Nuclear receptor coactivator 3

The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the NCOA3 gene. 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).

NCOA3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1KBH, 3L3X, 3L3Z
Identifiers
Aliases	NCOA3, ACTR, AIB-1, AIB1, CAGH16, CTG26, KAT13B, RAC3, SRC-3, SRC3, TNRC14, TNRC16, TRAM-1, bHLHe42, pCIP, nuclear receptor coactivator 3
External IDs	OMIM: 601937; MGI: 1276535; HomoloGene: 4764; GeneCards: NCOA3; OMA:NCOA3 - orthologs
Gene location (Human) Chr. Chromosome 20 (human) Band 20q13.12 Start 47,501,887 bp End 47,656,877 bp
Gene location (Mouse) Chr. Chromosome 2 (mouse) Band 2|2 H3 Start 165,992,636 bp End 166,073,242 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in secondary oocyte tendon of biceps brachii epithelium of nasopharynx buccal mucosa cell nipple superficial temporal artery bone marrow cells oral cavity palpebral conjunctiva parotid gland Top expressed in zygote secondary oocyte granulocyte blood medulla of thymus ciliary body morula ascending aorta primary oocyte lacrimal gland More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity protein dimerization activity protein N-terminus binding transcription coactivator activity thyroid hormone receptor binding histone acetyltransferase activity protein binding androgen receptor binding nuclear receptor binding nuclear receptor coactivator activity acyltransferase activity protein heterodimerization activity disordered domain specific binding RNA polymerase II complex binding DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component cytoplasm nucleoplasm extracellular exosome nucleus cytosol protein-containing complex Biological process androgen receptor signaling pathway regulation of RNA biosynthetic process regulation of transcription, DNA-templated positive regulation of keratinocyte differentiation cellular response to estradiol stimulus transcription, DNA-templated positive regulation of transcription, DNA-templated positive regulation of gene expression positive regulation of transcription by RNA polymerase II receptor transactivation intracellular receptor signaling pathway histone acetylation cellular response to hormone stimulus cell dedifferentiation positive regulation of stem cell population maintenance regulation of stem cell division Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 2: 165.99 – 166.07 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

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.

Clinical significance

The ratio of PAX2 to AIB-1 protein expression may be predictive of the effectiveness of tamoxifen in breast cancer treatment.

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, and in the other hand in the inhibition of the proteasome-dependent AIB1 turn-over and therefore, in AIB1 overexpression. 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. 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.

Mechanisms for AIB1-dependent anti-estrogen therapy resistance

Interactions

Nuclear receptor coactivator 3 has been shown to interact with:

• Androgen receptor,
• CHUK and
• CREB-binding protein,
• Estrogen receptor alpha,
• Estrogen receptor beta,
• Glucocorticoid receptor,
• IKBKG,
• IKK2,
• Retinoid X receptor alpha.

External links

• nuclear receptor coactivator 3 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• NURSA C91

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.