The Experts below are selected from a list of 3468 Experts worldwide ranked by ideXlab platform
Pierre Chambon - One of the best experts on this subject based on the ideXlab platform.
-
glucocorticoid induced tethered Transrepression requires sumoylation of gr and formation of a sumo smrt ncor1 hdac3 repressing complex
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Krishna Priya Ganti, Pierre ChambonAbstract:Upon binding of a glucocorticoid (GC), the GC receptor (GR) can exert one of three transcriptional regulatory functions. We recently reported that SUMOylation of the GR at position K293 in humans (K310 in mice) within the N-terminal domain is indispensable for GC-induced evolutionary conserved inverted repeated negative GC response element (IR nGRE)-mediated direct Transrepression. We now demonstrate that the integrity of this GR SUMOylation site is mandatory for the formation of a GR-small ubiquitin-related modifiers (SUMOs)-SMRT/NCoR1-HDAC3 repressing complex, which is indispensable for NF-κB/AP1-mediated GC-induced tethered indirect Transrepression in vitro. Using GR K310R mutant mice or mice containing the N-terminal truncated GR isoform GRα-D3 lacking the K310 SUMOylation site, revealed a more severe skin inflammation than in WT mice. Importantly, cotreatment with dexamethasone (Dex) could not efficiently suppress a 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced skin inflammation in these mutant mice, whereas it was clearly decreased in WT mice. In addition, in mice selectively ablated in skin keratinocytes for either nuclear receptor corepressor 1 (NCoR1)/silencing mediator for retinoid or thyroid-hormone receptors (SMRT) corepressors or histone deacetylase 3 (HDAC3), Dex-induced tethered Transrepression and the formation of a repressing complex on DNA-bound NF-κB/AP1 were impaired. We previously suggested that GR ligands that would lack both (+)GRE-mediated transactivation and IR nGRE-mediated direct Transrepression activities of GCs may preferentially exert the therapeutically beneficial GC antiinflammatory properties. Interestingly, we now identified a nonsteroidal antiinflammatory selective GR agonist (SEGRA) that selectively lacks both Dex-induced (+)GRE-mediated transactivation and IR nGRE-mediated direct Transrepression functions, while still exerting a tethered indirect Transrepression activity and could therefore be clinically lesser debilitating on long-term GC therapy.
-
Glucocorticoid-induced tethered Transrepression requires SUMOylation of GR and formation of a SUMO-SMRT/NCoR1-HDAC3 repressing complex.
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Guoqiang Hua, Krishna Priya Ganti, Pierre ChambonAbstract:Upon binding of a glucocorticoid (GC), the GC receptor (GR) can exert one of three transcriptional regulatory functions. We recently reported that SUMOylation of the GR at position K293 in humans (K310 in mice) within the N-terminal domain is indispensable for GC-induced evolutionary conserved inverted repeated negative GC response element (IR nGRE)-mediated direct Transrepression. We now demonstrate that the integrity of this GR SUMOylation site is mandatory for the formation of a GR-small ubiquitin-related modifiers (SUMOs)-SMRT/NCoR1-HDAC3 repressing complex, which is indispensable for NF-κB/AP1-mediated GC-induced tethered indirect Transrepression in vitro. Using GR K310R mutant mice or mice containing the N-terminal truncated GR isoform GRα-D3 lacking the K310 SUMOylation site, revealed a more severe skin inflammation than in WT mice. Importantly, cotreatment with dexamethasone (Dex) could not efficiently suppress a 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced skin inflammation in these mutant mice, whereas it was clearly decreased in WT mice. In addition, in mice selectively ablated in skin keratinocytes for either nuclear receptor corepressor 1 (NCoR1)/silencing mediator for retinoid or thyroid-hormone receptors (SMRT) corepressors or histone deacetylase 3 (HDAC3), Dex-induced tethered Transrepression and the formation of a repressing complex on DNA-bound NF-κB/AP1 were impaired. We previously suggested that GR ligands that would lack both (+)GRE-mediated transactivation and IR nGRE-mediated direct Transrepression activities of GCs may preferentially exert the therapeutically beneficial GC antiinflammatory properties. Interestingly, we now identified a nonsteroidal antiinflammatory selective GR agonist (SEGRA) that selectively lacks both Dex-induced (+)GRE-mediated transactivation and IR nGRE-mediated direct Transrepression functions, while still exerting a tethered indirect Transrepression activity and could therefore be clinically lesser debilitating on long-term GC therapy.
-
widespread negative response elements mediate direct repression by agonist liganded glucocorticoid receptor
Cell, 2011Co-Authors: Milan Surjit, Krishna Priya Ganti, Atish Mukherji, Tao Ye, Daniel Metzger, Mei Li, Pierre ChambonAbstract:The glucocorticoid (GC) receptor (GR), when liganded to GC, activates transcription through direct binding to simple (+)GRE DNA binding sequences (DBS). GC-induced direct repression via GR binding to complex “negative” GREs (nGREs) has been reported. However, GR-mediated Transrepression was generally ascribed to indirect “tethered” interaction with other DNA-bound factors. We report that GC-induces direct Transrepression via the binding of GR to simple DBS (IR nGREs) unrelated to (+)GRE. These DBS act on agonist-liganded GR, promoting the assembly of cis-acting GR-SMRT/NCoR repressing complexes. IR nGREs are present in over 1000 mouse/human ortholog genes, which are repressed by GC in vivo. Thus variations in the levels of a single ligand can coordinately turn genes on or off depending in their response element DBS, allowing an additional level of regulation in GR signaling. This mechanism suits GR signaling remarkably well, given that adrenal secretion of GC fluctuates in a circadian and stress-related fashion.
-
rar specific agonist antagonists which dissociate transactivation and ap1 Transrepression inhibit anchorage independent cell proliferation
The EMBO Journal, 1995Co-Authors: Jiayang Chen, Pierre Chambon, S Penco, J Ostrowski, Patrick Balaguer, Michel Pons, J E Starrett, P Reczek, Hinrich GronemeyerAbstract:Using retinoic acid receptor (RAR) reporter cells specific for either RAR alpha, beta or gamma, we have identified synthetic retinoids which specifically induce transactivation by RAR beta, while antagonizing RA-induced transactivation by RAR alpha and RAR gamma. Like RA, these synthetic retinoids allow all three RAR types to repress AP1 (c-Jun/c-Fos) activity, demonstrating that the transactivation and Transrepression functions of RARs can be dissociated by properly designed ligands. Using AP1 reporter cells, we also show that glucocorticoids or vitamin D3, together with either RA or these 'dissociating' synthetic retinoids, can synergistically repress phorbol ester-induced AP1 activity. RA, but not these 'dissociating' retinoids, induced transcription of an interleukin-6 promoter-based reporter gene transiently transfected into HeLa cells together with RARs. Using Ki-ras-transformed 3T3 cells as a model system, we show that both RA and the 'dissociating' retinoids inhibit anchorage-independent cell proliferation, suggesting that retinoid-induced growth inhibition may be related to AP1 Transrepression.
-
RAR-specific agonist/antagonists which dissociate transactivation and AP1 Transrepression inhibit anchorage-independent cell proliferation.
The EMBO journal, 1995Co-Authors: Jiayang Chen, Pierre Chambon, S Penco, J Ostrowski, Patrick Balaguer, Michel Pons, J E Starrett, P Reczek, Hinrich GronemeyerAbstract:Using retinoic acid receptor (RAR) reporter cells specific for either RAR alpha, beta or gamma, we have identified synthetic retinoids which specifically induce transactivation by RAR beta, while antagonizing RA-induced transactivation by RAR alpha and RAR gamma. Like RA, these synthetic retinoids allow all three RAR types to repress AP1 (c-Jun/c-Fos) activity, demonstrating that the transactivation and Transrepression functions of RARs can be dissociated by properly designed ligands. Using AP1 reporter cells, we also show that glucocorticoids or vitamin D3, together with either RA or these 'dissociating' synthetic retinoids, can synergistically repress phorbol ester-induced AP1 activity. RA, but not these 'dissociating' retinoids, induced transcription of an interleukin-6 promoter-based reporter gene transiently transfected into HeLa cells together with RARs. Using Ki-ras-transformed 3T3 cells as a model system, we show that both RA and the 'dissociating' retinoids inhibit anchorage-independent cell proliferation, suggesting that retinoid-induced growth inhibition may be related to AP1 Transrepression.
Eckardt Treuter - One of the best experts on this subject based on the ideXlab platform.
-
New wrestling rules of anti-inflammatory Transrepression by oxysterol receptor LXR revealed
Cell research, 2011Co-Authors: Eckardt TreuterAbstract:New wrestling rules of anti-inflammatory Transrepression by oxysterol receptor LXR revealed
-
Wrestling rules in Transrepression : As easy as SUMO-1, -2, -3?
Molecular cell, 2007Co-Authors: Eckardt Treuter, Jan-ake GustafssonAbstract:A recent study in Molecular Cell (Ghisletti et al., 2007) uncovered parallel yet distinct SUMOylation pathways that provide insights into molecular mechanisms of Transrepression mediated by activated nuclear receptors LXRα/β and PPARγ, thereby clarifying receptor, signal, and gene specificity of Transrepression in inflammatory processes.
-
wrestling rules in Transrepression as easy as sumo 1 2 3
Molecular Cell, 2007Co-Authors: Eckardt Treuter, Jan-ake GustafssonAbstract:A recent study in Molecular Cell (Ghisletti et al., 2007) uncovered parallel yet distinct SUMOylation pathways that provide insights into molecular mechanisms of Transrepression mediated by activated nuclear receptors LXRα/β and PPARγ, thereby clarifying receptor, signal, and gene specificity of Transrepression in inflammatory processes.
Jan-ake Gustafsson - One of the best experts on this subject based on the ideXlab platform.
-
LXR Suppresses Inflammatory Gene Expression and Neutrophil Migration through cis-Repression and Cholesterol Efflux
Elsevier, 2018Co-Authors: David G. Thomas, Jan-ake Gustafsson, Amanda C. Doran, Panagiotis Fotakis, Marit Westerterp, Per Antonson, Hui Jiang, Xian-cheng Jiang, Ira Tabas, Alan R. TallAbstract:Summary: The activation of liver X receptor (LXR) promotes cholesterol efflux and repression of inflammatory genes with anti-atherogenic consequences. The mechanisms underlying the repressive activity of LXR are controversial and have been attributed to cholesterol efflux or to Transrepression of activator protein-1 (AP-1) activity. Here, we find that cholesterol efflux contributes to LXR repression, while the direct repressive functions of LXR also play a key role but are independent of AP-1. We use assay for transposase-accessible chromatin using sequencing (ATAC-seq) to show that LXR reduces chromatin accessibility in cis at inflammatory gene enhancers containing LXR binding sites. Targets of this repressive activity are associated with leukocyte adhesion and neutrophil migration, and LXR agonist treatment suppresses neutrophil recruitment in a mouse model of sterile peritonitis. These studies suggest a model of repression in which liganded LXR binds in cis to canonical nuclear receptor binding sites and represses pro-atherogenic leukocyte functions in tandem with the induction of LXR targets mediating cholesterol efflux. : Thomas et al. show the roles of cholesterol efflux and direct repression in anti-inflammatory effects of LXR and establish the mechanism of LXR cis-repression using ATAC-seq. LXR agonists suppress neutrophil migration genes and neutrophil recruitment during inflammation, highlighting a potential role for these compounds in the control of neutrophil-predominant inflammatory conditions. Keywords: liver X receptor, Transrepression, cholesterol efflux, nuclear receptor, oxysterol, LXR, cis-repression, cholesterol, neutrophil migration, peritoniti
-
Wrestling rules in Transrepression : As easy as SUMO-1, -2, -3?
Molecular cell, 2007Co-Authors: Eckardt Treuter, Jan-ake GustafssonAbstract:A recent study in Molecular Cell (Ghisletti et al., 2007) uncovered parallel yet distinct SUMOylation pathways that provide insights into molecular mechanisms of Transrepression mediated by activated nuclear receptors LXRα/β and PPARγ, thereby clarifying receptor, signal, and gene specificity of Transrepression in inflammatory processes.
-
wrestling rules in Transrepression as easy as sumo 1 2 3
Molecular Cell, 2007Co-Authors: Eckardt Treuter, Jan-ake GustafssonAbstract:A recent study in Molecular Cell (Ghisletti et al., 2007) uncovered parallel yet distinct SUMOylation pathways that provide insights into molecular mechanisms of Transrepression mediated by activated nuclear receptors LXRα/β and PPARγ, thereby clarifying receptor, signal, and gene specificity of Transrepression in inflammatory processes.
Krishna Priya Ganti - One of the best experts on this subject based on the ideXlab platform.
-
glucocorticoid induced tethered Transrepression requires sumoylation of gr and formation of a sumo smrt ncor1 hdac3 repressing complex
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Krishna Priya Ganti, Pierre ChambonAbstract:Upon binding of a glucocorticoid (GC), the GC receptor (GR) can exert one of three transcriptional regulatory functions. We recently reported that SUMOylation of the GR at position K293 in humans (K310 in mice) within the N-terminal domain is indispensable for GC-induced evolutionary conserved inverted repeated negative GC response element (IR nGRE)-mediated direct Transrepression. We now demonstrate that the integrity of this GR SUMOylation site is mandatory for the formation of a GR-small ubiquitin-related modifiers (SUMOs)-SMRT/NCoR1-HDAC3 repressing complex, which is indispensable for NF-κB/AP1-mediated GC-induced tethered indirect Transrepression in vitro. Using GR K310R mutant mice or mice containing the N-terminal truncated GR isoform GRα-D3 lacking the K310 SUMOylation site, revealed a more severe skin inflammation than in WT mice. Importantly, cotreatment with dexamethasone (Dex) could not efficiently suppress a 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced skin inflammation in these mutant mice, whereas it was clearly decreased in WT mice. In addition, in mice selectively ablated in skin keratinocytes for either nuclear receptor corepressor 1 (NCoR1)/silencing mediator for retinoid or thyroid-hormone receptors (SMRT) corepressors or histone deacetylase 3 (HDAC3), Dex-induced tethered Transrepression and the formation of a repressing complex on DNA-bound NF-κB/AP1 were impaired. We previously suggested that GR ligands that would lack both (+)GRE-mediated transactivation and IR nGRE-mediated direct Transrepression activities of GCs may preferentially exert the therapeutically beneficial GC antiinflammatory properties. Interestingly, we now identified a nonsteroidal antiinflammatory selective GR agonist (SEGRA) that selectively lacks both Dex-induced (+)GRE-mediated transactivation and IR nGRE-mediated direct Transrepression functions, while still exerting a tethered indirect Transrepression activity and could therefore be clinically lesser debilitating on long-term GC therapy.
-
Glucocorticoid-induced tethered Transrepression requires SUMOylation of GR and formation of a SUMO-SMRT/NCoR1-HDAC3 repressing complex.
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Guoqiang Hua, Krishna Priya Ganti, Pierre ChambonAbstract:Upon binding of a glucocorticoid (GC), the GC receptor (GR) can exert one of three transcriptional regulatory functions. We recently reported that SUMOylation of the GR at position K293 in humans (K310 in mice) within the N-terminal domain is indispensable for GC-induced evolutionary conserved inverted repeated negative GC response element (IR nGRE)-mediated direct Transrepression. We now demonstrate that the integrity of this GR SUMOylation site is mandatory for the formation of a GR-small ubiquitin-related modifiers (SUMOs)-SMRT/NCoR1-HDAC3 repressing complex, which is indispensable for NF-κB/AP1-mediated GC-induced tethered indirect Transrepression in vitro. Using GR K310R mutant mice or mice containing the N-terminal truncated GR isoform GRα-D3 lacking the K310 SUMOylation site, revealed a more severe skin inflammation than in WT mice. Importantly, cotreatment with dexamethasone (Dex) could not efficiently suppress a 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced skin inflammation in these mutant mice, whereas it was clearly decreased in WT mice. In addition, in mice selectively ablated in skin keratinocytes for either nuclear receptor corepressor 1 (NCoR1)/silencing mediator for retinoid or thyroid-hormone receptors (SMRT) corepressors or histone deacetylase 3 (HDAC3), Dex-induced tethered Transrepression and the formation of a repressing complex on DNA-bound NF-κB/AP1 were impaired. We previously suggested that GR ligands that would lack both (+)GRE-mediated transactivation and IR nGRE-mediated direct Transrepression activities of GCs may preferentially exert the therapeutically beneficial GC antiinflammatory properties. Interestingly, we now identified a nonsteroidal antiinflammatory selective GR agonist (SEGRA) that selectively lacks both Dex-induced (+)GRE-mediated transactivation and IR nGRE-mediated direct Transrepression functions, while still exerting a tethered indirect Transrepression activity and could therefore be clinically lesser debilitating on long-term GC therapy.
-
widespread negative response elements mediate direct repression by agonist liganded glucocorticoid receptor
Cell, 2011Co-Authors: Milan Surjit, Krishna Priya Ganti, Atish Mukherji, Tao Ye, Daniel Metzger, Mei Li, Pierre ChambonAbstract:The glucocorticoid (GC) receptor (GR), when liganded to GC, activates transcription through direct binding to simple (+)GRE DNA binding sequences (DBS). GC-induced direct repression via GR binding to complex “negative” GREs (nGREs) has been reported. However, GR-mediated Transrepression was generally ascribed to indirect “tethered” interaction with other DNA-bound factors. We report that GC-induces direct Transrepression via the binding of GR to simple DBS (IR nGREs) unrelated to (+)GRE. These DBS act on agonist-liganded GR, promoting the assembly of cis-acting GR-SMRT/NCoR repressing complexes. IR nGREs are present in over 1000 mouse/human ortholog genes, which are repressed by GC in vivo. Thus variations in the levels of a single ligand can coordinately turn genes on or off depending in their response element DBS, allowing an additional level of regulation in GR signaling. This mechanism suits GR signaling remarkably well, given that adrenal secretion of GC fluctuates in a circadian and stress-related fashion.
Minoru Ishikawa - One of the best experts on this subject based on the ideXlab platform.
-
Structure-activity relationships of rosiglitazone for peroxisome proliferator-activated receptor gamma Transrepression
Bioorganic & medicinal chemistry letters, 2017Co-Authors: Yosuke Toyota, Sayaka Nomura, Makoto Makishima, Yuichi Hashimoto, Minoru IshikawaAbstract:Abstract Anti-inflammatory effects of peroxisome proliferator-activated receptor gamma (PPRAγ) ligands are thought to be largely due to PPARγ-mediated Transrepression. Thus, Transrepression-selective PPARγ ligands without agonistic activity or with only partial agonistic activity should exhibit anti-inflammatory properties with reduced side effects. Here, we investigated the structure-activity relationships (SARs) of PPARγ agonist rosiglitazone, focusing on Transrepression activity. Alkenic analogs showed slightly more potent Transrepression with reduced efficacy of transactivating agonistic activity. Removal of the alkyl group on the nitrogen atom improved selectivity for Transrepression over transactivation. Among the synthesized compounds, 3l exhibited stronger Transrepressional activity (IC 50 : 14 μM) and weaker agonistic efficacy (11%) than rosiglitazone or pioglitazone.
-
Styrylphenylphthalimides as Novel Transrepression-Selective Liver X Receptor (LXR) Modulators
ACS medicinal chemistry letters, 2015Co-Authors: Sayaka Nomura, Makoto Makishima, Yuichi Hashimoto, Kaori Endo-umeda, Atsushi Aoyama, Minoru IshikawaAbstract:Anti-inflammatory effects of liver X receptor (LXR) ligands are thought to be largely due to LXR-mediated Transrepression, whereas side effects are caused by activation of LXR-responsive gene expression (transactivation). Therefore, selective LXR modulators that preferentially exhibit Transrepression activity should exhibit anti-inflammatory properties with fewer side effects. Here, we synthesized a series of styrylphenylphthalimide analogues and evaluated their structure-activity relationships focusing on LXRs-transactivating-agonistic/antagonistic activities and Transrepressional activity. Among the compounds examined, 17l showed potent LXR-Transrepressional activity with high selectivity over transactivating activity and did not show characteristic side effects of LXR-transactivating agonists in cells. This representative compound, 17l, was confirmed to have LXR-dependent Transrepressional activity and to bind directly to LXRβ. Compound 17l should be useful not only as a chemical tool for studying the biological functions of LXRs Transrepression but also as a candidate for a safer agent to treat inflammatory diseases.
-
Styrylphenylphthalimides as Novel Transrepression-Selective Liver X Receptor (LXR) Modulators
2015Co-Authors: Sayaka Nomura, Makoto Makishima, Yuichi Hashimoto, Kaori Endo-umeda, Atsushi Aoyama, Minoru IshikawaAbstract:Anti-inflammatory effects of liver X receptor (LXR) ligands are thought to be largely due to LXR-mediated Transrepression, whereas side effects are caused by activation of LXR-responsive gene expression (transactivation). Therefore, selective LXR modulators that preferentially exhibit Transrepression activity should exhibit anti-inflammatory properties with fewer side effects. Here, we synthesized a series of styrylphenylphthalimide analogues and evaluated their structure–activity relationships focusing on LXRs-transactivating-agonistic/antagonistic activities and Transrepressional activity. Among the compounds examined, 17l showed potent LXR-Transrepressional activity with high selectivity over transactivating activity and did not show characteristic side effects of LXR-transactivating agonists in cells. This representative compound, 17l, was confirmed to have LXR-dependent Transrepressional activity and to bind directly to LXRβ. Compound 17l should be useful not only as a chemical tool for studying the biological functions of LXRs Transrepression but also as a candidate for a safer agent to treat inflammatory diseases
