Alternative titles; symbols
HGNC Approved Gene Symbol: NCOA3
Cytogenetic location: 20q13.12 Genomic coordinates (GRCh38): 20:47,501,887-47,656,872 (from NCBI)
NCOA3 is a nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in hormone-dependent fashion. NCOA3 recruits 2 other nuclear factors, CBP (600140) and PCAF (602303), and thus plays a central role in creating a multisubunit coactivator complex (Chen et al., 1997).
Gene amplification is a frequent mechanism of increased gene expression in human cancers. In breast cancer, commonly amplified regions are 17q12, 8q24, and 11q13 and encode ERBB2 (164870), MYC (190080), and cyclin D1 (168461), respectively. Another amplification region is 20q. Guan et al. (1996) used chromosome microdissection and hybrid selection to clone from 20q partial cDNAs for a candidate target gene on 20q, designated AIB1 (for 'amplified in breast cancer-1'), which was ubiquitously expressed in normal human tissues. They also identified 2 other amplified genes, which they designated AIB3 (NCOA6; 605299) and AIB4.
Anzick et al. (1997) reported the deduced sequence of the 1,420-amino acid AIB1 polypeptide, and found that AIB1 is a member of the SRC-1 family of nuclear receptor coactivators.
Chen et al. (1997) independently cloned ACTR using a yeast 1-hybrid selection to identify proteins that interact with nuclear receptors. They found that ACTR has a basic helix-loop-helix domain in the amino terminus, at least 2 receptor-interaction domains (RIDs) in the central region, and a CBP-interaction domain (CID) and a histone acetyltransferase (HAT) domain in the carboxy-terminal end.
By far Western-based expression screening, Takeshita et al. (1997) independently cloned NCOA3, which they called TRAM1 for 'thyroid hormone receptor activator molecule,' a 160-kD member of the nuclear receptor coactivator family.
Reiter et al. (2001) identified a splice variant of AIB1 that lacks exon 3. This variant, which they called AIB-delta-3, encodes a 130-kD protein lacking the N-terminal basic helix-loop-helix domain and the first of the 2 PAS dimerization domains of full-length AIB1. Northern and Western blot analyses detected higher AIB-delta-3 expression in breast tumor samples and cell lines than in normal breast tissue.
Anzick et al. (1997) found that AIB1 was amplified and overexpressed in breast and ovarian cancer cell lines, as well as in breast cancer biopsies. AIB1 interacted with estrogen receptors (133430) in a ligand-dependent fashion and enhanced estrogen-dependent transcription. Anzick et al. (1997) suggested that altered AIB1 expression may contribute to development of steroid-dependent cancers.
Chen et al. (1997) found that ACTR is a potent histone acetyltransferase and appears to define a distinct evolutionary branch of this family. They found that ACTR enhances the transactivation function of nuclear receptors in mammalian cells and that it interacts with nuclear hormone receptors, including RAR (see 180240), thyroid hormone receptor (see 190120), and VDR (601769), in an agonist- and AF2/tauC-dependent manner. Chen et al. (1997) demonstrated that ACTR recruits PCAF and has intrinsic histone acetyltransferase activity.
Takeshita et al. (1997) found that TRAM1 binds to thyroid hormone receptor and other nuclear receptors in a ligand-dependent manner and enhances ligand-induced transcriptional activity of the thyroid hormone receptor. Takeshita et al. (1997) also observed that TRAM1 retained strong ligand-dependent interaction with an AF2 mutant of the thyroid receptor, while SRC1 (602691) failed to interact with this mutant, suggesting that TRAM1 may function through a subdomain of nuclear receptors other than the AF2 region.
To clarify the role of the polymorphic polyglutamine sequences of the AIB1 gene in breast cancer, Dai and Wong (2003) used PCR/cloning followed by sequencing of individual clones to study DNA derived from sporadic primary breast cancers, breast cancer cell lines, and blood samples from breast cancer patients with BRCA1/BRCA2 mutations and from the general population. More than 2 distinct sequence patterns were found in a significantly higher proportion of tumors and cells lines than that of the general population, suggesting somatic instability. A significantly higher proportion of cancer cell lines or primary breast tumors than that of the general population contained rare sequence patterns. The proportion of sporadic breast tumors having at least 1 allele of 27 repeats or less was significantly higher than that in the blood of the breast cancer patients or the general population. Dai and Wong (2003) proposed that the polyglutamine tract modulates AIB1 activity resulting in cotransactivation of gene expression.
Bai et al. (2000) identified a Drosophila gene, which they named 'taiman' (meaning 'too slow'), that encodes a steroid hormone receptor coactivator related to AIB1. Mutations in the tai gene caused defects in the migration of specific follicle cells, the border cells, in the Drosophila ovary. Mutant cells exhibited abnormal accumulation of E-cadherin (192090), beta-catenin (116806), and focal adhesion kinase (600758). Tai protein colocalized with the ecdysone receptor in vivo and augmented transcriptional activation by the ecdysone receptor in cultured cells. The authors concluded that the finding of this type of coactivator required for cell motility suggests a novel role for steroid hormones in stimulating invasive cell behavior, independent of effects on proliferation.
Reiter et al. (2001) found that the AIB-delta-3 isoform had a significantly greater ability to promote transcription mediated by estrogen or progesterone receptors than the full-length AIB1 protein. AIB-delta-3 was also more effective than AIB1 in promoting transcription induced by epidermal growth factor (EGF; 131530).
To elucidate the molecular basis of assembling the multiprotein activation complex, Demarest et al. (2002) undertook a structural and thermodynamic analysis of the interaction domains of CBP and the activator for thyroid hormone and retinoid receptors (TRAM1). Demarest et al. (2002) demonstrated that although the isolated domains are intrinsically disordered, they combine with high affinity to form a cooperatively folded helical heterodimer. The authors concluded that their study uncovers a unique mechanism, which they termed 'synergistic folding,' through which p160 coactivators recruit CBP to allow transmission of the hormonal signal to the transcriptional machinery.
Using immunoprecipitation analysis, Li et al. (2006) found that endogenous SRC3 and REG-gamma (PSME3; 605129) interacted in HeLa cell nuclear extracts and MCF-7 breast cancer cells. Protein pull-down assays showed the REG-gamma interacted specifically with the HAT domain of SRC3. Knockdown of REG-gamma via RNA interference (RNAi) in breast cancer and human embryonic kidney cell lines resulted in a 2- to 3-fold increase in SRC3 protein levels. Conversely, REG-gamma overexpression in HeLa cells reduced SRC3 protein levels. In vitro proteasome assays using purified proteins showed that REG-gamma promoted degradation of SRC3 by the 20S proteasome in a ubiquitin- and ATP-independent manner. Knockdown of REG-gamma via RNAi increased estrogen receptor (ESR; see 133430) target gene expression and enhanced estradiol-mediated cell growth in MCF-7 cells, and these effects were secondary to the effect of REG-gamma on SRC3.
Li et al. (2007) demonstrated that SRC3 is expressed in cardiovascular cells and localized to the nucleus after exposure to serum. In vitro and in vivo studies showed that SRC3 interacts with myocardin (MYOCD; 606127). The N terminus of SRC3 binds the C-terminal activation domain of myocardin and enhances myocardin-mediated transcriptional activation of vascular smooth muscle cell-specific genes. This interaction identified a site of convergence for nuclear hormone receptor-mediated and smooth muscle cell-specific gene regulation, suggesting a possible mechanism for the vascular protective effects of estrogen on vascular injury.
Li et al. (2008) stated that SRC3 is activated by phosphorylation. Using a functional genomic screen of human serine/threonine phosphatases, they identified PDXP (609246), PP1 (see PPP1CA; 176875), and PP2A (see PP2CA; 176915) as key negative regulators of SRC3 transcriptional coregulatory activity in steroid receptor signaling. PDXP and PP2A dephosphorylated SRC3 and inhibited its ligand-dependent association with estrogen receptor. PP1 stabilized SRC3 protein by blocking its proteasome-dependent turnover through dephosphorylating ser101 and ser102, which are required for SRC3 activity. These serines are located within the SRC3 destabilization signal, or degron, and were the primary determinants of SRC3 turnover.
Using yeast 2-hybrid analysis, Wu et al. (2001) found that the basic helix-loop-helix (bHLH)-PAS domain of RAC3 (SRC3) interacted with the C-terminal domain of MMS19 (614777). Mutation analysis revealed that MMS19 interacted with the PAS-A and PAS-B domains, but not the bHLH domain, in a synergistic manner. Both the C-terminal domain and full-length MMS19 also interacted with estrogen receptors ESR-alpha (ESR1; 133430) and ESR-beta (ESR2; 601663) in an estrogen-independent manner and activated an ESR reporter gene in an estrogen-dependent manner. MMS19 also enhanced RAC3-dependent ESR activation. MMS19 specifically enhanced the activity of the N-terminal, but not the C-terminal, transactivation domain of ESR-alpha. However, the isolated C-terminal domain of MMS19 functioned in a dominant-negative manner, which was reversed by coexpression of RAC3. Since the C-terminal domain of MMS19 interacted with both ESR and RAC3, Wu et al. (2001) proposed that the interactions may be mutually exclusive and regulatory.
Using a kinomewide RNA interference-based screening method, Dasgupta et al. (2018) identified the metabolic enzyme PFKFB4 (605320) as a robust stimulator of SRC3, which coregulates the estrogen receptor (see 133430). PFKFB4 phosphorylates SRC3 at serine-857 and enhances its transcriptional activity, whereas either suppression of PFKFB4 or ectopic expression of a phosphorylation-deficient ser857-to-ala (S857A) mutant SRC3 abolished the SRC3-mediated transcriptional output. PFKFB4-driven SRC3 activation drives glucose flux towards the pentose phosphate pathway and enables purine synthesis by transcriptionally upregulating the expression of the enzyme transketolase (TKT; 606781). Dasgupta et al. (2018) identified adenosine monophosphate deaminase-1 (AMPD1; 102770) and xanthine dehydrogenase (XDH; 607633), which are involved in purine metabolism, as SRC3 targets that may or may not be directly involved in purine synthesis. Phosphorylation of SRC3 at ser857 increases its interaction with the transcription factor ATF4 (604064) by stabilizing the recruitment of SRC3 and ATF4 to target gene promoters. Ablation of SRC3 or PFKFB4 suppressed breast tumor growth in mice and prevented metastasis to the lung from an orthotopic setting, as did S857A-mutant SRC3. Dasgupta et al. (2018) found that PFKFB4 and phosphorylated SRC3 levels are increased and correlate in estrogen receptor-positive tumors, and in patients with the basal subtype, PFKFB4 and SRC3 drive a common protein signature that correlates with poor survival. Dasgupta et al. (2018) concluded that the Warburg pathway enzyme PFKFB4 acts as a molecular fulcrum that couples sugar metabolism to transcriptional activation by stimulating SRC3 to promote aggressive metastatic tumors.
He et al. (2019) found that mouse Src3 interacted with Ror-gamma-t (RORC; 602943) in Th17 cells, but not in thymocytes. T cells from Src3 -/- mice showed impaired Th17 differentiation and were defective in induction of experimental autoimmune encephalomyelitis, but loss of Src3 did not affect thymocyte development. Expression of a Ror-gamma-t mutant that could interact with Src1, but not Src3, was unable restore Th17 differentiation in Ror-gamma-t-deficient Cd4-positive cells, but it could rescue thymocyte development in Ror-gamma-t-deficient thymocytes.
Reiter et al. (2001) reported that the NCOA3 gene contains 22 exons.
Guan et al. (1996) mapped AIB1 to 20q12. Shirazi et al. (1998) identified polymorphic exonic CAG microsatellites in the AIB1 gene.
Associations Pending Confirmation
Salazar-Silva et al. (2020) reported a 5-generation Brazilian pedigree in which 15 individuals had nonsyndromic bilateral sensorineural progressive hearing loss, which segregated in an autosomal dominant manner. Linkage analysis using a SNP-array and microsatellite analysis identified a region of interest of about 13.5 Mb on chromosome 20, which included the NCOA3 gene. Whole-exome sequencing in 2 affected individuals identified a heterozygous c.2810C-G transition (NM_181659) in the NCOA3 gene, predicted to result in a ser937-to-cys (S937C) substitution (rs142951578). The S937C variant was present at a low frequency in several databases, including gnomAD (0.0003465), NHLBI-ESP (0.000538), and 1000 Genomes Project (0.001). The variant was present in all 7 affected individuals from the family who were tested as well as in 4 unaffected individuals. The 4 unaffected heterozygotes were in the range of onset of hearing loss observed in the family, and Salazar-Silva et al. (2020) stated that it was possible they could manifest later. Functional studies of the variant were not performed.
In 12 members of a 3-generation family with nonsyndromic adult-onset deafness, Tesolin et al. (2021) identified heterozygosity for a c.2909G-C transversion (NM_181659.3) in exon 15 of the NCOA3 gene, resulting in a gly970-to-ala (G970A) substitution. The mutation was identified by linkage analysis and whole-exome sequencing. One member of the family (patient III:8), a 70-year-old woman, had hearing loss but didn't have the mutation. Another unaffected family member (IV:5), a 32-year-old woman, was heterozygous for the G970A mutation in the NCOA3 gene and didn't have hearing loss. Tesolin et al. (2021) hypothesized that this patient may present later in life. Functional studies in patient cells were not performed.
Coste et al. (2006) found that Src3 -/- mice had a hematologic deficit characterized by a decrease in platelets and an increase in lymphocytes, often resulting in lymphoma formation. Expansion of T and B cells in Src3 -/- mice correlated with induction of both proliferative and antiapoptotic genes, secondary to constitutive NF-kappa-B (see 164011) activation. Coste et al. (2006) noted that these data contradicted previous results on the proliferative role of SRC3 in epithelial cancers and suggested that absence of SRC3 can lead to proliferation in lymphocytes.
Louet et al. (2006) showed that the early stages of mouse adipocyte differentiation were accompanied by an increase in nuclear levels of Src3. Src3 -/- mouse embryonic fibroblasts were impaired in adipocyte differentiation. Moreover, Src3 -/- animals showed reduced body weight and adipose tissue mass, with a significant decrease in expression of Pparg2 (601487), a master gene required for adipogenesis. At the molecular level, Src3 acted synergistically with transcription factor Cebp (CEBPA; 116897) to control Pparg2 expression.
Yu et al. (2007) found that Src3-deficient mice were highly susceptible to lipopolysaccharide (LPS)-induced endotoxic shock. In response to LPS, macrophages from Src3-deficient mice produced significantly more proinflammatory cytokines than wildtype controls, although they expressed similar amounts of cytokine mRNAs. The translational repressive effect of Src3 was dependent on the presence of an AU-rich element in the target mRNA and on association of Src3 with the translational repressors Tia1 (603518) and Tiar (TIAL1; 603413).
Salazar-Silva et al. (2020) used CRISPR/Cas9 editing to generate zebrafish with a homozygous 5-bp deletion (delTACGA) in the ncoa3 gene, leading to a premature stop codon at position 518. The authors identified ectopic chondrocytes at the cristae and internal region of inner ear of the zebrafish larvae at 3 days postfertilization (dpf) and disorganized distribution of stereocilia of the macula of the ear at 5 dpf. Examination of the mutant 1-year-old zebrafish by microcomputerized tomography showed a higher bone mineral density of craniofacial bones compared to wildtype. The mutant zebrafish also had abnormal swimming behavior, suggesting possible hearing malfunction. Salazar-Silva et al. (2020) hypothesized that ncoa3 has a role in bone mineralization regulation in the ears, and that abnormalities could lead to progressive hearing impairment in adult zebrafish.
Anzick, S. L., Kononen, J., Walker, R. L., Azorsa, D. O., Tanner, M. M., Guan, X.-Y., Sauter, G., Kallioniemi, O.-P., Trent, J. M., Meltzer, P. S. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277: 965-968, 1997. [PubMed: 9252329] [Full Text: https://doi.org/10.1126/science.277.5328.965]
Bai, J., Uehara, Y., Montell, D. J. Regulation of invasive cell behavior by taiman, a Drosophila protein related to AIB1, a steroid receptor coactivator amplified in breast cancer. Cell 103: 1047-1058, 2000. [PubMed: 11163181] [Full Text: https://doi.org/10.1016/s0092-8674(00)00208-7]
Chen, H., Lin, R. J., Schiltz, R. L., Chakravarti, D., Nash, A., Nagy, L., Privalsky, M. L., Nakatani, Y., Evans, R. M. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90: 569-580, 1997. [PubMed: 9267036] [Full Text: https://doi.org/10.1016/s0092-8674(00)80516-4]
Coste, A., Antal, M. C., Chan, S., Kastner, P., Mark, M., O'Malley, B. W., Auwerx, J. Absence of the steroid receptor coactivator-3 induces B-cell lymphoma. EMBO J. 25: 2453-2464, 2006. [PubMed: 16675958] [Full Text: https://doi.org/10.1038/sj.emboj.7601106]
Dai, P., Wong, L.-J. C. Somatic instability of the DNA sequences encoding the polymorphic polyglutamine tract of the AIB1 gene. J. Med. Genet. 40: 885-890, 2003. [PubMed: 14684685] [Full Text: https://doi.org/10.1136/jmg.40.12.885]
Dasgupta, S., Rajapakshe, K., Zhu, B., Nikolai, B. C., Yi, P., Putluri, N., Choi, J. M., Jung, S. Y., Coarfa, C., Westbrook, T. F., Zhang, X. H.-F., Foulds, C. E., Tsai, S. Y., Tsai, M.-J., O'Malley, B. W. Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer. Nature 556: 249-254, 2018. [PubMed: 29615789] [Full Text: https://doi.org/10.1038/s41586-018-0018-1]
Demarest, S. J., Martinez-Yamout, M., Chung, J., Chen, H., Xu, W., Dyson, H. J., Evans, R. M., Wright, P. E. Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators. Nature 415: 549-553, 2002. [PubMed: 11823864] [Full Text: https://doi.org/10.1038/415549a]
Guan, X.-Y., Xu, J., Anzick, S. L., Zhang, H., Trent, J. M., Meltzer, P. S. Hybrid selection of transcribed sequences from microdissected DNA: isolation of genes within amplified region at 20q11-q13.2 in breast cancer. Cancer Res. 56: 3446-3450, 1996. [PubMed: 8758910]
He, Z., Zhang, J., Du, Q., Xu, J., Gwack, Y., Sun, Z. SRC3 is a cofactor for ROR-gamma-t in Th17 differentiation but not thymocyte development. J. Immun. 202: 760-769, 2019. [PubMed: 30567733] [Full Text: https://doi.org/10.4049/jimmunol.1801187]
Li, C., Liang, Y.-Y., Feng, X.-H., Tsai, S. Y., Tsai, M.-J., O'Malley, B. W. Essential phosphatases and a phospho-degron are critical for regulation of SRC-3/AIB1 coactivator function and turnover. Molec. Cell 31: 835-849, 2008. [PubMed: 18922467] [Full Text: https://doi.org/10.1016/j.molcel.2008.07.019]
Li, H. J., Haque, Z., Lu, Q., Li, L., Karas, R., Mendelsohn, M. Steroid receptor coactivator 3 is a coactivator for myocardin, the regulator of smooth muscle transcription and differentiation. Proc. Nat. Acad. Sci. 104: 4065-4070, 2007. [PubMed: 17360478] [Full Text: https://doi.org/10.1073/pnas.0611639104]
Li, X., Lonard, D. M., Jung, S. Y., Malovannaya, A., Feng, Q., Qin, J., Tsai, S. Y., Tsai, M.-J., O'Malley, B. W. The SRC-3/AIB1 coactivator is degraded in a ubiquitin- and ATP-independent manner by the REG-gamma proteasome. Cell 124: 381-392, 2006. [PubMed: 16439211] [Full Text: https://doi.org/10.1016/j.cell.2005.11.037]
Louet, J.-F., Coste, A., Amazit, L., Tannour-Louet, M., Wu, R.-C., Tsai, S. Y., Tsai, M.-J., Auwerx, J., O'Malley, B. W. Oncogenic steroid receptor coactivator-3 is a key regulator of the white adipogenic program. Proc. Nat. Acad. Sci. 103: 17868-17873, 2006. [PubMed: 17098861] [Full Text: https://doi.org/10.1073/pnas.0608711103]
Reiter, R., Wellstein, A., Riegel, A. T. An isoform of the coactivator AIB1 that increases hormone and growth factor sensitivity is overexpressed in breast cancer. J. Biol. Chem. 276: 39736-39741, 2001. [PubMed: 11502741] [Full Text: https://doi.org/10.1074/jbc.M104744200]
Salazar-Silva, R., Dantas V. L. G., Alves, L. U., Batissoco, A. C., Oiticica, J., Lawrence, E. A., Kawafi, A., Yang, Y., Nicastro, F. S., Novaes, B. C., Hammond, C., Kague, E., Mingroni Netto, R. C. NCOA3 identified as a new candidate to explain autosomal dominant progressive hearing loss. Hum. Molec. Genet. 29: 3691-3705, 2020. Note: Erratum: Hum. Molec. Genet. 31: 156 only, 2022. [PubMed: 33326993] [Full Text: https://doi.org/10.1093/hmg/ddaa240]
Shirazi, S. K., Bober, M. A., Coetzee, G. A. Polymorphic exonic CAG microsatellites in the gene amplified in breast cancer (AIB1 gene). Clin. Genet. 54: 102-103, 1998. [PubMed: 9727751] [Full Text: https://doi.org/10.1111/j.1399-0004.1998.tb03704.x]
Takeshita, A., Cardona, G. R., Koibuchi, N., Suen, C.-S., Chin, W. W. TRAM-1, a novel 160-kDa thyroid hormone receptor activator molecule, exhibits distinct properties from steroid receptor coactivator-1. J. Biol. Chem. 272: 27629-27634, 1997. [PubMed: 9346901] [Full Text: https://doi.org/10.1074/jbc.272.44.27629]
Tesolin, P., Morgan, A., Notarangelo, M., Ortore, R. P., Concas, M. P., Notarangelo, A., Girotto, G. Non-syndromic autosomal dominant hearing loss: the first Italian family carrying a mutation in the NCOA3 Gene. Genes 12: 1043, 2021. [PubMed: 34356059] [Full Text: https://doi.org/10.3390/genes12071043]
Wu, X., Li, H., Chen, J. D. The human homologue of the yeast DNA repair and TFIIH regulator MMS19 is an AF-1-specific coactivator of estrogen receptor. J. Biol. Chem. 276: 23962-23968, 2001. [PubMed: 11279242] [Full Text: https://doi.org/10.1074/jbc.M101041200]
Yu, C., York, B., Wang, S., Feng, Q., Xu, J., O'Malley, B. W. An essential function of the SRC-3 coactivator in suppression of cytokine mRNA translation and inflammatory response. Molec. Cell 25: 765-778, 2007. [PubMed: 17349961] [Full Text: https://doi.org/10.1016/j.molcel.2007.01.025]