)Chr 20: 47.5 – 47.66 MbChr 2: 165.99 – 166.07 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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:

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000124151 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000027678 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ "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.
  10. ↑ 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. Bibcode:2008Natur.456..663H. doi:10.1038/nature07483. PMC 2920208. PMID 19005469.
  11. ↑ 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. doi:10.1128/MCB.20.14.5041-5047.2000. PMC 85954. PMID 10866661.
  12. ↑ Ferrero M, Avivar A, García-Macías MC, Font de Mora J (July 2008). "Phosphoinositide 3-kinase/AKT signaling can promote AIB1 stability independently of GSK3 phosphorylation". Cancer Research. 68 (13): 5450–9. doi:10.1158/0008-5472.CAN-07-6433. PMID 18593948.
  13. ↑ Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, Fuqua SA, et al. (March 2003). "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. doi:10.1093/jnci/95.5.353. PMID 12618500.
  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. Bibcode:2008Natur.456..663H. doi:10.1038/nature07483. PMC 2920208. PMID 19005469.
  15. ↑ 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.
  16. ↑ 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. doi:10.1054/bjoc.2001.2179. PMC 2364015. PMID 11747336.
  17. ↑ Wang Q, Udayakumar TS, Vasaitis TS, Brodie AM, Fondell JD (April 2004). "Mechanistic relationship between androgen receptor polyglutamine tract truncation and androgen-dependent transcriptional hyperactivity in prostate cancer cells". J. Biol. Chem. 279 (17): 17319–28. doi:10.1074/jbc.M400970200. PMID 14966121.
  18. 1 2 3 4 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:10.1128/MCB.22.10.3549-3561.2002. PMC 133790. PMID 11971985.
  19. ↑ 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. doi:10.1152/ajplung.2000.279.6.l1066. PMID 11076796. S2CID 27872061.
  20. 1 2 3 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. doi:10.1093/emboj/20.6.1341. PMC 145523. PMID 11250900.
  21. 1 2 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. doi:10.1021/bi010379h. PMID 11389589.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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. doi:10.1128/MCB.23.17.6210-6220.2003. PMC 180928. PMID 12917342.
  25. ↑ Zilliacus J, Holter E, Wakui H, Tazawa H, Treuter E, Gustafsson JA (April 2001). "Regulation of glucocorticoid receptor activity by 14--3-3-dependent intracellular relocalization of the corepressor RIP140". Mol. Endocrinol. 15 (4): 501–11. doi:10.1210/mend.15.4.0624. PMID 11266503.
  26. ↑ Kodera Y, Takeyama K, Murayama A, Suzawa M, Masuhiro Y, Kato S (October 2000). "Ligand type-specific interactions of peroxisome proliferator-activated receptor gamma with transcriptional coactivators". J. Biol. Chem. 275 (43): 33201–4. doi:10.1074/jbc.C000517200. PMID 10944516.
  27. ↑ 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.
  28. ↑ 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. doi:10.1021/bi011764+. PMID 11851396.

Further reading

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