Disease relevance of NCOR2

• In contrast to the results obtained with differentiating osteoclasts, addition of 17beta-estradiol (0.001-10 nM) to mature osteoclasts did not affect bone resorption or TRACP activity [1].
• Transcriptional repression mediated by corepressors N-CoR and SMRT is a critical function of nuclear hormone receptors, and is dysregulated in human myeloid leukemias [2].
• Two SMRT fragments bind symmetrically to the BCL6 BTB homodimer and, in combination with biochemical and in vivo data, the structure provides insight into the basis of transcriptional repression by this critical B cell lymphoma protein [3].
• Here we show the effects of reducing N-CoR and SMRT levels on the actions of estrogen and tamoxifen in breast cancer cells [4].
• These data demonstrate that elevated SMRT levels are common in prostate cancer cells, resulting in suppression of target genes associated with antiproliferative action and apparent 1alpha,25(OH)2D3-insensitivity [5].

Psychiatry related information on NCOR2

• Methylation gets SMRT. Functional insights into Rett syndrome [6].
• Exclusion of non-synonymous SNPs and a polyglutamine tract in SMRT/N-CoR2 as common deleterious mutation for bipolar disorder in the Sagnenay-Lac-St-Jean population [7].
• The TRACP reaction time should not exceed 9 min and the cell number should not exceed 2 x 10(5)/100 micro l test [8].

High impact information on NCOR2

• Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase [9].
• The transcriptional corepressors SMRT and N-CoR function as silencing mediators for retinoid and thyroid hormone receptors [9].
• Here we report the crystal structure of a ternary complex containing the peroxisome proliferator-activated receptor-alpha ligand-binding domain bound to the antagonist GW6471 and a SMRT co-repressor motif [10].
• Here we identify a receptor-interacting factor, SMRT, as a silencing mediator (co-repressor) for retinoid and thyroid-hormone receptors [11].
• Early studies have suggested that HDAC3 activity is regulated by association with the corepressors N-CoR and SMRT [12].

Chemical compound and disease context of NCOR2

• These results suggest that N-CoR and SMRT play an active role in preventing tamoxifen from stimulating proliferation in breast cancer cells through repression of a subset of target genes involved in ERalpha function and cell proliferation [4].
• The orphan nuclear receptor chicken ovalbumin upstream promoter transcription factor (COUP-TF)-I interacts directly with 4-hydroxytamoxifen (4-OHT)- and estradiol (E(2))-occupied ERalpha, corepressors NCoR and SMRT, and inhibit E(2)-induced gene transcription in breast cancer cells [13].
• These data suggest that COUP-TFI, N-CoR, and SMRT may play a differential role in steroid biosynthesis of non-hyperfunctioning adenomas [14].
• Here, we show that IKK is activated in colorectal tumors concomitant with the presence of phosphorylated SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) corepressor that is aberrantly localized in the cytoplasm [15].
• Here, we report the use of transformed non-Hodgkin lymphoma cell lines and primary samples to identify the involvement of the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) gene that maps at chromosome 12q24 in transformed non-Hodgkin lymphomas [16].

Biological context of NCOR2

• A SANT motif in the SMRT corepressor interprets the histone code and promotes histone deacetylation [17].
• Here we show that SMRTe inhibits MEF2C transcriptional activation by targeting selective HDACs to unique subnuclear domains [18].
• Transient cotransfections of mammalian cells (Hepa1c1c7, MCF-7, and BG-1) with SMRT and a TCDD-inducible luciferase reporter containing the dioxin-responsive domain from the mouse CYP1A1 regulatory region revealed that SMRT does not repress, but enhances, AhR signaling [19].
• Using a nonphosphorylatable SMRT protein, we demonstrate that IKKalpha-induced phosphorylation is required to recruit 14-3-3epsilon and Ubc5 for SMRT derepression [20].
• Failure of IKKalpha to stimulate the removal of SMRT from chromatin inhibits the recruitment of NF-kappaB to promoters, blocking transcription and sensitizing cells to apoptosis [20].

Anatomical context of NCOR2

• 4- Hydroxy-tamoxifen (4-OHT) increased ER-alpha and silencing mediator for retinoid and thyroid receptors (SMRT) expression and increased ER-ERE binding [21].
• It attaches to the nuclear matrix and associates with histone deacetylases and the co-repressors N-CoR, SMRT, and mSin3A, and may act as a co-repressor for site-specific transcriptions factors [22].
• Addition of 0.1-10 nM 17beta-estradiol to differentiating osteoclasts resulted in a dose-dependent reduction in tartrate resistant acid phosphatase (TRACP) activity reaching 60% at 0.1 nM [1].
• Here we report the isolation of a novel SMRT-containing complex from HeLa cells [23].
• For example, PC-3 and DU-145 prostate cancer cell lines had 1.8-fold and twofold increases in SMRT mRNA relative to normal PrEC cells (P<0.05) [5].

Associations of NCOR2 with chemical compounds

• We show that the HDAC3-containing SMRT and N-CoR complexes can bind to unliganded thyroid hormone receptors (TRs) in vitro [24].
• Furthermore, coimmunoprecipitation experiments indicated that HDAC10v1 associated with HDAC2 and SMRT (silencing mediator for retinoid and thyroid hormone receptors) [25].
• Overexpression of SMRT inhibits dihydrotestosterone-dependent transactivation by AR and further suppresses the antiandrogen flutamide-mediated inhibition of AR activity [26].
• The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT [27].
• Overexpression of SMRT suppressed the induction of STAT5 target genes by interleukin-3, whereas the histone deacetylase inhibitor trichostatin A effectively enhanced and prolonged their expression [28].

Physical interactions of NCOR2

• Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR [29].
• Unexpectedly, the PLZF moiety itself can interact with SMRT corepressor [30].
• We found that AR possesses an intrinsic transcriptional repression activity, and AR interacts directly with SMRT [26].
• Conversely, in cells treated with 4-OHT, ER-alpha and ER-beta bound SMRT [21].
• Here we report that HDAC3 interacts with SMRT only after priming by cellular chaperones including the TCP-1 ring complex (TRiC), which is required for proper folding of HDAC3 in an ATP-dependent process [31].

Co-localisations of NCOR2

• RIP140 foci do not correspond to PML bodies but partly colocalize with domains harboring the corepressor SMRT [32].

Regulatory relationships of NCOR2

• Surprisingly, histone deacetylase inhibitor trichostatin A was unable to block the repressive effect of SMRT while dramatically stimulating the Nur77 transactivation [33].
• In this study, we show that exogenous expression of NCoR or SMRT suppresses all 8-bromo-cAMP-mediated potentiation of PR transcriptional activity [34].
• Here we report that SMRT functions as an activating cofactor of HDAC3 [35].
• The SMRT corepressor is regulated by a MEK-1 kinase pathway: inhibition of corepressor function is associated with SMRT phosphorylation and nuclear export [36].
• The activity of Oct-1 could be determined by a regulated balance between SMRT and OCA-B [37].

Other interactions of NCOR2

• We present evidence that both corepressors SMRT and N-CoR exist in large protein complexes with estimated sizes of 1.5-2 MDa in HeLa nuclear extracts [24].
• SMRT was released from STAT5b-RARalpha/SMRT complexes by ATRA at 10(-6) M, whereas TRAM-1 became associated with STAT5b-RARalpha at 10(-7) M [38].
• In contrast, N-CoR-2 contained predominantly HDAC1 and HDAC2 as well as several other subunits that are found in the Sin3A.HDAC complex [39].
• Our data establish a significant role of SMRT in modulating AR transcriptional activity [26].
• We show that SMRT and DAX-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases [40].

Analytical, diagnostic and therapeutic context of NCOR2

• SRC-1 and SMRT were identified at the ER-ERE complex, and interactions between ER isoforms and coregulatory proteins were determined using immunoprecipitation [21].
• Association of SMRT with the AhR:ARNT:DNA complex was not detected by GST pull-down or gel retardation assays [19].
• In yeast two-hybrid assays, the SMRT aa 1291 to 1495 domain interacted with SKIP and SMRT aa 1291 to 1495 colocalized with SKIP within the nuclei of cotransfected cells [41].
• Finally, chromatin immunoprecipitation results indicate that SMRT and steroid receptor coactivator-1 dynamically compete for receptor bindings in vivo in the presence of ligand [42].
• Using quantitative RT-PCR we therefore measured the levels of transcripts encoding these coregulators, as well as the corepressor SMRT, and the coactivator SRC-1, in a small cohort of tamoxifen resistant and sensitive breast tumors [43].

References