Biology:Nuclear receptor coactivator 3
 Generic protein structure example |
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[14] and
- CREB-binding protein,[14][15]
- DDX17,[16]
- DDX5,[16]
- Estrogen receptor alpha,[16][17][18]
- Estrogen receptor beta,[17][19]
- Glucocorticoid receptor,[20][21]
- IKBKG,[14]
- IKK2,[14]
- Peroxisome proliferator-activated receptor gamma,[22] and
- Retinoid X receptor alpha.[23][24]
References
- ↑ "AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer". Science 277 (5328): 965–8. August 1997. doi:10.1126/science.277.5328.965. PMID 9252329. https://zenodo.org/record/1231118.
- ↑ "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. doi:10.1074/jbc.272.44.27629. PMID 9346901.
- ↑ "AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer". Science 277 (5328): 965–8. 1997. doi:10.1126/science.277.5328.965. PMID 9252329. https://zenodo.org/record/1231118.
- ↑ "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. doi:10.1074/jbc.272.44.27629. PMID 9346901.
- ↑ "Study sheds new light on tamoxifen resistance". Cordis News. Cordis. 2008-11-13. http://cordis.europa.eu/fetch?CALLER=EN_NEWS&ACTION=D&SESSION=&RCN=30093.
- ↑ "Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen". Nature 456 (7222): 663–6. December 2008. doi:10.1038/nature07483. PMID 19005469. Bibcode: 2008Natur.456..663H.
- ↑ "AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor". Molecular and Cellular Biology 20 (14): 5041–7. July 2000. doi:10.1128/MCB.20.14.5041-5047.2000. PMID 10866661.
- ↑ "Phosphoinositide 3-kinase/AKT signaling can promote AIB1 stability independently of GSK3 phosphorylation". Cancer Research 68 (13): 5450–9. July 2008. doi:10.1158/0008-5472.CAN-07-6433. PMID 18593948.
- ↑ "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. doi:10.1093/jnci/95.5.353. PMID 12618500.
- ↑ "Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen". Nature 456 (7222): 663–6. December 2008. doi:10.1038/nature07483. PMID 19005469. Bibcode: 2008Natur.456..663H.
- ↑ "Thyroid receptor activator molecule, TRAM-1, is an androgen receptor coactivator". Endocrinology 141 (9): 3440–50. September 2000. doi:10.1210/endo.141.9.7680. PMID 10965917.
- ↑ "Expression of RAC 3, a steroid hormone receptor co-activator in prostate cancer". Br. J. Cancer 85 (12): 1928–36. December 2001. doi:10.1054/bjoc.2001.2179. PMID 11747336.
- ↑ "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. doi:10.1074/jbc.M400970200. PMID 14966121.
- ↑ 14.0 14.1 14.2 14.3 "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. doi:10.1128/MCB.22.10.3549-3561.2002. PMID 11971985.
- ↑ "Temporal/spatial expression of nuclear receptor coactivators in the mouse lung". Am. J. Physiol. Lung Cell Mol. Physiol. 279 (6): L1066-74. December 2000. doi:10.1152/ajplung.2000.279.6.l1066. PMID 11076796.
- ↑ 16.0 16.1 16.2 "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. doi:10.1093/emboj/20.6.1341. PMID 11250900.
- ↑ 17.0 17.1 "Structure-function evaluation of ER alpha and beta interplay with SRC family coactivators. ER selective ligands". Biochemistry 40 (23): 6756–65. June 2001. doi:10.1021/bi010379h. PMID 11389589.
- ↑ "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. doi:10.1073/pnas.220427297. PMID 11050174. Bibcode: 2000PNAS...9712536T.
- ↑ "Differential mechanisms of nuclear receptor regulation by receptor-associated coactivator 3". J. Biol. Chem. 275 (8): 5976–82. February 2000. doi:10.1074/jbc.275.8.5976. PMID 10681591.
- ↑ "BAF60a mediates critical interactions between nuclear receptors and the BRG1 chromatin-remodeling complex for transactivation". Mol. Cell. Biol. 23 (17): 6210–20. September 2003. doi:10.1128/MCB.23.17.6210-6220.2003. PMID 12917342.
- ↑ "Regulation of glucocorticoid receptor activity by 14--3-3-dependent intracellular relocalization of the corepressor RIP140". Mol. Endocrinol. 15 (4): 501–11. April 2001. doi:10.1210/mend.15.4.0624. PMID 11266503.
- ↑ "Ligand type-specific interactions of peroxisome proliferator-activated receptor gamma with transcriptional coactivators". J. Biol. Chem. 275 (43): 33201–4. October 2000. doi:10.1074/jbc.C000517200. PMID 10944516.
- ↑ "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. doi:10.1016/S0092-8674(00)80516-4. PMID 9267036.
- ↑ "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. doi:10.1021/bi011764+. PMID 11851396.
External links
- nuclear receptor coactivator 3 at the US National Library of Medicine Medical Subject Headings (MeSH)
- NURSA C91
Further reading
- "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. doi:10.1016/S0960-0760(02)00254-6. PMID 12650696.
- "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. doi:10.1128/mcb.15.7.3479. PMID 7791754.
- "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. PMID 8758910.
- "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. 1997. doi:10.1101/gr.6.9.791. PMID 8889548.
- "cDNAs with long CAG trinucleotide repeats from human brain". Hum. Genet. 100 (1): 114–22. 1997. doi:10.1007/s004390050476. PMID 9225980.
- "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. doi:10.1073/pnas.94.16.8479. PMID 9238002. Bibcode: 1997PNAS...94.8479L.
- "AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer". Science 277 (5328): 965–8. 1997. doi:10.1126/science.277.5328.965. PMID 9252329. https://zenodo.org/record/1231118.
- "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. doi:10.1016/S0092-8674(00)80516-4. PMID 9267036.
- "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. doi:10.1074/jbc.272.44.27629. PMID 9346901.
- "Transcription factor-specific requirements for coactivators and their acetyltransferase functions". Science 279 (5351): 703–7. 1998. doi:10.1126/science.279.5351.703. PMID 9445475. Bibcode: 1998Sci...279..703K.
- "Polymorphic exonic CAG microsatellites in the gene amplified in breast cancer (AIB1 gene)". Clin. Genet. 54 (1): 102–3. 1998. doi:10.1111/j.1399-0004.1998.tb03704.x. PMID 9727751.
- "SRC-1 and GRIP1 coactivate transcription with hepatocyte nuclear factor 4". J. Biol. Chem. 273 (47): 30847–50. 1998. doi:10.1074/jbc.273.47.30847. PMID 9812974.
- "Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1". Genes Dev. 12 (22): 3488–98. 1999. doi:10.1101/gad.12.22.3488. PMID 9832502.
- "Regulation of hormone-induced histone hyperacetylation and gene activation via acetylation of an acetylase". Cell 98 (5): 675–86. 1999. doi:10.1016/S0092-8674(00)80054-9. PMID 10490106.
- "Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation". J. Cell Sci. 112 (20): 3519–27. 2000. doi:10.1242/jcs.112.20.3519. PMID 10504300.
- "Constitutive activation of transcription and binding of coactivator by estrogen-related receptors 1 and 2". Mol. Endocrinol. 13 (12): 2151–62. 2000. doi:10.1210/mend.13.12.0381. PMID 10598588.
- "CBP/p300 interact with and function as transcriptional coactivators of BRCA1". Proc. Natl. Acad. Sci. U.S.A. 97 (3): 1020–5. 2000. doi:10.1073/pnas.97.3.1020. PMID 10655477. Bibcode: 2000PNAS...97.1020P.
- "Differential mechanisms of nuclear receptor regulation by receptor-associated coactivator 3". J. Biol. Chem. 275 (8): 5976–82. 2000. doi:10.1074/jbc.275.8.5976. PMID 10681591.
- "AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor". Mol. Cell. Biol. 20 (14): 5041–7. 2000. doi:10.1128/MCB.20.14.5041-5047.2000. PMID 10866661.
- "Thyroid receptor activator molecule, TRAM-1, is an androgen receptor coactivator". Endocrinology 141 (9): 3440–50. 2000. doi:10.1210/endo.141.9.7680. PMID 10965917.
PDB gallery | |
|---|---|
|
 |  |
