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1
Poizat, Jean-Claude, and Françoise Dasturová. "Smrt." REFLEXE 2019, no. 57 (February 25, 2020): 143–60. http://dx.doi.org/10.14712/25337637.2020.11.
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Vukčević, Vladan. "Iznenadna srčana smrt." Srce i krvni sudovi 30, no. 4 (2011): 175–76. http://dx.doi.org/10.5937/siks1103175v.
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Ghoshal, Pushpankur, Christiane Houde, Angela Szafranek, Alain Nganga, Timothy Johnson, Ashley Bigelow, Joseph Moran-Guiati, Dominic Smiraglia, Asher Alban Chanan-Khan, and Lionel J. Coignet. "SMRT; Not So Smart in Multiple Myeloma." Blood 110, no. 11 (November 16, 2007): 4137. http://dx.doi.org/10.1182/blood.v110.11.4137.4137.
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Abstract Multiple myeloma (MM), a clonal B-cell malignancy, characterized by accumulation of plasma cells in bone marrow is the second most hematological malignancy in United States. In the BM, the myeloma and stromal cells secrete cytokines, which support the growth and survival of the myeloma cells. We previously showed that JAG2, one of the NOTCH ligand, is over-expressed in MM cells (Blood. 2004 Dec 1;104(12)). We hypothesized that over-expression of JAG2 in myeloma cells induce secretion of IL-6 from the stromal cells and subsequently enhances the proliferation of myeloma cells. JAG2 has been shown to be over-expressed in all cell lines and patient samples studied To identify the mechanism for JAG2 overexpression in MM cells, we assessed the potential modifications of the JAG2 promoter in MM cell lines as well as patient samples (an JAG2 negative controls) by studying both methylation and histone acetylation level of the JAG2 promoter. We show that difference in H4 acetylation level might play a crucial role in JAG2 expression. Acetylation state of histones can be regulated by the recruitment of histone deacetylases (HDACs). HDACs are typically recruited to promoter regions through interaction with nuclear co-repressors such as SMRT. The cell lines and patient samples studied presented significantly reduced levels of SMRT. Therefore, based on these observations we propose a model in which partial down-regulation of SMRT recruits less active HDAC3 (as confirmed by immunoprecipitation). As a result the deactylation process of histones in the JAG2 promoter region has been impaired and the cells lost their regulatory mechanism on transcriptional regulation of JAG2. This provides a mechanistic explanation for JAG2 over-expression in MM and on the direct involvement of the SMRT co-repressor in MM pathogenesis.
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Nikolić, Milica, and Radomir Konstantinović. "Dekartova smrt." World Literature Today 72, no. 3 (1998): 653. http://dx.doi.org/10.2307/40154171.
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Koch, Linda. "SMRT move?" Nature Reviews Genetics 15, no. 3 (February 4, 2014): 146. http://dx.doi.org/10.1038/nrg3678.
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Stanya, Kristopher J., Yu Liu, Anthony R. Means, and Hung-Ying Kao. "Cdk2 and Pin1 negatively regulate the transcriptional corepressor SMRT." Journal of Cell Biology 183, no. 1 (October 6, 2008): 49–61. http://dx.doi.org/10.1083/jcb.200806172.
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Silencing mediator for retinoic acid and thyroid hormone receptor (SMRT) is a transcriptional corepressor that participates in diverse signaling pathways and human diseases. However, regulation of SMRT stability remains largely unexplored. We show that the peptidyl-prolyl isomerase Pin1 interacts with SMRT both in vitro and in mammalian cells. This interaction requires the WW domain of Pin1 and SMRT phosphorylation. Pin1 regulates SMRT protein stability, thereby affecting SMRT-dependent transcriptional repression. SMRT phosphorylation at multiple sites is required for Pin1 interaction, and these sites can be phosphorylated by Cdk2, which interacts with SMRT. Cdk2-mediated phosphorylation of SMRT is required for Pin1 binding and decreases SMRT stability, whereas mutation of these phosphorylation sites abrogates Pin1 binding and stabilizes SMRT. Finally, decreases in SMRT stability occur in response to the activation of Her2/Neu/ErbB2, and this receptor functions upstream of both Pin1 and Cdk2 in the signaling cascade that regulates SMRT stability and cellular response to tamoxifen.
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Chen, Rui, Hongqian Xue, and Bin Li. "Comparison of SP, SMAT, SMRT, LSP, and UNSM Based on Treatment Effects on the Fatigue Properties of Metals in the HCF and VHCF Regimes." Metals 12, no. 4 (April 10, 2022): 642. http://dx.doi.org/10.3390/met12040642.
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This paper aims to provide a better understanding regarding the effects of shot peening (SP), surface mechanical attrition treatment (SMAT), laser shock peening (LSP), surface mechanical rolling treatment (SMRT), and ultrasonic nanocrystal surface modification (UNSM) on the fatigue properties of metals in high-cycle fatigue (HCF) and very-high-cycle fatigue (VHCF) regimes. The work in this paper finds that SMRT and UNSM generally improve the high-cycle and very-high-cycle fatigue properties of metals, while SP, SMAT, and LSP can have mixed effects. The differences are discussed and analyzed with respect to the aspects of surface finish, microstructure and microhardness, and residual stress. SMRT and UNSM generally produce a smooth surface finish, while SP and SMAT tend to worsen the surface finish on metals, which is harmful to their fatigue properties. In addition to inducing a plastic deformation zone and increasing microhardness, surface treatments can also generate a nanograin layer and gradient microstructure to enhance the fatigue properties of metals. The distribution of treatment-induced residual stress and residual stress relaxation can cause mixed effects on the fatigue properties of metals. Furthermore, increasing residual stress through SP and SMAT can cause further deterioration of the surface finish, which is detrimental to the fatigue properties of metals.
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Vetter, Monica L. "Methylation Gets SMRT." Developmental Cell 5, no. 3 (September 2003): 359–60. http://dx.doi.org/10.1016/s1534-5807(03)00267-3.
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Li, Hui, Christopher Leo, Daniel J. Schroen, and J. Don Chen. "Characterization of Receptor Interaction and Transcriptional Repression by the Corepressor SMRT." Molecular Endocrinology 11, no. 13 (December 1, 1997): 2025–37. http://dx.doi.org/10.1210/mend.11.13.0028.
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Abstract SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) and N-CoR (nuclear receptor corepressor) are two related transcriptional corepressors that contain separable domains capable of interacting with unliganded nuclear receptors and repressing basal transcription. To decipher the mechanisms of receptor interaction and transcriptional repression by SMRT/N-CoR, we have characterized protein-protein interacting surfaces between SMRT and nuclear receptors and defined transcriptional repression domains of both SMRT and N-CoR. Deletional analysis reveals two individual nuclear receptor domains necessary for stable association with SMRT and a C-terminal helix essential for corepressor dissociation. Coordinately, two SMRT domains are found to interact independently with the receptors. Functional analysis reveals that SMRT contains two distinct repression domains, and the corresponding regions in N-CoR also repress basal transcription. Both repression domains in SMRT and N-CoR interact weakly with mSin3A, which in turn associates with a histone deacetylase HDAC1 in a mammalian two-hybrid assay. Far-Western analysis demonstrates a direct protein-protein interaction between two N-CoR repression domains with mSin3A. Finally we demonstrate that overexpression of full-length SMRT further represses basal transcription from natural promoters. Together, these results support a role of SMRT/N-CoR in corepression through the utilization of multiple mechanisms for receptor interactions and transcriptional repression.
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Amano, Izuki, Ayane Ninomiya, Megan Ritter, Kristen R. Vella, Anthony Neil Hollenberg, and Noriyuki Koibuchi. "Nuclear Receptor Corepressors NCoR1 and SMRT Plays Unique Roles in Central Nervous System." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A976. http://dx.doi.org/10.1210/jendso/bvab048.1995.
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Abstract The nuclear corepressor 1 (NCoR1) and the silencing mediator of retinoid and thyroid hormone receptors (SMRT) are critical coregulators of the thyroid hormone receptor (TR), mediating transcriptional repression via histone deacetylation. Thyroid hormone (TH) plays an essential role in many physiological processes via the TR. How the corepressors regulate TR signaling is not fully understood, especially in central nervous system (CNS). To determine the role of NCoR1 and SMRT in the CNS, we used mice with conditional NCoR1 (NCoR1lox/lox) and SMRT (SMRTlox/lox) alleles in combination with mice that express Cre recombinase in a neuronal specific fashion (Snap25-Cre). Global deletion of NCoR1 or SMRT during embryogenesis results in lethality. We also showed that NCoR1/SMRT double knock-out mice die within two weeks after induction of Cre activity in adult mice. Now, we found that neuronal specific NCoR1 or SMRT KO mice survive without obvious impairment of neuronal development. However, NCoR1/SMRT double knock-out mice die within postnatal 1-2 weeks and have impaired body growth. Thus, both NCoR1 and SMRT have important roles in maintaining normal neuronal function. Recently, cased of mutations in NCoR1 and SMRT in humans have been reported. These cases report phenotypes including Autism Spectrum Disorder (ASD) and intellectual disability. The cerebellum has been thought to contribute to motor control and learning. Surprisingly, it has also been shown to be a key brain structure involved in social cognition and its dysfunction may play a role in ASD. The Purkinje cell is the main neuron in the cerebellum. Thus, we generated cerebellar Purkinje cell specific NCoR1/SMRT knock-out mice using L7/Pcp2-Cre mice. In contrast to neuronal specific KO mice, both NCoR1 or SMRT single or double knock-out mice survive until adulthood. SMRT Purkinje cell knock-out mice showed abnormalities in 3ch social interaction test indicating impaired social functioning, similar to some ASD symptoms. Electrophysiological testing showed current injection evoked more action potentials in SMRT KO mice. These results suggest Purkinje cell dysfunction caused by SMRT deletion may result in social disability. Our data demonstrate for the first time that NCoR1 and SMRT have separate functions in different areas of the brain but also have some redundant function when knocked out together in all neurons.
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Hong, Suk-Hyun, and Martin L. Privalsky. "The SMRT Corepressor Is Regulated by a MEK-1 Kinase Pathway: Inhibition of Corepressor Function Is Associated with SMRT Phosphorylation and Nuclear Export." Molecular and Cellular Biology 20, no. 17 (September 1, 2000): 6612–25. http://dx.doi.org/10.1128/mcb.20.17.6612-6625.2000.
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ABSTRACT The SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) corepressor participates in the repression of target gene expression by a variety of transcription factors, including the nuclear hormone receptors, promyelocytic leukemia zinc finger protein, and B-cell leukemia protein 6. The ability of SMRT to associate with these transcription factors and thereby to mediate repression is strongly inhibited by activation of tyrosine kinase signaling pathways, such as that represented by the epidermal growth factor receptor. We report here that SMRT function is potently inhibited by a mitogen-activated protein kinase (MAPK) kinase kinase (MAPKKK) cascade that operates downstream of this growth factor receptor. Intriguingly, the SMRT protein is a substrate for phosphorylation by protein kinases operating at multiple levels in this MAPKKK pathway, including the MAPKs, MAPK–extracellular signal-regulated kinase 1 (MEK-1), and MEK-1 kinase (MEKK-1). Phosphorylation of SMRT by MEKK-1 and, to a lesser extent, MEK-1 inhibits the ability of SMRT to physically tether to its transcription factor partners. Notably, activation of MEKK-1 or MEK-1 signaling in transfected cells also leads to a redistribution of the SMRT protein from a nuclear compartment to a more perinuclear or cytoplasmic compartment. We suggest that SMRT-mediated repression is regulated by the MAPKKK cascade and that changes both in the affinity of SMRT for its transcription factors and in the subcellular distribution of SMRT contribute to the loss of SMRT function that is observed in response to kinase signal transduction.
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Blackmore, Julia K., Sudipan Karmakar, Guowei Gu, Vaishali Chaubal, Liguo Wang, Wei Li, and Carolyn L. Smith. "The SMRT Coregulator Enhances Growth of Estrogen Receptor-α-Positive Breast Cancer Cells by Promotion of Cell Cycle Progression and Inhibition of Apoptosis." Endocrinology 155, no. 9 (September 1, 2014): 3251–61. http://dx.doi.org/10.1210/en.2014-1002.
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Abstract The SMRT coregulator functions as a dual coactivator and corepressor for estrogen receptor-α (ERα) in a gene-specific manner, and in several studies its elevated expression correlates with poor outcome for breast cancer patients. A specific role of SMRT in breast cancer progression has not been elucidated, but SMRT knock-down limits estradiol-dependent growth of MCF-7 breast cancer cells. In this study, small-interfering RNA (siRNA) and short-hairpin RNA (shRNA) approaches were used to determine the effects of SMRT depletion on growth of ERα-positive MCF-7 and ZR-75–1 breast cancer cells, as well as the ERα-negative MDA-MB-231 breast cancer line. Depletion of SMRT inhibited growth of ERα-positive cells grown in monolayer but had no effect on growth of the ERα-negative cells. Reduced SMRT levels also negatively impacted the anchorage-independent growth of MCF-7 cells as assessed by soft agar colony formation assays. The observed growth inhibitions were due to a loss of estradiol-induced progression through the G1/S transition of the cell cycle and increased apoptosis in SMRT-depleted compared with control cells. Gene expression analyses indicated that SMRT inhibits apoptosis by a coordinated regulation of genes involved in apoptosis. Functioning as a dual coactivator for anti-apoptotic genes and corepressor for pro-apoptotic genes, SMRT can limit apoptosis. Together these data indicate that SMRT promotes breast cancer progression through multiple pathways leading to increased proliferation and decreased apoptosis.
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Hong, Suk-Hyun, Zhihong Yang, and Martin L. Privalsky. "Arsenic Trioxide Is a Potent Inhibitor of the Interaction of SMRT Corepressor with Its Transcription Factor Partners, Including the PML-Retinoic Acid Receptor α Oncoprotein Found in Human Acute Promyelocytic Leukemia." Molecular and Cellular Biology 21, no. 21 (November 1, 2001): 7172–82. http://dx.doi.org/10.1128/mcb.21.21.7172-7182.2001.
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ABSTRACT The SMRT corepressor complex participates in transcriptional repression by a diverse array of vertebrate transcription factors. The ability to recruit SMRT appears to play a crucial role in leukemogenesis by the PML-retinoic acid receptor α (RARα) oncoprotein, an aberrant nuclear hormone receptor implicated in human acute promyelocytic leukemia (APL). Arsenite induces clinical remission of APL through a incompletely understood mechanism. We report here that arsenite is a potent inhibitor of the interaction of SMRT with its transcription factor partners, including PML-RARα. Arsenite operates, in part, through a mitogen-activated protein (MAP) kinase cascade culminating in phosphorylation of the SMRT protein, dissociation of SMRT from its nuclear receptor partners, and a relocalization of SMRT out of the nucleus into the cytoplasm of the cell. Conversely, inhibition of this MAP kinase cascade attenuates the effects of arsenite on APL cells. Our results implicate SMRT as an important biological target for the actions of arsenite in both normal and neoplastic cells.
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Ritter, Megan J., Izuki Amano, Lorraine Soares De Oliveira, Kristen R. Vella, and Anthony Neil Hollenberg. "The Role of Nuclear Receptor Corepressors NCoR1 and SMRT on Physiologic Function in the Adult Mouse." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A979. http://dx.doi.org/10.1210/jendso/bvab048.2002.
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Abstract Thyroid hormone (TH) plays an essential role in maintaining homeostasis and regulating metabolism in all organ systems beginning with embryogenesis and continuing throughout life. TH action is mediated by the thyroid hormone receptor (TR), which is a nuclear receptor, and it’s coregulators. The nuclear receptor corepressor 1 (NCoR1) and the silencing mediator of retinoid and thyroid hormone receptors (SMRT) are two critical corepressors of the TR that inhibit gene transcription in the absence of TH. Repression is mediated by complexing with histone deacetylase 3 (HDAC3), which is stabilized by NCoR1 and SMRT. NCoR1 and SMRT are critical for maintaining metabolic homeostasis and act to mediate energy expenditure, insulin sensitivity, and body weight. We sought to elucidate the roles of NCoR1 and SMRT in maintaining global physiologic function in the adult mouse. In order to study the post-natal role of these corepressors, we used a tamoxifen-inducible Cre recombinase (UBC-Cre-ERT2) to knock-out (KO) NCoR1, SMRT, or NCoR1 and SMRT together in adult mice because global deletion of either corepressor during embryogenesis is lethal. Mice were injected with tamoxifen at 8 weeks of age to KO either NCoR1 (NCoR1-KO; NKO), SMRT (SMRT-KO; SKO), or both NCoR1 and SMRT (double KO; DKO) and metabolic parameters were analyzed. While postnatal deletion of either NCoR1 or SMRT did not impact mortality, KO of both NCoR1 and SMRT resulted in a rapidly lethal phenotype heralded by weight loss, hypoglycemia and hypothermia. Metabolic phenotyping confirmed a loss of body mass and in particular fat mass in addition to a reduction in energy expenditure and increase in fecal caloric density. Further analysis showed the rapid development of hepatosteatosis and disturbances in lipid metabolism with a profound increase in beta-oxidation. We also found a reduction in HDAC3 protein levels in the DKO mice but no rapidly lethal phenotype in HDAC3 KO mice. Overall, we show that NCoR1 and SMRT together are critical for life as their deletion results in a rapidly lethal phenotype. While NCoR1 and SMRT are required to stabilize the corepressor complex, including HDAC3, HDAC3 KO resulted in a distinct and separate phenotype.
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Guenther, Matthew G., Orr Barak, and Mitchell A. Lazar. "The SMRT and N-CoR Corepressors Are Activating Cofactors for Histone Deacetylase 3." Molecular and Cellular Biology 21, no. 18 (September 15, 2001): 6091–101. http://dx.doi.org/10.1128/mcb.21.18.6091-6101.2001.
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ABSTRACT Repression of gene transcription is linked to regulation of chromatin structure through deacetylation of core histone amino-terminal tails. This action is mediated by histone deacetylases (HDACs) that function within active multiprotein complexes directed to the promoters of repressed genes. In vivo, HDAC3 forms a stable complex with the SMRT corepressor. The SMRT-HDAC3 complex exhibits histone deacetylase activity, whereas recombinant HDAC3 is an inactive enzyme. Here we report that SMRT functions as an activating cofactor of HDAC3. In contrast, SMRT does not activate the class II HDAC4, with which it also interacts. Activation of HDAC3 is mediated by a deacetylase activating domain (DAD) that includes one of two SANT motifs present in SMRT. A cognate DAD is present in the related corepressor N-CoR, which can also activate HDAC3. Mutations in the DAD that abolish HDAC3 interaction also eliminate reconstitution of HDAC activity. Using purified components, the SMRT DAD is shown to be necessary and sufficient for activation of HDAC3. Moreover, the DAD is required both for HDAC3 to function enzymatically and for the major repression function of SMRT. Thus, SMRT and N-CoR do not serve merely as platforms for HDAC recruitment but function as an integral component of an active cellular HDAC3 enzyme.
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Dreer, Marcel, Saskia Blondzik, Elke Straub, Thomas Iftner, and Frank Stubenrauch. "Contribution of HDAC3 to transcriptional repression by the human papillomavirus 31 E8^E2 protein." Journal of General Virology 101, no. 7 (July 1, 2020): 751–59. http://dx.doi.org/10.1099/jgv.0.001438.
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Human papillomaviruses (HPV) such as HPV16 and HPV31 encode an E8^E2 protein that acts as a repressor of viral replication and transcription. E8^E2′s repression activities are mediated via the interaction with host-cell NCoR (nuclear receptor corepressor)/SMRT (silencing mediator of retinoid and thyroid receptors) corepressor complexes, which consist of NCoR, its homologue SMRT, GPS2 (G-protein pathway suppressor 2), HDAC3 (histone deacetylase 3), TBL1 (transducin b-like protein 1) and its homologue TBLR1 (TBL1-related protein 1). We now provide evidence that transcriptional repression by HPV31 E8^E2 is NCoR/SMRT-dependent but surprisingly always HDAC3-independent when analysing different HPV promoters. This is in contrast to the majority of several cellular transcription factors using NCoR/SMRT complexes whose transcriptional repression activities are both NCoR/SMRT- and HDAC3-dependent. However, NCoR/SMRT-dependent but HDAC3-independent repression has been described for specific cellular genes, suggesting that this may not be specific for HPV promoters but could be a feature of a subset of NCoR/SMRT-HDAC3 regulated genes.
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Kao, Hung-Ying, Michael Downes, Peter Ordentlich, and Ronald M. Evans. "Isolation of a novel histone deacetylase reveals that class I and class II deacetylases promote SMRT-mediated repression." Genes & Development 14, no. 1 (January 1, 2000): 55–66. http://dx.doi.org/10.1101/gad.14.1.55.
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The transcriptional corepressor SMRT functions by mediating the repressive effect of transcription factors involved in diverse signaling pathways. The mechanism by which SMRT represses basal transcription has been proposed to involve the indirect recruitment of histone deacetylase HDAC1 via the adaptor mSin3A. In contrast to this model, a two-hybrid screen on SMRT-interacting proteins resulted in the isolation of the recently described HDAC5 and a new family member termed HDAC7. Molecular and biochemical results indicate that this interaction is direct and in vivo evidence colocalizes SMRT, mHDAC5, and mHDAC7 to a distinct nuclear compartment. Surprisingly, HDAC7 can interact with mSin3A in yeast and in mammalian cells, suggesting association of multiple repression complexes. Taken together, our results provide the first evidence that SMRT-mediated repression is promoted by class I and class II histone deacetylases and that SMRT can recruit class II histone deacetylases in a mSin3A-independent fashion.
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Jiang, Jingjing, Na Li, Xiaolin Wang, Yan Lu, Yufang Bi, Weiqing Wang, Xiaoying Li, and Guang Ning. "Aberrant Expression and Modification of Silencing Mediator of Retinoic Acid and Thyroid Hormone Receptors Involved in the Pathogenesis of Tumoral Cortisol Resistance." Endocrinology 151, no. 8 (June 16, 2010): 3697–705. http://dx.doi.org/10.1210/en.2010-0335.
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Ectopic ACTH syndrome (EAS) accounts for 10–15% of cases of Cushing’s syndrome and is mostly caused by small cell lung cancers or thymic carcinoids. EAS is characterized by tumoral cortisol resistance, whose underlying mechanism remains unknown. In this study, we reported that silencing mediator of retinoic acid and thyroid hormone receptors (SMRT), a major nuclear corepressor, was aberrantly expressed in ACTH-secreting thymic carcinoids. Overexpression and knockdown of SMRT in the ACTH-secreting AtT-20 cell line demonstrated that SMRT participated in the negative feedback of dexamethasone-mediated suppression of proopiomelanocortin. Posttranslational modification by the small ubiquitin-like modifiers (SUMO), i.e. SUMOylation plays an important role in fine-tuning transcriptional activities. SUMOylation of SMRT was observed in dexamethasone-resistant cell lines. Moreover, overexpression of the deSUMOylation enzyme enhanced the suppression of proopiomelanocortin by dexamethasone in AtT-20 cells. An evolutionarily conserved consensus SUMOylation site was identified close to the histone deacetylase 3 recruiting domain of SMRT, which might interfere with the recruiting process. These results suggested that aberrant expression and modification of SMRT might be involved in the pathogenesis of tumoral cortisol resistance. A therapeutic approach targeting SMRT SUMOylation might be developed for EAS patients.
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Peterson, Theresa J., Sudipan Karmakar, Margaret C. Pace, Tong Gao, and Carolyn L. Smith. "The Silencing Mediator of Retinoic Acid and Thyroid Hormone Receptor (SMRT) Corepressor Is Required for Full Estrogen Receptor α Transcriptional Activity." Molecular and Cellular Biology 27, no. 17 (June 25, 2007): 5933–48. http://dx.doi.org/10.1128/mcb.00237-07.
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ABSTRACT Multiple factors influence estrogen receptor α (ERα) transcriptional activity. Current models suggest that the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressor functions within a histone deactylase-containing protein complex that binds to antiestrogen-bound ERα and contributes to negative regulation of gene expression. In this report, we demonstrate that SMRT is required for full agonist-dependent ERα activation. Chromatin immunoprecipitation assays demonstrate that SMRT, like ERα and the SRC-3 coactivator, is recruited to an estrogen-responsive promoter in estrogen-treated MCF-7 cells. Depletion of SMRT, but not histone deacetylases 1 or 3, negatively impacts estradiol-stimulated ERα transcriptional activity, while exogenous expression of SMRT's receptor interaction domains blocks ERα activity, indicating a functional interaction between this corepressor and agonist-bound ERα. Stimulation of estradiol-induced ERα activity by SMRT overexpression occurred in HeLa and MCF-7 cells, but not HepG2 cells, indicating that these positive effects are cell type specific. Similarly, the ability of SMRT depletion to promote the agonist activity of tamoxifen was observed for HeLa but not MCF-7 cells. Furthermore, impairment of agonist-stimulated activity by SMRT depletion is specific to ERα and not observed for receptors for vitamin D, androgen, or thyroid hormone. Nuclear receptor corepressor (N-CoR) depletion increased the transcriptional activity of all four tested receptors. SMRT is required for full expression of the ERα target genes cyclin D1, BCL-2, and progesterone receptor but not pS2, and its depletion significantly attenuated estrogen-dependent proliferation of MCF-7 cells. Taken together, these data indicate that SMRT, in conjunction with gene-specific and cell-dependent factors, is required for positively regulating agonist-dependent ERα transcriptional activity.
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Faist, Flavie, Stephen Short, G. Geoff Kneale, and Colinb R. Sharpe. "Alternative splicing determines the interaction of SMRT isoforms with nuclear receptor–DNA complexes." Bioscience Reports 29, no. 3 (March 3, 2009): 143–49. http://dx.doi.org/10.1042/bsr20080093.
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Signalling by small molecules, such as retinoic acid, is mediated by heterodimers comprising a class II nuclear receptor and an RXR (retinoid X receptor) subunit. The receptors bind to DNA response elements and act as ligand-dependent transcription factors, but, in the absence of signal, the receptors bind the co-repressors SMRT [silencing mediator for RAR (retinoic acid receptor) and TR (thyroid hormone receptor)] and NCoR (nuclear receptor co-repressor) and repress gene expression. Alternative splicing of the SMRT transcript in mammals generates six isoforms containing 1, 2 or 3 CoRNR (co-repressor for nuclear receptor) box motifs which are responsible for the interactions with nuclear receptors. We show that human cell lines express all six SMRT isoforms and then determine the binding affinity of mouse SMRT isoforms for RAR/RXR and three additional class II nuclear receptor–DNA complexes. This approach demonstrates the importance of the full complement of CoRNR boxes within each SMRT protein, rather than the identity of individual CoRNR boxes, in directing the interaction of SMRT with nuclear receptors. Each class of SMRT isoform displays a distinct feature, as the 1-box isoform discriminates between DNA response elements, the 2-box isoforms promote high-affinity binding to TR complexes and the 3-box isoforms show differential binding to nuclear receptors. Consequently, the differential deployment of SMRT isoforms observed in vivo could significantly expand the regulatory capacity of nuclear receptor signalling.
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Dotzlaw, Helmut, Udo Moehren, Sigrun Mink, Andrew C. B. Cato, Jorge A. Iñiguez Lluhí, and Aria Baniahmad. "The Amino Terminus of the Human AR Is Target for Corepressor Action and Antihormone Agonism." Molecular Endocrinology 16, no. 4 (April 1, 2002): 661–73. http://dx.doi.org/10.1210/mend.16.4.0798.
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Abstract Antiandrogens inhibit the ligand-induced transactivation by the androgen receptor (AR) and have a widespread use in the treatment of prostate cancer but their mode of action is not fully understood. Here we show that the ability of the antiandrogen cyproterone acetate (CPA) to inhibit transactivation by the human AR (hAR) involves the corepressor SMRT (silencing mediator for retinoic acid and thyroid hormone receptor). We detect binding of SMRT to hAR when treating with the antiandrogen CPA, but not with the antihormones casodex or hydroxyflutamide. Interestingly, we find that SMRT binds to the N terminus of the hAR. Thereby, SMRT modulates the activity of hAR in receptor-negative CV1 cells. In addition, we have used receptor point mutants that exhibit normal transactivation potential and unchanged partial agonistic activity when treated with CPA, but lack both SMRT binding and SMRT-mediated inhibition of CPA-bound AR. This indicates that mechanisms involved in hAR-mediated transactivation are distinct from antihormone-induced receptor inactivation. Furthermore, we show that treatment of transfected cells with a cAMP analog or coexpression of the catalytic subunit of PKA, known to activate hAR, inhibits the binding of SMRT to the AR. This suggests that the association of SMRT with hAR is regulated at the level of cross-talk mechanisms and that ligand-independent receptor activation is due to corepressor dissociation. Taken together, we provide novel insights in AR regulation, antihormone action, and functional nuclear receptor-corepressor interaction.
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Shimizu, Hiroaki, Yasuhiro Horibata, Izuki Amano, Megan J. Ritter, Mariko Domae, Hiromi Ando, Hiroyuki Sugimoto, Ronald N. Cohen, and Anthony N. Hollenberg. "Nuclear corepressor SMRT acts as a strong regulator of both β-oxidation and suppressor of fibrosis in the differentiation process of mouse skeletal muscle cells." PLOS ONE 17, no. 12 (December 1, 2022): e0277830. http://dx.doi.org/10.1371/journal.pone.0277830.
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Background Silencing Mediator of Retinoid and Thyroid hormone receptors (SMRT; NCoR2) is a transcriptional corepressor (CoR) which has been recognized as an important player in the regulation of hepatic lipogenesis and in somatic development in mouse embryo. SMRT protein is also widely expressed in mouse connective tissues, for example adipocytes and muscle. We recently reported that mice with global deletion of SMRT develop significant obesity and muscle wasting which are independent from thyroid hormone (TH) signaling and thermogenesis. However, the tissue specific role of SMRT in skeletal muscle is still not clear. Methods To clarify role of SMRT in muscle differentiation, we made myogenic C2C12 clones which lack SMRT protein (C2C12-SKO) by using CRISPR-Cas9. Wild-type C2C12 (C2C12-WT) and C2C12-SKO cells were cultured in differentiation medium, and the resulting gene and protein profiles were compared between the two cell lines both before and after differentiation. We also analyzed muscle tissues which were dissected from whole body SMRT knockout (KO) mice and their controls. Results We found significant up-regulation of muscle specific β-oxidation markers; Peroxisome proliferator-activated receptor δ (PPARδ) and PPARγ coactivator-1α (PGC-1α) in the C2C12-SKO cells, suggesting that the cells had a similar gene profile to what is found in exercised rodent skeletal muscle. On the other hand, confocal microscopic analysis showed the significant loss of myotubes in C2C12-SKO cells similar to the morphology found in immature myoblasts. Proteomics analysis also confirmed that the C2C12-SKO cells had higher expression of markers of fibrosis (ex. Collagen1A1; COL1A1 and Fibroblast growth factor-2; FGF-2), indicating the up-regulation of Transforming growth factor-β (TGF-β) receptor signaling. Consistent with this, treatment with a specific TGF-β receptor inhibitor ameliorated both the defects in myotube differentiation and fibrosis. Conclusion Taken together, we demonstrate that SMRT functions as a pivotal transcriptional mediator for both β-oxidation and the prevention for the fibrosis via TGF-β receptor signaling in the differentiation of C2C12 myoblasts. In contrast to the results from C2C12 cells, SMRT does not appear to play a role in adult skeletal muscle of whole body SMRT KO mice. Thus, SMRT plays a significant role in the differentiation of myoblasts.
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Opašić, Maja, and Maja Gregorović. "Smrt u hrvatskoj frazeologiji." Croatica et Slavica Iadertina, no. 6 (January 18, 2017): 55. http://dx.doi.org/10.15291/csi.679.
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Nastanak je ovoga priloga motivirala činjenica da nema radova koji se odnose na konceptualnu analizu smrti u frazeologiji hrvatskoga jezika. U radu se analiziraju frazemi hrvatskoga jezika koji su svojim značenjem i/ili sastavnicama vezani za pojam smrti. Smrt je jedna od pojava koje se ljudi pomalo pribojavaju i ne vole o njoj govoriti ni razmišljati. Stoga u jeziku postoje mnogi izrazi kojima se na eufemiziran način govori o smrti, a jedni od takvih izraza su frazemi.Analizirani se frazemi u radu svrstavaju u dvije veće skupine, a to su: frazemi koji su svojim značenjem vezani za koncept smrti; frazemi koji sadrže sastavnice iz semantičkoga polja smrti, ali im značenje nije vezano za koncept smrti. Unutar prve skupine frazema razlikuju se: frazemi povezani sa značenjem biti blizu smrti; frazemi okupljeni oko koncepta način i razlog smrti; frazemi sa značenjem umrijeti, preminuti; frazemi značenjem povezani s trenucima i događajima nakon čije smrti. Svaka se od navedenih skupina dijeli na podskupine frazema s obzirom na specifičnost značenja ili sastavnice koje se javljaju. Frazemi čije su sastavnice iz semantičkoga polja smrti, ali im značenje nije vezano uz taj koncept dijele se u skupine s obzirom na to o kojoj je sastavnici riječ. Polazeći od pretpostavke da je shvaćanje smrti kao dijela života i svega vezano uz nju kulturološki i religijski uvjetovano pokušavase objasniti motiviranost značenja prikupljenih frazema kao i njihova pozadinska slika te povijesno podrijetlo. Daje se osvrt i na stilističko-ekspresivna i konotativna obilježja pojedinih frazema. Provedena analiza pokazala je da frazemi koji su svojim značenjem i/ili sastavnicama vezani za pojam smrti čine vrlo bogat dio frazeologije hrvatskoga jezika. Također je potvrđena pretpostavka da se o smrti najčešće govori eufemiziranim izrazima koji su posljedica kulturnih osobitosti pojedinoga naroda kao i religijskoga uvjerenja.
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Luo, Shiqiang, Xingyuan Chen, Dingyuan Zeng, Ning Tang, Dejian Yuan, Qingyan Zhong, Aiping Mao, Ruofan Xu, and Tizhen Yan. "The value of single-molecule real-time technology in the diagnosis of rare thalassemia variants and analysis of phenotype–genotype correlation." Journal of Human Genetics 67, no. 4 (October 25, 2021): 183–95. http://dx.doi.org/10.1038/s10038-021-00983-1.
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AbstractTo compare single-molecule real-time technology (SMRT) and conventional genetic diagnostic technology of rare types of thalassemia mutations, and to analyze the molecular characteristics and phenotypes of rare thalassemia gene variants, we used 434 cases with positive hematology screening as the cohort, then used SMRT technology and conventional gene diagnosis technology [(Gap-PCR, multiple ligation probe amplification technology (MLPA), PCR-reverse dot blot (RDB)] for thalassemia gene screening. Among the 434 enrolled cases, conventional technology identified 318 patients with variants (73.27%) and 116 patients without variants (26.73%), SMRT identified 361 patients with variants (83.18%), and 73 patients without variants (16.82%). The positive detection rate of SMRT was 9.91% higher than conventional technology. Combination of the two methods identified 485 positive alleles among 49 types of variant. The genotypes of 354 cases were concordant between the two methods, while 80 cases were discordant. Among the 80 cases, 76 cases had variants only identified in SMRT method, 3 cases had variants only identified in conventional method, and 1 false positive result by the traditional PCR detection technology. Except the three variants in HS40 and HBG1-HBG2 loci, which was beyond the design of SMRT method in this study, all the other discordant variants identified by SMRT were validated by further Sanger sequencing or MLPA. The hematological phenotypic parameters of 80 discordant cases were also analyzed. SMRT technology increased the positive detection rate of thalassemia genes, and detected rare thalassemia cases with variable phenotypes, which had great significance for clinical thalassemia gene screening.
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Hoberg, Jamie E., Anita E. Popko, Catherine S. Ramsey, and Marty W. Mayo. "IκB Kinase α-Mediated Derepression of SMRT Potentiates Acetylation of RelA/p65 by p300." Molecular and Cellular Biology 26, no. 2 (January 15, 2006): 457–71. http://dx.doi.org/10.1128/mcb.26.2.457-471.2006.
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ABSTRACT Over the last several years, significant progress has been made in identifying chromatin-regulated events that govern NF-κB transcription. Using either laminin attachment or tumor necrosis factor alpha as a physiological stimulus of NF-κB activation, we demonstrate that IκB kinase α (IKKα) is recruited to chromatin in distinct phases. In the initial phase, IKKα is responsible for derepressing the silencing mediator for retinoic acid and thyroid hormone receptor (SMRT)-histone deacetylase 3 (HDAC3) corepressor complex from the p50 homodimer. However, in the latter phase, chromatin-bound IKKα coordinates the simultaneous phosphorylation of RelA/p65(S536) and SMRT(S2410) as detected by chromatin immunoprecipitation (ChIP) assays. Although phosphorylated SMRT remains bound to the active p50-RelA/p65 heterodimer of NF-κB, derepression of SMRT is evidenced by the loss of chromatin-associated HDAC3 activity. ChIP and re-ChIP analysis demonstrates that phosphorylation of RelA/p65(S536) and SMRT(S2410) occurs prior to acetylation of RelA/p65 at K310. Moreover, IKKα-induced phosphorylation of RelA/p65(S536) displaces corepressor activity, allowing p300-mediated acetylation of RelA/p65. Introduction of nonphosphorylatable mutants of RelA/p65 and SMRT proteins or the inhibition of IKK activity results in active repression of NF-κB promoters by tethering the SMRT-HDAC3 complex. Similar to phosphorylation within the Rel homology domain of RelA/p65, which governs an exchange of HDAC1 for CBP/p300 acetyltransferases, we demonstrate that phosphorylation within the transactivation domain of RelA/p65(S536) displaces SMRT-HDAC3 repressor activity, allowing p300 to acetylate RelA/p65.
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Manju, B., V. L. Jaya, K. Meenakshy, and R. Gopikakumari. "8 × 8 SMRT Based Texture Descriptors." Lecture Notes on Software Engineering 3, no. 4 (2015): 295–98. http://dx.doi.org/10.7763/lnse.2015.v3.207.
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Gajić, Živojin. "Punomoćnik u parnici i smrt stranke." Glasnik Advokatske komore Vojvodine 75, no. 9-10 (2003): 146–55. http://dx.doi.org/10.5937/gakv0304146g.
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Coignet, Lionel, Jean Dolcce, Pushpankur Ghoshal, Alain Nganga, Timothy Johnson, Heather Foreman, Joseph Moran-Guiati, and Christiane Houde. "The FRA12E Fragile Site Is Localized within the SMRT Gene at 12q24." Blood 108, no. 11 (November 16, 2006): 4274. http://dx.doi.org/10.1182/blood.v108.11.4274.4274.
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Abstract The Silencing Mediator of retinoid and Thyroid hormone (SMRT) is a transcription co-repressor whose association with nuclear receptors both in solution and bound to DNA response elements is destabilized by ligand. SMRT and a related co-repressor N-CoR are recruiting a transcriptional repression complex, that contains sin3A/B protein and histone deacetylases (HDAC1/2) to nuclear receptors. It is now well established that SMRT can interact with non-receptor proteins such as BCL6, for its repression activities. The ability of the “silencing complex” to deacetylate histones results in a condensed chromatin state that is inhibitory to transcription. We have previously shown that SMRT was localized at chromosome 12q24. In addition, down-regulation of the SMRT protein due to 12q24 rearrangements was recurrently associated with NHL transformation, supporting a tumor suppressor function for SMRT (Cancer Res, 65(11):4554–4561, 2005). We further investigated the reasons why the 12q24 region and SMRT was targeted by chromosomal rearrangements. Genetic breakage is one mechanism by which functional loss of tumor suppressor gene activity may occur. Chromosomal locations in which genetic breakage may be induced are known as fragile sites. Fragile sites have been shown to be involved in some malignancies in which the fragile site lies within known genes, such as the FHIT gene (chromosome 3p) in lung cancer, and where small deletions are consistently observed on chromosome 3. Two fragile sites exist on the long arm of chromosome 12. FRA12B is located at 12q24.13 and FRA12E has been located at 12q24.2–3. Interestingly the FRA12E region corresponds to the site of SMRT (12q24.2). To assess whether the FRA12E fragile site is localized within the SMRT gene, we studied normal lymphocytes cultured in the presence of aphidicolin (an inducer of fragile sites) and metaphase chromosomes were subsequently prepared following classical cytogenetics protocols. These preparations were then subjected to fluorescence in situ hybridization (FISH) using a set of SMRT-specific RPCI BAC clones. Using this approach, we were able to demonstrate that the FRA12E fragile site is localized within the SMRT gene. We further characterize several lymphoblastoid cell lines that were either carrier or not of the FRA12E fragile site. This provides us with a mechanistic explanation for recurrent 12q24 rearrangements seen in transformed NHLs. The FRA12E-carrier lymphoblastoid cell lines will provide us the opportunity to characterize the structure of this fragile site.
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Shimizu, Hiroaki, Inna Astapova, Felix Ye, Martin Bilban, Ronald N. Cohen, and Anthony N. Hollenberg. "NCoR1 and SMRT Play Unique Roles in Thyroid Hormone ActionIn Vivo." Molecular and Cellular Biology 35, no. 3 (November 24, 2014): 555–65. http://dx.doi.org/10.1128/mcb.01208-14.
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NCoR1 (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors; NCoR2) are well-recognized coregulators of nuclear receptor (NR) action. However, their unique roles in the regulation of thyroid hormone (TH) signaling in specific cell types have not been determined. To accomplish this we generated mice that lacked function of either NCoR1, SMRT, or both in the liver only and additionally a global SMRT knockout model. Despite both corepressors being present in the liver, deletion of SMRT in either euthyroid or hypothyroid animals had little effect on TH signaling. In contrast, disruption of NCoR1 action confirmed that NCoR1 is the principal mediator of TH sensitivityin vivo. Similarly, global disruption of SMRT, unlike the global disruption of NCoR1, did not affect TH levels. While SMRT played little role in TH-regulated pathways, when disrupted in combination with NCoR1, it greatly accentuated the synthesis and storage of hepatic lipid. Taken together, these data demonstrate that corepressor specificity existsinvivo and that NCoR1 is the principal regulator of TH action. However, both corepressors collaborate to control hepatic lipid content, which likely reflects their cooperative activity in regulating the action of multiple NRs including the TH receptor (TR).
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Goodson, Michael, Brian A. Jonas, and Martin A. Privalsky. "Corepressors: Custom Tailoring and Alterations While you Wait." Nuclear Receptor Signaling 3, no. 1 (January 2005): nrs.03003. http://dx.doi.org/10.1621/nrs.03003.
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A diverse cadre of metazoan transcription factors mediate repression by recruiting protein complexes containing the SMRT (silencing mediator of retinoid and thyroid hormone receptor) or N-CoR (nuclear receptor corepressor) corepressors. SMRT and N-CoR nucleate the assembly of still larger corepressor complexes that perform the specific molecular incantations necessary to confer transcriptional repression. Although SMRT and N-CoR are paralogs and possess similar molecular architectures and mechanistic strategies, they nonetheless exhibit distinct molecular and biological properties. It is now clear that the functions of both SMRT and N-CoR are further diversified through alternative mRNA splicing, yielding a series of corepressor protein variants that participate in distinctive transcription factor partnerships and display distinguishable repression properties. This review will discuss what is known about the structure and actions of SMRT, N-CoR, and their splicing variants, and how alternative splicing may allow the functions of these corepressors to be adapted and tailored to different cells and to different developmental stages.
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Franke, Julian. "The death of the author | the death of the architect: Meaning in architecture and the role of users." SAJ - Serbian Architectural Journal 10, no. 1 (2018): 1–12. http://dx.doi.org/10.5937/saj1801001f.
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In his work The Death of the Author (1967), Roland Barthes creates a new definition of authorship, in that the author is not the real originator of meaning in literature, but rather the reader. This questions the influence and responsibility of originators in creative fields in general. This paper applies Barthes's thesis to the profession of architecture. Therefore the role of users is discussed, as well as meaning and language in architecture. With the help of the semiotic work by Umberto Eco and texts by Roman Ingarden and Jonathan Hill, the paper will attempt to show how the sole image of the architect is challenged, but also what makes him/her still recognisable and responsible.
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Choi, Kyung-Chul, So-Young Oh, Hee-Bum Kang, Yoo-Hyun Lee, Seungjoo Haam, Ha-Il Kim, Kunhong Kim, Young-Ho Ahn, Kyung-Sup Kim, and Ho-Geun Yoon. "The functional relationship between co-repressor N-CoR and SMRT in mediating transcriptional repression by thyroid hormone receptor α." Biochemical Journal 411, no. 1 (March 13, 2008): 19–26. http://dx.doi.org/10.1042/bj20071393.
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A central issue in mediating repression by nuclear hormone receptors is the distinct or redundant function between co-repressors N-CoR (nuclear receptor co-repressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptor). To address the functional relationship between SMRT and N-CoR in TR (thyroid hormone receptor)-mediated repression, we have identified multiple TR target genes, including BCL3 (B-cell lymphoma 3-encoded protein), Spot14 (thyroid hormone-inducible hepatic protein), FAS (fatty acid synthase), and ADRB2 (β-adrenergic receptor 2). We demonstrated that siRNA (small interfering RNA) treatment against either N-CoR or SMRT is sufficient for the de-repression of multiple TR target genes. By the combination of sequence mining and physical association as determined by ChIP (chromatin immunoprecipitation) assays, we mapped the putative TREs (thyroid hormone response elements) in BCL3, Spot14, FAS and ADRB2 genes. Our data clearly show that SMRT and N-CoR are independently recruited to various TR target genes. We also present evidence that overexpression of N-CoR can restore repression of endogenous genes after knocking down SMRT. Finally, unliganded, co-repressor-free TR is defective in repression and interacts with a co-activator, p300. Collectively, these results suggest that both SMRT and N-CoR are limited in cells and that knocking down either of them results in co-repressor-free TR and consequently de-repression of TR target genes.
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Ruse, Michael D., Martin L. Privalsky, and Frances M. Sladek. "Competitive Cofactor Recruitment by Orphan Receptor Hepatocyte Nuclear Factor 4α1: Modulation by the F Domain." Molecular and Cellular Biology 22, no. 6 (March 15, 2002): 1626–38. http://dx.doi.org/10.1128/mcb.22.6.1626-1638.2002.
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ABSTRACT For most ligand-dependent nuclear receptors, the status of endogenous ligand modulates the relative affinities for corepressor and coactivator complexes. It is less clear what parameters modulate the switch between corepressor and coactivator for the orphan receptors. Our previous work demonstrated that hepatocyte nuclear factor 4α1 (HNF4α1, NR2A1) interacts with the p160 coactivator GRIP1 and the cointegrators CBP and p300 in the absence of exogenously added ligand and that removal of the F domain enhances these interactions. Here, we utilized transient-transfection analysis to demonstrate repression of HNF4α1 activity by the corepressor silencing mediator of retinoid and thyroid receptors (SMRT) in several cell lines and on several HNF4α-responsive promoter elements. Glutathione S-transferase pulldown assays confirmed a direct interaction between HNF4α1 and receptor interaction domain 2 of SMRT. Loss of the F domain resulted in marked reduction of the ability of SMRT to interact with HNF4α1 in vitro and repress HNF4α1 activity in vivo, although the isolated F domain itself failed to interact with SMRT. Surprisingly, loss of both the A/B and F domains restored full repression by SMRT, suggesting involvement of both domains in the SMRT interaction. Finally, we show that when coexpressed along with HNF4α1 and GRIP1, CBP, or p300, SMRT can titer out HNF4α1-mediated transactivation in a dose-dependent manner and that this competition derives from mutually exclusive binding. Collectively, these results suggest that HNF4α can functionally interact with both a coactivator and a corepressor without altering the status of any putative ligand and that the presence of the F domain may play a role in discriminating between the different coregulators.
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Pajnić, Sanja. "The Language of Death and the Death of Language: The Holocaust in Literature for Children and Young Adults." Libri et Liberi 4, no. 1 (November 5, 2015): 45–60. http://dx.doi.org/10.21066/carcl.libri.2015-04(01).0014.
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Guenther, Matthew G., William S. Lane, Wolfgang Fischle, Eric Verdin, Mitchell A. Lazar, and Ramin Shiekhattar. "A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness." Genes & Development 14, no. 9 (May 1, 2000): 1048–57. http://dx.doi.org/10.1101/gad.14.9.1048.
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The corepressor SMRT mediates repression by thyroid hormone receptor (TR) as well as other nuclear hormone receptors and transcription factors. Here we report the isolation of a novel SMRT-containing complex from HeLa cells. This complex contains transducin β-like protein 1 (TBL1), whose gene is mutated in human sensorineural deafness. It also contains HDAC3, a histone deacetylase not previously thought to interact with SMRT. TBL1 displays structural and functional similarities to Tup1 and Groucho corepressors, sharing their ability to interact with histone H3. In vivo, TBL1 is bridged to HDAC3 through SMRT and can potentiate repression by TR. Intriguingly, loss-of-function TRβ mutations cause deafness in mice and humans. These results define a new TR corepressor complex with a physical link to histone structure and a potential biological link to deafness.
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Vidmar, Luka. "Tine Germ: Smrt kraljuje povsod in bela Smrt triumfira: Valvasorjevo Prizorišče človeške smrti v evropskem kontekstu." Ars & Humanitas 11, no. 1 (July 31, 2017): 232–34. http://dx.doi.org/10.4312/ah.11.1.232-234.
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Tine Germ: Smrt kraljuje povsod in bela Smrt triumfira: Valvasorjevo Prizorišče človeške smrti v evropskem kontekstuLjubljana: Znanstvena založba Filozofske fakultete Univerze v Ljubljani, 2015, 176 strani, 68 ilustracijUmetnostni zgodovinar Tine Germ je v zadnjih letih Valvasorjevemu delu Theatrum mortis humanae tripartitum iz leta 1682 posvetil vrsto raziskav, njihove ugotovitve pa je leta 2015 razširil in povezal še v monografijo Smrt kraljuje povsod in bela Smrt triumfira. Raziskave so bile vsekakor potrebne: Prizorišče človeške smrti je bilo namreč do tedaj v slovenski umetnostni, literarni in kulturni zgodovini kljub pomembnosti avtorja in kljub primerljivosti z najkvalitetnejšimi sorodnimi deli iz drugih evropskih dežel skoraj prezrto ali vsaj zelo pomanjkljivo obravnavano. Raziskave so bile tudi uspešne: prvič so prinesle poglobljeno ikonografsko analizo omenjenega polihistorjevega dela in prvič obširneje opisale njegovo mesto v sočasni evropski likovni in literarni umetnosti. Iz uvoda k monografiji Smrt kraljuje povsod in bela Smrt triumfira je jasno razvidno, da je bilo to mogoče najprej zato, ker je avtor kritično dekonstruiral tradicionalne paradigme, zlasti (umetnostnih ali literarnih) »centrov« oziroma »obrobij«, pa tudi (slogovne ali idejne) »naprednosti« oziroma »zaostalosti«, ki so v humanističnih vedah ovirale in v določeni meri še vedno ovirajo neobremenjeno raziskovanje del, kakršno je Prizorišče človeške smrti. Germova monografija nas tako že na začetku implicitno opozarja, da čaka na temeljitejšo znanstveno obravnavo še veliko umetniških in literarnih del, nastalih na Slovenskem v srednjem in zgodnjem novem veku, ki smo jih puščali ob strani zaradi različnih predsodkov, oblikovanih v 19. in 20. stoletju.
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Vidmar, Luka. "Tine Germ: Smrt kraljuje povsod in bela Smrt triumfira: Valvasorjevo Prizorišče človeške smrti v evropskem kontekstu." Ars & Humanitas 11, no. 1 (July 31, 2017): 232–34. http://dx.doi.org/10.4312/ars.11.1.232-234.
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Tine Germ: Smrt kraljuje povsod in bela Smrt triumfira: Valvasorjevo Prizorišče človeške smrti v evropskem kontekstuLjubljana: Znanstvena založba Filozofske fakultete Univerze v Ljubljani, 2015, 176 strani, 68 ilustracijUmetnostni zgodovinar Tine Germ je v zadnjih letih Valvasorjevemu delu Theatrum mortis humanae tripartitum iz leta 1682 posvetil vrsto raziskav, njihove ugotovitve pa je leta 2015 razširil in povezal še v monografijo Smrt kraljuje povsod in bela Smrt triumfira. Raziskave so bile vsekakor potrebne: Prizorišče človeške smrti je bilo namreč do tedaj v slovenski umetnostni, literarni in kulturni zgodovini kljub pomembnosti avtorja in kljub primerljivosti z najkvalitetnejšimi sorodnimi deli iz drugih evropskih dežel skoraj prezrto ali vsaj zelo pomanjkljivo obravnavano. Raziskave so bile tudi uspešne: prvič so prinesle poglobljeno ikonografsko analizo omenjenega polihistorjevega dela in prvič obširneje opisale njegovo mesto v sočasni evropski likovni in literarni umetnosti. Iz uvoda k monografiji Smrt kraljuje povsod in bela Smrt triumfira je jasno razvidno, da je bilo to mogoče najprej zato, ker je avtor kritično dekonstruiral tradicionalne paradigme, zlasti (umetnostnih ali literarnih) »centrov« oziroma »obrobij«, pa tudi (slogovne ali idejne) »naprednosti« oziroma »zaostalosti«, ki so v humanističnih vedah ovirale in v določeni meri še vedno ovirajo neobremenjeno raziskovanje del, kakršno je Prizorišče človeške smrti. Germova monografija nas tako že na začetku implicitno opozarja, da čaka na temeljitejšo znanstveno obravnavo še veliko umetniških in literarnih del, nastalih na Slovenskem v srednjem in zgodnjem novem veku, ki smo jih puščali ob strani zaradi različnih predsodkov, oblikovanih v 19. in 20. stoletju.
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Zhang, Jinsong, Bruce A. Hug, Eric Y. Huang, Clarice W. Chen, Vania Gelmetti, Marco Maccarana, Saverio Minucci, Pier Giuseppe Pelicci, and Mitchell A. Lazar. "Oligomerization of ETO Is Obligatory for Corepressor Interaction." Molecular and Cellular Biology 21, no. 1 (January 1, 2001): 156–63. http://dx.doi.org/10.1128/mcb.21.1.156-163.2001.
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ABSTRACT Nearly 40% of cases of acute myelogenous leukemia (AML) of the M2 subtype are due to a chromosomal translocation that combines a sequence-specific DNA binding protein, AML1, with a potent transcriptional repressor, ETO. ETO interacts with nuclear receptor corepressors SMRT and N-CoR, which recruit histone deacetylase to the AML1-ETO oncoprotein. SMRT–N-CoR interaction requires each of two zinc fingers contained in C-terminal Nervy homology region 4 (NHR4) of ETO. However, here we show that polypeptides containing NHR4 are insufficient for interaction with SMRT. NHR2 is also required for SMRT interaction and repression by ETO, as well as for inhibition of hematopoietic differentiation by AML1-ETO. NHR2 mediates oligomerization of ETO as well as AML1-ETO. Fusion of NHR4 polypeptide to a heterologous dimerization domain allows strong interaction with SMRT in vitro. These data support a model in which NHR2 and NHR4 have complementary functions in repression by ETO. NHR2 functions as an oligomerization domain bringing together NHR4 polypeptides that together form the surface required for high-affinity interaction with corepressors. As nuclear receptors also interact with corepressors as dimers, oligomerization may be a common mechanism regulating corepressor interactions.
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Stojanović, Aleksandra. "JAČA OD ŽIVOTA JE SMRT." Nasledje Kragujevac 18, no. 48 (2021): 395–400. http://dx.doi.org/10.46793/naskg2148.395s.
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Brčić Kuljiš, Marita. "Smrt multikulturalizma i život Mediterana." Filozofska istraživanja 41, no. 2 (July 9, 2021): 389–402. http://dx.doi.org/10.21464/fi41210.
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Već se duže vrijeme govori o neuspjehu multikulturalizma. Štoviše, izjave su vodećih europskih političara zapravo potvrdile ono u što se sumnjalo. Kada to postane stav država članica zajednice koja svojim temeljnim dokumentima zagovara ‘jednakost u različitosti’, to postaje zabrinjavajuće. Kao antitezu neuspjehu odnosno smrti multikulturalizma stavljamo život Mediterana, iz više razloga. Prvi je razlog taj što se za Mediteran uvijek konstatira multikulturalnost. Mediteran je po sebi multikulturalan i on je rasadište kulturnog pluralizma u Zapadnoj Europi. Drugi je razlog mediteranska ruta kojom veliki broj imigranata pokušava doći u Europsku uniju, upravo sada kada je ona proglasila neuspjeh multikulturalizma. Odnos između Europske unije i Mediterana povijesno je duboko složen. Duboko povezan i duboko razdvojen. U ovom ćemo se radu dotaknuti samo djelića tog složenog odnosa.
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Hestand, Matthew S., and Adam Ameur. "The Versatility of SMRT Sequencing." Genes 10, no. 1 (January 4, 2019): 24. http://dx.doi.org/10.3390/genes10010024.
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Burgess, Darren J. "Bacterial DNA methylation gets SMRT." Nature Reviews Genetics 14, no. 1 (November 27, 2012): 5. http://dx.doi.org/10.1038/nrg3389.
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KATO, Joji. "Report on SMRT in 1998." Japanese Journal of Radiological Technology 54, no. 7 (1998): 916–17. http://dx.doi.org/10.6009/jjrt.kj00003110354.
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Compton, Leigh A., and Scott W. Hiebert. "Anticancer Therapy SMRT-ens Up: Targeting the BCL6-SMRT Interaction in B Cell Lymphoma." Cancer Cell 17, no. 4 (April 2010): 315–16. http://dx.doi.org/10.1016/j.ccr.2010.03.012.
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Singh, Tejinder, Kamesh Ayasolla, Partab Rai, Nirupama Chandel, Shabirul Haque, Rivka Lederman, Mohammad Husain, et al. "AT1R blockade in adverse milieus: role of SMRT and corepressor complexes." American Journal of Physiology-Renal Physiology 309, no. 3 (August 1, 2015): F189—F203. http://dx.doi.org/10.1152/ajprenal.00476.2014.
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ANG II type 1 receptor blockade (AT1R-BLK) is used extensively to slow down the progression of proteinuric kidney diseases. We hypothesized that AT1R-BLK provides podocyte protection through regulation of silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) and vitamin D receptor (VDR) expression under adverse milieus such as high glucose and human immunodeficiency virus infection. Both AT1R-BLK and VDR agonists (VDAs) stimulated VDR complex formation that differed not only in their composition but also in their functionality. AT1R-BLK-induced VDR complexes contained predominantly unliganded VDR, SMRT, and phosphorylated histone deacetylase 3, whereas VDA-VDR complexes were constituted by liganded VDR and CREB-binding protein/p300. AT1R-BLK-induced complexes attenuated podocyte acetyl-histone 3 levels as well as cytochrome P-450 family 24A1 expression, thus indicating their deacetylating and repressive properties. On the other hand, VDA-VDR complexes not only increased podocyte acetyl-histone 3 levels but also enhanced cytochrome P-450 family 24A1 expression, thus suggesting their acetylating and gene activation properties. AT1R-BLK- induced podocyte SMRT inhibited expression of the proapoptotic gene BAX through downregulation of Wip1 and phosphorylation of checkpoint kinase 2 in high-glucose milieu. Since SMRT-depleted podocytes lacked AT1R-BLK-mediated protection against DNA damage, it appears that SMRT is necessary for DNA repairs during AT1R-BLK. We conclude that AT1R-BLK provides podocyte protection in adverse milieus predominantly through SMRT expression and partly through unliganded VDR expression in 1,25(OH)2D-deficient states; on the other hand, AT1R-BLK contributes to liganded VDR expression in 1,25(OH)2D-sufficient states.
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Tomita, Akihiro, Daniel R. Buchholz, and Yun-Bo Shi. "Recruitment of N-CoR/SMRT-TBLR1 Corepressor Complex by Unliganded Thyroid Hormone Receptor for Gene Repression during Frog Development." Molecular and Cellular Biology 24, no. 8 (April 15, 2004): 3337–46. http://dx.doi.org/10.1128/mcb.24.8.3337-3346.2004.
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ABSTRACT The corepressors N-CoR (nuclear receptor corepressor) and SMRT (silencing mediator for retinoid and thyroid hormone receptors) interact with unliganded nuclear hormone receptors, including thyroid hormone (T3) receptor (TR). Several N-CoR/SMRT complexes containing histone deacetylases have been purified. The best studied among them are N-CoR/SMRT complexes containing TBL1 (transducin beta-like protein 1) or TBLR1 (TBL1-related protein). Despite extensive studies of these complexes, there has been no direct in vivo evidence for the interaction of TBL1 or TBLR1 with TR or the possible involvement of such complexes in gene repression by any nuclear receptors in any animals. Here, we used the frog oocyte system to demonstrate that unliganded TR interacts with TBLR1 and recruits TBLR1 to its chromatinized target promoter in vivo, accompanied by histone deacetylation and gene repression. We further provide evidence to show that the recruitment of TBLR1 or related proteins is important for repression by unliganded TR. To investigate the potential role for TBLR1 complexes during vertebrate development, we made use of T3-dependent amphibian metamorphosis as a model. We found that TBLR1, SMRT, and N-CoR are recruited to T3-inducible promoters in premetamorphic tadpoles and are released upon T3 treatment, which induces metamorphosis. More importantly, we demonstrate that the dissociation of N-CoR/SMRT-TBLR1 complexes from endogenous TR target promoters is correlated with the activation of these genes during spontaneous metamorphosis. Taken together, our studies provide in vivo evidence for targeted recruitment of N-CoR/SMRT-TBLR1 complexes by unliganded TR in transcriptional repression during vertebrate development.
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Ki, Sung Hwan, Il Je Cho, Dal Woong Choi, and Sang Geon Kim. "Glucocorticoid Receptor (GR)-Associated SMRT Binding to C/EBPβ TAD and Nrf2 Neh4/5: Role of SMRT Recruited to GR in GSTA2 Gene Repression." Molecular and Cellular Biology 25, no. 10 (May 15, 2005): 4150–65. http://dx.doi.org/10.1128/mcb.25.10.4150-4165.2005.
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ABSTRACT The expression of the glutathione S-transferase gene (GST), whose induction accounts for cancer chemoprevention, is regulated by activation of CCAAT/enhancer binding protein β (C/EBPβ) and NF-E2-related factor 2 (Nrf2). The present study investigated the repressing effects of activating glucocorticoid receptor (GR) on C/EBPβ- and Nrf2-mediated GSTA2 gene induction and the mechanism. Dexamethasone that activates GR inhibited constitutive and oltipraz- or tert-butylhydroquinone (t-BHQ)-inducible GSTA2 expression in H4IIE cells. Also, dexamethasone repressed GSTA2 promoter-luciferase gene activity. Dexamethasone-GR activation did not inhibit nuclear translocation of C/EBPβ or Nrf2 nor their DNA binding activities induced by oltipraz or t-BHQ. Deletion of the glucocorticoid response element (GRE) in the GSTA2 promoter abolished dexamethasone inhibition of the gene induction. Immunoprecipitation-immunoblotting, chromatin immunoprecipitation, and GST pull-down assays revealed that silencing mediator for retinoid and thyroid hormone receptors (SMRT), a corepressor recruited to steroid-GR complex for histone deacetylation, bound to TAD domain of C/EBPβ and Neh4/5 domain of Nrf2. The GSTA2 promoter-luciferase activities were decreased by SMRT but not by truncated SMRTs. The small interference RNA (siRNA) against SMRT abolished SMRT repression of the gene induction by C/EBPβ or Nrf2. The plasmid transfection and siRNA experiments directly evidenced the functional role of SMRT in GSTA2 repression. In conclusion, dexamethasone antagonizes C/EBPβ- and Nrf2-mediated GSTA2 gene induction via ligand-GR binding to the GRE, and steroid-mediated GSTA2 repression involves inactivation of C/EBPβ and Nrf2 by SMRT recruited to steroid-GR complex.
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Keeton, Erika Krasnickas, and Myles Brown. "Cell Cycle Progression Stimulated by Tamoxifen-Bound Estrogen Receptor-α and Promoter-Specific Effects in Breast Cancer Cells Deficient in N-CoR and SMRT." Molecular Endocrinology 19, no. 6 (June 1, 2005): 1543–54. http://dx.doi.org/10.1210/me.2004-0395.
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Abstract Estrogen receptor α (ERα) mediates the effects of estrogens in breast cancer development and growth via transcriptional regulation of target genes. Tamoxifen can antagonize ERα activity and has been used in breast cancer therapy. Tamoxifen-bound ERα associates with nuclear receptor corepressor (N-CoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT) at certain target genes. Here we show the effects of reducing N-CoR and SMRT levels on the actions of estrogen and tamoxifen in breast cancer cells. Silencing both corepressors led to tamoxifen-stimulated cell cycle progression without activation of the ERα target genes c-myc, cyclin D1, or stromal cell-derived factor 1, which play a role in estrogen-induced proliferation. By contrast, expression of X-box binding protein 1 was markedly elevated in tamoxifen-treated cells in which N-CoR and SMRT had been silenced. The gain in cell cycle entry seen with tamoxifen when N-CoR and SMRT were silenced was dependent on ERα and not observed upon treatment with estradiol or epidermal growth factor. 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 ERα function and cell proliferation.
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Wagner, Brandee L., John D. Norris, Trina A. Knotts, Nancy L. Weigel, and Donald P. McDonnell. "The Nuclear Corepressors NCoR and SMRT Are Key Regulators of Both Ligand- and 8-Bromo-Cyclic AMP-Dependent Transcriptional Activity of the Human Progesterone Receptor." Molecular and Cellular Biology 18, no. 3 (March 1, 1998): 1369–78. http://dx.doi.org/10.1128/mcb.18.3.1369.
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ABSTRACT Previously, we defined a novel class of ligands for the human progesterone receptor (PR) which function as mixed agonists. These compounds induce a conformational change upon binding the receptor that is different from those induced by agonists and antagonists. This establishes a correlation between the structure of a ligand-receptor complex and its transcriptional activity. In an attempt to define the cellular components which distinguish between different ligand-induced PR conformations, we have determined, by using a mammalian two-hybrid assay, that the nuclear receptor corepressor (NCoR) and the silencing mediator for retinoid and thyroid hormone receptor (SMRT) differentially associate with PR depending upon the class of ligand bound to the receptor. Specifically, we observed that the corepressors preferentially associate with antagonist-occupied PR and that overexpression of these corepressors suppresses the partial agonist activity of antagonist-occupied PR. Binding studies performed in vitro, however, reveal that recombinant SMRT can interact with PR in a manner which is not influenced by the nature of the bound ligand. Thus, the inability of SMRT or NCoR to interact with agonist-activated PR when assayed in vivo may relate more to the increased affinity of PR for coactivators, with a subsequent displacement of corepressors, than to an inherent low affinity for the corepressor proteins. Previous work from other groups has shown that 8-bromo-cyclic AMP (8-bromo-cAMP) can convert the PR antagonist RU486 into an agonist and, additionally, can potentiate the transcriptional activity of agonist-bound PR. In this study, we show that exogenous expression of NCoR or SMRT suppresses all 8-bromo-cAMP-mediated potentiation of PR transcriptional activity. Further analysis revealed that 8-bromo-cAMP addition decreases the association of NCoR and SMRT with PR. Thus, we propose that 8-bromo-cAMP-mediated potentiation of PR transcriptional activity is due, at least in part, to a disruption of the interaction between PR and the corepressors NCoR and SMRT. Cumulatively, these results suggest that NCoR and SMRT expression may play a pivotal role in PR pharmacology.
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Huang, Eric Y., Jinsong Zhang, Eric A. Miska, Matthew G. Guenther, Tony Kouzarides, and Mitchell A. Lazar. "Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway." Genes & Development 14, no. 1 (January 1, 2000): 45–54. http://dx.doi.org/10.1101/gad.14.1.45.
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Transcriptional repression mediated by corepressors N-CoR and SMRT is a critical function of nuclear hormone receptors, and is dysregulated in human myeloid leukemias. At the present time, these corepressors are thought to act exclusively through an mSin3/HDAC1 complex. Surprisingly, however, numerous biochemical studies have not detected N-CoR or SMRT in mSin3- and HDAC1-containing complexes. Each corepressor contains multiple repression domains (RDs), the significance of which is unknown. Here we show that these RDs are nonredundant, and that one RD, which is conserved in N-CoR and SMRT, represses transcription by interacting directly with class II HDAC4 and HDAC5. Endogenous N-CoR and SMRT each associate with HDAC4 in a complex that does not contain mSin3A or HDAC1. This is the first example of a single corepressor utilizing distinct domains to engage multiple HDAC complexes. The alternative HDAC complexes may mediate specific repression pathways in normal as well as leukemic cells.