Search results for NCOR2

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Reaction (11 results from a total of 11)

Identifier: R-HSA-3927886
Species: Homo sapiens
Compartment: nucleoplasm
As inferred from mouse homologs, NCOR2 (SMRT) is sumoylated at lysine-668 with SUMO1. SUMOylation reduces repression of transcription by NCOR2.
Identifier: R-HSA-8986939
Species: Homo sapiens
Compartment: nucleoplasm
MECP2 binds the nuclear receptor co-repressor complex (NCoR/SMRT). This interaction is inhibited by MECP2 phosphorylation at threonine residue T308. The following NCoR/SMRT complex components were co-immunoprecipitated with MECP2: NCOR1, NCOR2, HDAC3, TBL1 (TBL1X), TBLR1 (TBL1XR1) and GPS2 (Lyst et al. 2013, Ebert et al. 2013). Direct interaction was confirmed between the transcriptional repressor domain of MECP2 and NCOR1, NCOR2, TBL1X and TBLR1 (Lyst et al. 2013). NCoR/SMRT complex consists of either NCOR1 (NCoR) or NCOR2 (SMRT), GPS2, HDAC3 and tetramers of either TBL1X or TBL1XR1 (Oberoi et al. 2011, reviewed by Watson et al. 2012).
Identifier: R-NUL-2064264
Species: Mus musculus, Cercopithecus aethiops, Homo sapiens
Compartment: nucleoplasm
Interaction of RBPJ (CSL) with NCOR2 (SMRT) was initially discovered in a yeast two-hybrid assay, using human recombinant proteins, and was confirmed in mammalian cells by co-immunoprecipitation of exogenously expressed human RBPJ and NCOR2 from the mouse fibroblast cell line NIH 3T3, as well as by a mammalian two-hybrid assay. These experiments also established, using a RBPJ repression domain mutant, that the repression domain was necessary for interaction with NCOR2 (Kao et al. 1998). Using a mammalian two-hybrid assay, it was found that RBPJ also interacts with NCOR1 in a repression domain dependent way. Over-expression of NCOR2 inhibits transcriptional activity of TAN-1, a gain-of-function NOTCH1 mutant found in T-ALL, through disrupting the interaction of TAN-1 with RBPJ (Kao et al. 1998). NOTCH target genes were found to be de-repressed when cells were treated with TSA (trichostatin A), an inhibitor of HDAC1. HDAC1, known to interact with NCOR2, was found to interact with RBPJ: exogenously expressed human RBPJ co-immunoprecipitated endogenous mouse HDAC1 from CV-1 cell line, derived by from kidney cells of the vervet monkey (also known as the African green monkey, Cercopithecus aethiops or Chlorobus aethiops). The interaction of HDAC1 with RBPJ was dependent on the presence of repression domain (Kao et al. 1998). The recombinant human protein SNW1 (SKIP) was shown to interact with recombinant human RBPJ as part of a transcriptional repression complex, but stays bound to recombinant mouse NICD1 and RBPJ and aids NOTCH-mediated transcription once the NCOR co-repression complex is displaced by NICD1 (Zhou et al. 2000). Mouse Tbl1x and Tbl1xr1 were also found in the NCOR co-repressor complex (Perissi et al. 2004). Once the NCOR complex is displaced, Tbl1x and Tbl1xr1 remain bound to it and facilitate NICD1-mediated transcription probably by acting as adaptors for recruitment of the ubiquitin conjugating/19S proteasome complex that degrades displaced transcriptional repressors (Perissi et al. 2008, Perissi et al. 2004).
Identifier: R-HSA-400183
Species: Homo sapiens
Compartment: nucleoplasm
In the absence of activating ligands of PPAR-alpha, the PPAR-alpha:RXR-alpha heterodimers recruit corepressors NCoR1, NCoR2(SMRT), and histone deacetylases (HDACs) to genes regulated by PPAR-alpha. The corepressors maintain chromatin at the gene in an inactive conformation and prevent expression of the gene.
Identifier: R-HSA-381290
Species: Homo sapiens
Compartment: nucleoplasm
The PPARG:RXRA heterodimer binds specific the PPRE element, two 6-bp DR-1 motifs separated by 1 nucleotide, in the promoters of target genes such as aP2/FABP4 even in the absence of fatty acid ligands that activate PPARG. When activating ligands of PPARG are absent PPARG:RXRA recruits corepressors such as NCoR2(SMRT), NCoR, and HDAC3 to maintain the target gene in an inactive state.
Identifier: R-HSA-3777129
Species: Homo sapiens
Compartment: nucleoplasm
HDAC3 mediates the gene silencing activity of Retinoic acid and thyroid hormone receptor (SMRT) complex or the homologous nuclear receptor corepressor (NCoR). These coregulators are involved in a wide range of developmental and homeostatic processes, including metabolism, inflammation, and circadian rhythms (Mottis et al. 2013). HDAC3 interacts with a conserved SANT-like domain known as the deacetylase activating domain (DAD) within NCOR2 (SMRT) or NCOR1 (Li et al. 2000, Wen et al. 2000, Zhang et al. 2002, Yoon et al. 2003, Oberoi et al. 2011). This interaction both recruits and activates HDAC3 (Wen et al. 2000, Guenther et al. 2001, Zhang et al. 2002). Recruitment of HDAC3 to the DAD is essential for repression by the nuclear thyroid hormone receptor and for the maintenance of normal circadian physiology (You et al. 2010, Yin et al. 2007). A second SANT-like domain has been reported to interact directly with histone tails and termed the histone interaction domain (HID) (Hartman et al. 2005, Yu et al. 2003). NCORs are largely unstructured platform proteins that act as a scaffold upon which the enzymatic machinery of the repression complex is built (Watson et al. 2012). They can recruit other deacetylases such as HDAC4 (Fischle et al. 2002), HDAC5, HDAC7 (Kao et al. 2000), Sirt1 (Picard et al. 2004), and via mSin3, HDAC1 (Heinzel et al. 1997, Nagy et al. 1997). The importance of these deacetylase enzymes is not yet established. It has been demonstrated HDAC3 was shown to be responsible for deacetylase activities associated with HDAC4 and HDAC7 (Fischle et al. 2002). Corepressor complexes are heterogeneous, context-specific and transient in nature, but in addition to HDAC3, some additional partners are regularly found in stoichiometric association with NCOR1/NCOR2 and are essential for repressive function. These partners include the G protein pathway suppressor (GPS2) and transducing beta-like 1 (TBL1) and its homologue, TBL-related 1 (TBLR1), which together form the core repression complex (Oberoi et al. 2011). Ins(1,4,5,6)P4 is a further component of the complex (Watson et al. 2012).
Identifier: R-HSA-1912388
Species: Homo sapiens
Compartment: nucleoplasm
In the absence of NICD1, RBPJ (CSL) is bound to a co-repressor complex that includes NCOR proteins, NCOR1 and/or NCOR2 (also known as SMRT) and HDAC histone deacetylases. Both NCOR and HDAC proteins interact with RBPJ (CSL) through a repression domain in RBPJ. When bound to the co-repressor complex, RBPJ (CSL) represses transcription of NOTCH target genes (Kao et al. 1998). The co-repressor complex also contains SNW1 (SKIP), which interacts with RBPJ (CSL) in a repression-domain independent way (Zhou et al. 2000), TBL1X (TBL1) and TBL1XR1 (TBLR1) (Perissi et al. 2004). NICD1 binds to RBPJ (CSL) and SNW1 (SKIP) and displaces NCOR and HDAC proteins (Kao et al. 1998). TBL1X and TBL1XR1 facilitate displacement of NCOR and HDAC and positively regulated NOTCH-mediated transcription probably by recruiting the ubiquitin/19S proteasome complex that degrades transcriptional repressors (Perissi et al. 2004, Perissi et al. 2008). SNW1 facilitates NICD1 interaction with RBPJ and NOTCH-mediated transcription (Zhou et al. 2000). It is possible that the co-repressor complex contains additional proteins not described here. Loss-of-function mutations in RBPJ typically result in phenotypes associated with reduced NOTCH function, suggesting that RBPJ activation complex (i.e. NOTCH coactivator complex) is more important than RBPJ repressor complex in control of normal development and homeostasis (Oka et al. 1995).
Identifier: R-HSA-350058
Species: Homo sapiens
Compartment: nucleoplasm
Mammalian CSL Corepressor Complexes: In the absence of activated Notch signaling, DNA-bound CSL proteins recruit a corepressor complex to maintain target genes in the repressed state until Notch is specifically activated. The mammalian corepressor complexes include NCOR complexes, but may also include additional corepressor proteins, such as SHARP (reviewed in Mumm, 2000 and Kovall, 2007). The exact composition of the CSL NCOR complex is not known, but in other pathways the "core" NCOR corepressor complex includes at least one NCOR protein (NCOR1, NCOR2, CIR), one Histone Deacetylase protein (HDAC1, HDAC3, or certain others), and one TBL1 protein (TBL1X, TBL1XR1) (reviewed in Rosenfeld, 2006). In some contexts, the core NCOR corepressor complex may also recruit additional corepressor proteins or complexes, such as the SIN3 complex, which consists of SIN3 (SIN3A, SIN3B), and SAP30, or other SIN3-associated proteins. An additional CSL - NCOR binding corepressor, SHARP, may also contribute to the CSL corepressor complex in some contexts (Oswald, 2002). The CSL corepressor complex also includes a bifunctional cofactor, SKIP, that is present in both CSL corepressor complexes and CSL coactivator complexes, and may function in the binding of NICD and displacement of the corepressor complex during activated Notch signaling (Zhou, 2000). The formation of the CSL-NCOR corepressor complexes is modelled here as the simultaneous assembly of the various components shown. The order of addition of components is not known, and may vary in different contexts.
Identifier: R-HSA-381309
Species: Homo sapiens
Compartment: nucleoplasm
PPARG can be activated in cell cultures by adding ligands such as polyunsaturated fatty acids and certain prostanoids (prostaglandins). Endogenous fatty acids are relatively poor activators. Which ligands are most responsible for PPARG activation in the body has not yet been established. Generally, oxidized fatty acids such as 9(S')-hydroxyoctadeca-10,12-dienoic acid (9(S')-HODE) and 13(S')-HODE are more effective activators than are endogenous fatty acids. The thiazolidinedione (TZD) class of antidiabetic drugs are agonist ligands for PPARG (Lambe and Tugwood 1996).
FABP4 delivers ligands to PPARG directly. Binding of activator ligands to PPARG causes loss of corepressors such as SMRT/NCoR2, NCoR1, and HDAC3 and gain of interactions with the basal transcription machinery (Yoo et al. 2006). The TRAP220/MED1/DRIP205 subunit of the TRAP/Mediator (DRIP) complex binds directly to the LXXLL motif of PPARG and TRAP/Mediator is necessary for full transcriptional activation of target genes (Ge et al. 2008). PPARG also interacts with the MED14 subunit of the Mediator complex (Grontved et al. 2010).
Other coactivators, including NCOA1/SRC-1, NCOA2/TIF2/GRIP1, CBP, HAT/p300, and PRIP, interact with PPARG in a ligand-dependent way and enhance transcription (Gellman et al. 1999, Wallberg et al. 2003, Yang et al. 2000, Ge et al. 2002, Puigserver et al. 1999, Bugge et al. 2009, Steger et al. 2010).
The target genes of PPARG encode proteins involved in adipocyte differentiation (PGAR/ANGPTL4, PLIN, and aP2/FABP4), carbohydrate metabolism (PEPCK-C), and fatty acid transport (FAT/CD36, LPL).
Identifier: R-HSA-9024334
Species: Homo sapiens
Compartment: nucleoplasm
In the unliganded state, NR1H2,3 (LXR):RXR heterodimers are bound to DNA response elements in association with co-repressor complexes resulting in repression of target genes such as the ATP-binding cassette transporter (ABCA1) gene (Wagner BL et al. 2003; Jakobsson T et al. 2009). Ligand binding to NR1H2,3 induces conformational changes leading to release of co-repressor complexes and recruitment of co-activator complexes and transcription of target genes. A mammalian two-hybrid analysis, using GAL4 fusions of the receptor interacting domains (ID) from the nuclear receptor corepressor (NCOR1) and the silencing mediator of retinoic acid and thyroid hormone receptors (SMRT, also known as NCOR2) transiently co-expressed with VP-16 fusions of NR1H3 or NR1H2 ligand binding domains in the monkey kidney fibroblasts CV-1 cells showed that in the absence of ligand, both NR1H2 and NR1H3 interacted with the corepressor IDs of NCOR and SMRT (Wagner BL et al. 2003). Biochemical work has identified a core complex consisting of NCOR, histone deacetylase 3 (HDAC3), transducin β-like proteins (TBL1, TBLR1), and G protein pathway suppressor 2 (GPS2) (Zhang J et al. 2002). Chromatin immunoprecipitation (ChIP) assays in HepG2 cells revealed that, in the absence of GW3965, a synthetic NR1H2,3 agonist, NCOR and HDAC3 were associated with the ABCA1 promoter, while agonist treatment caused their dissociation and induced recruitment of histone acetyltransferase (HAT) CBP and RNA polymerase II (Jakobsson T et al. 2009). TBLR1 was also present at the promoter and unaffected by the ligand status. GPS2 was found to occupy the ABCA1 promoter in the absence of ligand but was released upon GW3965 treatment, while NR1H2,3 (LXR) recruitment was observed already in the absence of ligand and further enhanced upon ligand activation (Jakobsson T et al. 2009). The inclusion of anti-RXR antibody in the re-ChIP assays demonstrates that GPS2 associates with the LXR:RXR heterodimer. Importantly, similar recruitment patterns were obtained in human THP-1 macrophages. Thus, at the ABCA1 promoter, NR1H2,3 ligand triggers exchange of a GPS corepressor complex (containing NCoR, HDAC3, TBLR1) for the coactivator complex devoid of GPS2 (Jakobsson T et al. 2009).
Identifier: R-HSA-9024326
Species: Homo sapiens
Compartment: nucleoplasm
In macrophages, excess of cholesterol leads to the formation of oxysterols, the natural ligands of liver X receptors LXRα (NR1H3) and LXRβ (NR1H2), which belong to the nuclear receptor superfamily of ligand-activated transcription factors. Activation of NR1H2,3 induces expression of ATP-binding cassette transporter A1 (ABCA1), which acts in the plasma membrane and endosomal system to promote cellular cholesterol transfer to lipid-poor apolipoproteins, such as ApoA1 and ApoE associated with high density lipoprotein (HDL) formation (Ignatova ID et al. 2013; Vedhachalam C et a. 2007). NR1H3 (LXRα) was found to be a stronger activator of ABCA1 expression in response to LXR agonists in mouse bone marrow-derived macrophages and in human primary macrophages (Bischoff ED et al. 2010; Ishibashi M et al. 2013). Cholesteryl esters accumulate in various tissues of mice lacking NR1H3, and in cells of the male reproductive system this is directly attributable to reduced expression of ABCA1 (Ouvrier A et al. 2009). Moreover, loss of ABCA1 in humans results in Tangier disease, a condition in which patients have extremely low levels of circulating HDL, massive accumulation of cholesterol in macrophages, and an increased risk for developing atherosclerosis (Rust S et al. 1999). Treatment with the synthetic NR1H2,3 agonist, T0901317, increased expression of ABCA1 mRNA in cells and tissues of wild type, but not NR1H2,3-null mice (Wagner BL et al. 2003; Repa JJ et al. 2000). At the same time, “unliganded” NR1H2,3 repressed basal expression of ABCA1 in a tissue-specific manner, occurring in macrophages and intestinal mucosa but not in several other mouse tissues (Wagner BL et al. 2003). Treatment of human THP-1 macrophages with endogenous (25-hydroxycholesterol) or synthetic (T0901317) NR1H2,3 ligands stimulated both transcriptional and posttranscriptional pathways affecting ABCA1 expression (Ignatova ID et al. 2013).

NR1H2 or NR1H3 heterodimerizes with retinoid X receptors (RXR) and binds to LXR-response elements (LXREs) consisting of a direct repeat of the core sequence 5'-AGGTCA-3' separated by 4 nucleotides (DR4) in the DNA of target genes (Wiebel FF & Gustafsson JA 1997). The human ABCA1 promoter was found to contain a LXRE located about 50 bp upstream of the transcription start site (Costet P et al. 2000). Gel shift experiments showed that NR1H2,3:RXR heterodimers bind to the isolated LXREs from human ABCA1 (Costet P et al. 2000). Further, the ligand-selective regulation of ABCA1 was observed when ABCA1 promoter-luciferase reporter constructs were transfected into human embryonic kidney 293T cells or human liver carcinoma HepG2 cells that were then treated with T0901317 or 25-hydroxycholesterol to show enhanced luciferase activity (Ignatova ID et al. 2013). Unliganded LXR:RXR actively suppresses transcription by recruiting a corepressor complex. A mammalian two-hybrid analysis, using GAL4 fusions of the receptor interaction domains (ID) from the nuclear receptor corepressor (NCOR1) and the silencing mediator of retinoic acid and thyroid hormone receptors (SMRT or NCOR2) transiently co-expressed with VP-16 fusions of NR1H3 or NR1H2 ligand binding domains in monkey kidney fibroblasts CV-1 cells showed that in the absence of ligand, both NR1H2 and NR1H3 interacted with the corepressor IDs of NCOR and SMRT (Wagner BL et al. 2003). Biochemical work has identified a core complex consisting of NCOR, histone deacetylase 3 (HDAC3), transducin β-like proteins (TBL1, TBLR1), and G protein pathway suppressor 2 (GPS2) (Zhang J et al. 2002). The chromatin immunoprecipitation (ChIP) assays in HepG2 cells revealed that, in the absence of GW3965, a synthetic NR1H2,3 agonist, NCOR and HDAC3 were associated with ABCA1 promoter, while agonist treatment caused their dissociation and induced recruitment of histone acetyltransferase (HAT) CBP and RNA polymerase II (Jakobsson T et al. 2009). TBLR1 was also present at the promoter and unaffected by the ligand status. GPS2 was found to occupy the ABCA1 promoter in the absence of ligand but was released upon GW3965 treatment, while NR1H2,3 (LXR) recruitment was observed already in the absence of ligand and further enhanced upon ligand activation (Jakobsson T et al. 2009). The inclusion of RXR in the re-ChIP assays demonstrates that GPS2 associates with the LXR:RXR heterodimer. Importantly, similar recruitment patterns were obtained in human THP-1 macrophages. Thus, at the ABCA1 promoter, NR1H2,3 ligand triggers exchange of a GPS corepressor complex (containing NCoR, HDAC3, TBLR1) for the coactivator complex devoid of GPS2 (Jakobsson T et al. 2009).

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