Alternative titles; symbols
HGNC Approved Gene Symbol: NCOA1
Cytogenetic location: 2p23.3 Genomic coordinates (GRCh38) : 2:24,491,254-24,770,702 (from NCBI)
Onate et al. (1995) identified steroid receptor coactivator-1 (SRC1), a coactivator that is required for full transcriptional activity of the steroid receptor superfamily. They isolated a cDNA encoding SRC1 using the yeast 2-hybrid system to identify proteins that interact with the human progesterone receptor (PGR; 607311). The SRC1 protein has a glutamine-rich region and a serine/threonine-rich region. SRC1 is expressed as 2 mRNAs of approximately 5.5 and 7.5 kb in a variety of human tissues and cell lines.
Using a Far Western-based approach to screen a HeLa cell cDNA expression library with bacterially expressed rat thyroid hormone receptor (THRB; 190160), Takeshita et al. (1996) identified a partial SRC1 cDNA. They isolated the remaining sequence by 5-prime RACE. The full-length cDNA encodes a 1,440-amino acid protein with a mass of approximately 160 kD.
Hayashi et al. (1997) identified mRNA splicing variants encoding 3 isoforms: SRC1, SRC1E, and SRC1(-Q). SRC1(-Q) is identical to the protein described by Takeshita et al. (1996). The C-terminal 56 amino acids of SRC1 are replaced by 14 unique amino acids in SRC1E, while SRC1(-Q) differs from SRC1 by deletion of a single glutamine residue. RT-PCR analysis showed that SRC1E mRNA was more abundantly expressed than SRC1 or SRC1(-Q) mRNAs in all the cell lines tested. SRC1E enhanced thyroid hormone-dependent transactivation of reporter gene expression more efficiently than SRC1 or SRC1(-Q).
Onate et al. (1995) showed that SRC1 enhances the transcriptional activity of ligand-bound PGR but does not alter the basal activity of the target promoter. SRC1 also enhances estrogen receptor (ESR; 133430), glucocorticoid receptor (GRL; 138040), thyroid hormone receptor (e.g., 190120), and retinoid X receptor (e.g., RXRA; 180245) transcriptional activities through their cognate DNA response elements in the presence of hormone. Studies of the effects of SRC1 on unrelated transactivators showed that SRC1 can enhance the transcriptional activities of SP1 (189906) and the chimeric Gal4-VP16 protein, but not those of E2F (e.g., 189971), E47 (147141), or CREB (123810). Coexpression of SRC1 with PGR and ESR reversed the ability of ESR to squelch activation by PGR, suggesting that SRC1 is a limiting factor necessary for efficient PGR and ESR transactivation. A C-terminal form of SRC1 containing the receptor-binding region acted as a dominant-negative repressor of endogenous SRC1 function.
In vitro binding studies by Takeshita et al. (1996) showed that SRC1 can bind to TBP (600075) and to TFIIB (189963), in addition to a variety of nuclear hormone receptors in a ligand-dependent manner, suggesting that SRC1 may play a role as a bridging molecule between nuclear hormone receptors and general transcription factors. The conserved AF-2 region of nuclear hormone receptors was not required for receptor-SRC1 binding.
To dissect the role of SRC1 in PGR transactivation, Liu et al. (1999) used a cell-free transcription system with chromatin templates. They reported the successful reconstitution of ligand-dependent and PGR-dependent transcription using chromatin. They showed that, consistent with their previously proposed hypothesis (Jenster et al., 1997), the addition of liganded PGR to preassembled chromatin led to the reconfiguration of nucleosome structure in the vicinity of its binding site. This study suggested a dual role for SRC1 in PGR-mediated transactivation: SRC1 is involved in both chromatin remodeling and the process of recruitment/stabilization of general transcription factors.
Using yeast 2-hybrid analysis, Zhang et al. (2007) found that SIP (KANK2; 614610) interacted with the N-terminal domain of SRC1. Western blot analysis of MCF-7 human breast cancer cell immunoprecipitates confirmed interaction between SIP and SRC1. Mutation analysis showed that the ankyrin (612641) repeat domain of SIP was required for its interaction with SRC1. Zhang et al. (2007) found that estrogen stimulation of MCF-7 cells caused nuclear translocation of cytosolic SRC1, while SIP remained cytosolic. Knockdown of SIP via RNA interference resulted in SRC1 nuclear localization, independent of estrogen treatment, and increased expression of an estrogen-dependent reporter. Overexpression of SIP in MCF-7 cells reduced cell proliferation and caused accumulation of cells in G0/G1 phase in response to estrogen treatment. In contrast, knockdown of SIP led to an increase of cells in S and G2/M phases following estrogen treatment. Casein kinase II (see 115440) phosphorylated SIP in vitro, and phosphorylated SIP no longer interacted with SRC1 in MCF-7 cells, permitting SRC1 translocation to the nucleus. Zhang et al. (2007) concluded that SIP sequesters SRC1 in the cytoplasm and thereby regulates its transactivation activity.
By fluorescence in situ hybridization, Carapeti et al. (1998) mapped the NCOA1 gene to human chromosome 2p23.
Picard et al. (2002) found that Tif2 (601993) -/- mice were protected against obesity and displayed enhanced adaptive thermogenesis, whereas Src1 -/- mice were prone to obesity due to reduced energy expenditure. In white adipose tissue, lack of Tif2 decreased Pparg (601487) activity and reduced fat accumulation, whereas in brown adipose tissue, it facilitated the interaction between Src1 and Pgc1-alpha (604517), which induced the thermogenic activity of Pgc1-alpha. A high-fat diet increased the Tif2/Src1 expression ratio, which may have contributed to weight gain. These results revealed that the relative level of TIF2/SRC1 can modulate energy metabolism.
Ye et al. (2005) developed transgenic androgen receptor (AR; 313700)-reporter mice and crossed them with Src1 or Tif2 knockout mice to analyze the contributions of Src1 and Tif2 to AR activity in testis. In vivo imaging and reporter gene assays showed that testicular AR activity was decreased significantly in mice with the Tif2 +/- mutation, but not in those with an Src1 +/- background, suggesting that Tif2 is the preferential coactivator for AR in testis. Immunohistologic analysis confirmed that AR and Tif2 coexist in mouse testicular Sertoli cell nuclei under normal conditions. Although Src1 concentrated in Sertoli cell nuclei in the absence of Tif2, nuclear Src1 did not rescue AR activity in the Tif2 mutant background. Src1 appeared to negatively influence AR activity, whereas Tif2 stimulated AR activity.
Carapeti, M., Aguiar, R. C. T., Chase, A., Goldman, J. M., Cross, N. C. P. Assignment of the steroid receptor coactivator-1 (SRC-1) gene to human chromosome band 2p23. Genomics 52: 242-244, 1998. [PubMed: 9782096] [Full Text: https://doi.org/10.1006/geno.1998.5446]
Hayashi, Y., Ohmori, S., Ito, T., Seo, H. A splicing variant of steroid receptor coactivator-1 (SRC-1E): the major isoform of SRC-1 to mediate thyroid hormone action. Biochem. Biophys. Res. Commun. 236: 83-87, 1997. [PubMed: 9223431] [Full Text: https://doi.org/10.1006/bbrc.1997.6911]
Jenster, G., Spencer, T. E., Burcin, M. M., Tsai, S. Y., Tsai, M.-J., O'Malley, B. W. Steroid receptor induction of gene transcription: a two-step model. Proc. Nat. Acad. Sci. 94: 7879-7884, 1997. [PubMed: 9223281] [Full Text: https://doi.org/10.1073/pnas.94.15.7879]
Liu, Z., Wong, J., Tsai, S. Y., Tsai, M. J., O'Malley, B. W. Steroid receptor coactivator-1 (SRC-1) enhances ligand-dependent and receptor-dependent cell-free transcription of chromatin. Proc. Nat. Acad. Sci. 96: 9485-9490, 1999. [PubMed: 10449719] [Full Text: https://doi.org/10.1073/pnas.96.17.9485]
Onate, S. A., Tsai, S. Y., Tsai, M.-J., O'Malley, B. W. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270: 1354-1357, 1995. [PubMed: 7481822] [Full Text: https://doi.org/10.1126/science.270.5240.1354]
Picard, F., Gehin, M., Annicotte, J.-S., Rocchi, S., Champy, M.-F., O'Malley, B. W., Chambon, P., Auwerx, J. SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell 111: 931-941, 2002. [PubMed: 12507421] [Full Text: https://doi.org/10.1016/s0092-8674(02)01169-8]
Takeshita, A., Yen, P. M., Misiti, S., Cardona, G. R., Liu, Y., Chin, W. W. Molecular cloning and properties of a full-length putative thyroid hormone receptor coactivator. Endocrinology 137: 3594-3597, 1996. [PubMed: 8754792] [Full Text: https://doi.org/10.1210/endo.137.8.8754792]
Ye, X., Han, S. J., Tsai, S. Y., DeMayo, F. J., Xu, J., Tsai, M.-J., O'Malley, B. W. Roles of steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF) 2 in androgen receptor activity in mice. Proc. Nat. Acad. Sci. 102: 9487-9492, 2005. [PubMed: 15983373] [Full Text: https://doi.org/10.1073/pnas.0503577102]
Zhang, Y., Zhang, H., Liang, J., Yu, W., Shang, Y. SIP, a novel ankyrin repeat containing protein, sequesters steroid receptor coactivators in the cytoplasm. EMBO J. 26: 2645-2657, 2007. [PubMed: 17476305] [Full Text: https://doi.org/10.1038/sj.emboj.7601710]