Disease relevance of Ncoa3

• Genetic disruption of SRC-3 in mice results in a pleiotropic phenotype showing dwarfism, delayed puberty, reduced female reproductive function, and blunted mammary gland development [1].
• Previous studies indicate that SRC-3 is required for normal animal growth and is often amplified or overexpressed in many cancers, including breast and prostate cancers [2].
• We show that deletion of SRC-3 gene decreases platelet and increases lymphocytes numbers, leading to the development of malignant B-cell lymphomas upon aging [3].
• In TRbetaPV mice deficient in SRC-3, dysfunction of the pituitary-thyroid axis and hypercholesterolemia was lessened, but growth impairment of RTH was worsened [4].
• These results suggest that a more effective strategy to control breast cancer is to target AIB1-mediated and ovarian hormone-initiated pathways [5].

High impact information on Ncoa3

• The expansion of the lymphoid lineage in SRC-3(-/-) mice is cell autonomous, correlates with an induction of proliferative and antiapoptotic genes secondary to constitutive NF-kappaB activation, and can be reversed by restoration of SRC-3 expression [3].
• NF-kappaB activation is explained by the degradation of IkappaB, consequent to increases in free IkappaB kinase, which is no longer inhibited by SRC-3 [3].
• These results demonstrate that SRC-3 regulates lymphopoiesis and in combination with previous studies indicate that SRC-3 has vastly diverging effects on cell proliferation depending on the cellular context, ranging from proliferative and tumorigenic (breast) to antiproliferative (lymphoid cells) effects [3].
• Indeed, in SRC-3(-/-) mouse embryonic fibroblasts, adipocyte differentiation was severely impaired, and reexpression of SRC-3 was able to restore it [6].
• Collectively, these data suggest a crucial role for SRC-3 as an integrator of the complex transcriptional network controlling adipogenesis [6].

Chemical compound and disease context of Ncoa3

• Here, we exploited the mifepristone-induced SRC-3 LNCaP prostate cancer cell line generated in our laboratory to identify SRC-3-regulated genes by oligonucleotide microarray analysis [7].

Biological context of Ncoa3

• Hormonal analysis indicates that SRC-3 plays a role in both the growth hormone regulatory pathway and the production of estrogen, which may explain the observed phenotypes [1].
• Taken together, these results suggest that SRC-3 is an important modulator for mammalian cell growth [2].
• In contrast, down-regulation of SRC-3 expression in cells by small interfering RNA decreases cell growth, leading to a smaller cell size [2].
• The activity and stability of the transcriptional coactivator p/CIP/SRC-3 are regulated by CARM1-dependent methylation [8].
• We found that SRC-3 up-regulates the expression of multiple genes in the insulin-like growth factor (IGF)/AKT signaling pathway that are involved in cell proliferation and survival [7].

Anatomical context of Ncoa3

• Here, we show that mouse SRC-3 is expressed in a tissue-specific fashion and distributed mainly in the oocytes, mammary glands, hippocampus, olfactory bulb, smooth muscle, hepatocytes, and vaginal epithelium [1].
• In this study, we show that overexpression of SRC-3 stimulates cell growth to increase cell size in prostate cancer cell lines [2].
• Lastly, tumor growth after injection of ER(+) AIB1 tumor cell lines into wild-type animals is inhibited by RAD001 treatment [9].
• In contrast, an increase in PR activity in the luminal epithelium was not detected in SRC-3(-/-) mice with the same treatment [10].
• In the uterus, PR activity in the stroma compartment of both wild-type and SRC-3(-/-) mice was induced by estrogen + progesterone treatment [10].

Associations of Ncoa3 with chemical compounds

• Furthermore, our results indicate that overexpression of SRC-3 can modulate the AKT signaling pathway in a steroid-independent manner, which results in the activation of AKT/mTOR signaling concomitant with an increase in cell size [2].
• This latter finding contrasts with the impaired estrogen and progesterone-induced mammary gland development observed previously for steroid receptor coactivator type 1 (SRC-1) and SRC-3 female knockout mice [11].
• Targeting the AIB1 Oncogene through Mammalian Target of Rapamycin Inhibition in the Mammary Gland [9].
• We hypothesize that unlike antigen-presenting cells, vascular endothelial cells (ECs) lack the Trif protein TRAM and are therefore incapable of eliciting Trif-dependent immune responses to LPS [12].

Other interactions of Ncoa3

• These results suggest that the physiological role of SRC-3 is different from that of SRC-1 and prove the diversity among coactivator family members [1].
• In most brain structures where SRC-1 is expressed, SRC-2 is expressed at lower levels; however, SRC-3 mRNA is detectable only in the hippocampus [13].
• AIB1 deficiency did not alter the expression of estrogen and progesterone-responsive genes in the mammary gland, but it caused partial resistance to the insulin-like growth factor I because of a significant reduction in the insulin receptor substrates [5].
• Within the context of the more complex mouse mammary tumor virus promoter, GR recruits SRC-1e and SRC-2, whereas SRC-1a and SRC-3 are not implicated [14].
• An examination of potential compensatory mechanism(s) revealed an increase in adrenal weight, selective elevation of melanocortin 2 receptor mRNA, and a coincident increase in SRC-2 and SRC-3 expression in SRC-1-/- adrenals [15].

Analytical, diagnostic and therapeutic context of Ncoa3

• Chromatin immunoprecipitation assay revealed that SRC-3 was directly recruited to the promoters of these genes, indicating that they are direct targets of SRC-3 [7].
• By screening a mouse genomic DNA library, performing long-range polymerase chain reaction and sequencing, we have cloned and characterized the mouse SRC-3 gene [16].
• Through fluorescence in situ hybridization, we have mapped the mouse SRC-1, SRC-2, and SRC-3 genes to chromosomal locations 12A2-A3, 1A3-A5, and 2H2-H4, respectively [16].
• After ovariectomy, neointimal growth in wild-type mice was almost completely inhibited by estrogen treatment but only partially inhibited in SRC-3(-/-) mice [17].
• The role of SRC-3 during vascular remodeling was analyzed using a unilateral carotid ligation model [17].

References