Disease relevance of Ncoa1

• Although NCoAs are, in general, increased in response to hypothyroidism or in states of TH resistance, SRC-1 specifically does not regulate TR isoform expression [1].
• In TR beta(PV/PV) mice, however, lack of SRC-1 intensified the pathological progression of thyroid follicular cells to papillary hyperplasia, reminiscent of papillary neoplasia [2].
• Interestingly, a high-fat diet increases the TIF2/SRC-1 expression ratio, which may contribute to weight gain [3].
• TIF2-/- mice are protected against obesity and display enhanced adaptive thermogenesis, whereas SRC-1-/- mice are prone to obesity due to reduced energy expenditure [3].
• When challenged with a PPARalpha ligand, such as ciprofibrate or Wy-14,643, the SRC-1(-/-) mice displayed typical pleiotropic responses, including hepatomegaly, peroxisome proliferation in hepatocytes, and increased mRNA and protein levels of genes that are regulated by PPARalpha [4].

High impact information on Ncoa1

• These results reveal that the relative level of TIF2/SRC-1 can modulate energy metabolism [3].
• In white adipose tissue, lack of TIF2 decreases PPARgamma activity and reduces fat accumulation, whereas in brown adipose tissue it facilitates the interaction between SRC-1 and PGC-1alpha, which induces PGC-1alpha's thermogenic activity [3].
• The results indicate that SRC-1 mediates steroid hormone responses in vivo and that loss of its coactivator function results in partial resistance to hormone [5].
• Ligand-independent recruitment of SRC-1 to estrogen receptor beta through phosphorylation of activation function AF-1 [6].
• Also found at the array by immunofluorescence were two different steroid receptor coactivators (SRC1 and CBP) with acetyltransferase activity, a chromatin remodeler (BRG1), and two transcription factors (NFI and AP-2) [7].

Chemical compound and disease context of Ncoa1

• The SRC-1(-/-) mice showed high turnover osteopenia under physiological conditions and hardly responded to osteoanabolic actions of exogenous androgen and estrogen in males and females, respectively, after gonadectomies, indicating that SRC-1 is essential for the maintenance of bone mass by sex hormones [8].

Biological context of Ncoa1

• Genetic disruption of the steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF)2/SRC-2 in mouse resulted in distinctive mutant phenotypes [9].
• Steroid receptor coactivator 2 is critical for progesterone-dependent uterine function and mammary morphogenesis in the mouse [10].
• Role of the steroid receptor coactivator SRC-3 in cell growth [11].
• Using mass spectrometry, we have identified three CARM1-dependent methylation sites located in a glutamine-rich region within the carboxy terminus of p/CIP which are conserved among all steroid receptor coactivator proteins [12].
• During early embryonic development, PPARgamma, SRC-1, and PBP are differentially expressed, with only limited cell types displaying overlapping expression [13].

Anatomical context of Ncoa1

• Moreover, removal of SRC-1 in the PR(Cre/+) SRC-2(flox/flox) mouse uterus resulted in the absence of a decidual response, confirming that uterine SRC-2 and -1 cooperate in P-initiated transcriptional programs which lead to full decidualization [10].
• The expression of both SRC-1 and PBP is prominent in the breast epithelium of nonpregnant, pregnant, and lactating mice, whereas PPARgamma expression appeared prominent during lactation [13].
• In the colonic mucosa, PPARgamma expression occurs throughout the villi, whereas the expression of both SRC-1 and PBP is confined mostly to the crypts [13].
• In the mammary gland, PR activity in the luminal epithelium of both wild-type and SRC-1(-/-) mice was induced by estrogen + progesterone treatment [14].
• SRC-1 null mice exhibit moderate motor dysfunction and delayed development of cerebellar Purkinje cells [15].

Associations of Ncoa1 with chemical compounds

• A reduction in blood glucose was observed in SRC-1-/- mice after chronic stress, consistent with a generalized state of glucocorticoid resistance [16].
• However, after exposure to paradigms of acute and chronic stress, SRC-1-/- mice exhibited an elevation in serum corticosterone despite normal (nonsuppressed) ACTH, suggesting an increase in adrenal sensitivity as well as a concomitant defect in glucocorticoid-mediated feedback inhibition of the HPA axis [16].
• Two serine residues in ER beta AF-1, of which one is contained within a motif present in other steroid receptors, are critical for physical interaction with SRC-1 and transcriptional activation [6].
• Modulation by steroid receptor coactivator-1 of target-tissue responsiveness in resistance to thyroid hormone [2].
• In contrast, lack of SRC-1 did not affect responsiveness in the liver in regulating serum cholesterol in either TR beta(PV/+) or TR beta(PV/PV) mice [2].

Physical interactions of Ncoa1

• The minimal chimeric protein that is produced fuses MLL to the bromodomain, histone acetyltransferase (HAT) domain, EIA-binding domain and steroid-receptor coactivator binding domains of CBP [17].
• We have shown that SRC-1 unexpectedly interacts with GR via its two nuclear receptor binding domains, thus providing a novel mechanism of GR signaling within the nervous system [18].
• Ftz, on the other hand, influences Ftz-F1 activity by interacting with its AF-2 domain in a manner that mimics a nuclear receptor coactivator [19].
• The vitellogenin promoter construct, however, was only weakly activated by the Brn-3/Src-1 complex in the ND7 cells and there was even less effect on this promoter in the BHK21 cells [20].
• Our results suggest that the 50-kDa 12(S)-HETE binding protein is a receptor that may signal through interaction with a nuclear receptor coactivator protein [21].

Regulatory relationships of Ncoa1

• In the adult mouse brain, SRC-1 is highly expressed in the olfactory bulb, hippocampus, piriform cortex, amygdala, hypothalamus, cerebellum, and brainstem [15].
• We assessed the in vivo function of SRC-1 on the PPARalpha-regulated gene expression in liver by generating mice in which the SRC-1 gene was inactivated by gene targeting [4].
• cAMP-dependent protein kinase regulates ubiquitin-proteasome-mediated degradation and subcellular localization of the nuclear receptor coactivator GRIP1 [22].
• To investigate the role of nuclear receptor coactivator peroxisome proliferator-activated receptor-interacting protein (PRIP) in mammary gland development, we generated a conditional null mutation of PRIP in mammary glands [23].

Other interactions of Ncoa1

• 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 [24].
• Roles of steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF) 2 in androgen receptor activity in mice [9].
• PPARgamma and PBP are expressed in the transitional epithelium of urinary bladder and in brown adipose tissue, but not SRC-1 [13].
• PPARgamma and PBP expression overlapped in the brown fat and urogenital sinus at stage E15.5 of embryogenesis, whereas SRC-1 expression occurred mostly in neuroepithelium and cartilage between stages E9.5 and E13.5 of embryogenesis [13].
• Thus, the present studies show that a coactivator such as SRC-1 could modulate the in vivo action of TR beta mutants in a tissue-dependent manner [2].

Analytical, diagnostic and therapeutic context of Ncoa1

• Microarray analysis demonstrates that gene expression changes are specific and nonoverlapping for each SRC member in the liver [25].
• The in vivo biological function of a steroid receptor coactivator was assessed in mice in which the SRC-1 gene was inactivated by gene targeting [5].
• Indeed, chromatin immunoprecipitation assays demonstrated that endogenous MR, Ubc9, and SRC-1 were recruited to an endogenous ENaC gene promoter in a largely aldosterone-dependent manner [26].
• Thus, we assessed the skeletal response to ovariectomy (ovx) and E replacement in SRC-1 knockout (KO) mice compared with wild-type (WT) littermates [27].
• To study the possible involvement of these cofactors on tissue-specific regulation of gene expression by NRs, we examined the expression of the coactivator SRC-1 mRNA during mouse embryogenesis by in situ hybridization (ISH) [28].

References