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• W3155381855 abstract "Glucocorticoids are potent anti-inflammatory drugs that are used to treat an extraordinary range of human disease, including COVID-19, underscoring the ongoing importance of understanding their molecular mechanisms. Early studies of GR signaling led to broad acceptance of models in which glucocorticoid receptor (GR) monomers tether repressively to inflammatory transcription factors, thus abrogating inflammatory gene expression. However, newer data challenge this core concept and present an exciting opportunity to reframe our understanding of GR signaling. Here, we present an alternate, two-part model for transcriptional repression by glucocorticoids. First, widespread GR-mediated induction of transcription results in rapid, primary repression of inflammatory gene transcription and associated enhancers through competition-based mechanisms. Second, a subset of GR-induced genes, including targets that are regulated in coordination with inflammatory transcription factors such as NF-κB, exerts secondary repressive effects on inflammatory gene expression. Within this framework, emerging data indicate that the gene set regulated through the cooperative convergence of GR and NF-κB signaling is central to the broad clinical effectiveness of glucocorticoids in terminating inflammation and promoting tissue repair. Glucocorticoids are potent anti-inflammatory drugs that are used to treat an extraordinary range of human disease, including COVID-19, underscoring the ongoing importance of understanding their molecular mechanisms. Early studies of GR signaling led to broad acceptance of models in which glucocorticoid receptor (GR) monomers tether repressively to inflammatory transcription factors, thus abrogating inflammatory gene expression. However, newer data challenge this core concept and present an exciting opportunity to reframe our understanding of GR signaling. Here, we present an alternate, two-part model for transcriptional repression by glucocorticoids. First, widespread GR-mediated induction of transcription results in rapid, primary repression of inflammatory gene transcription and associated enhancers through competition-based mechanisms. Second, a subset of GR-induced genes, including targets that are regulated in coordination with inflammatory transcription factors such as NF-κB, exerts secondary repressive effects on inflammatory gene expression. Within this framework, emerging data indicate that the gene set regulated through the cooperative convergence of GR and NF-κB signaling is central to the broad clinical effectiveness of glucocorticoids in terminating inflammation and promoting tissue repair. Signaling through the glucocorticoid receptor (NR3C1, GR) is essential for normal human physiology (1Chrousos G.P. Detera-Wadleigh S.D. Karl M. Syndromes of glucocorticoid resistance.Ann. Intern. Med. 1993; 119: 1113-1124Crossref PubMed Google Scholar, 2Granner D.K. Wang J.C. Yamamoto K.R. Regulatory actions of glucocorticoid hormones: From Organisms to mechanisms.Adv. Exp. Med. Biol. 2015; 872: 3-31Crossref PubMed Scopus (17) Google Scholar, 3Nicolaides N.C. Chrousos G. Kino T. Glucocorticoid receptor.in: Feingold K.R. Anawalt B. Boyce A. Chrousos G. de Herder W.W. Dungan K. Grossman A. Hershman J.M. Hofland J. Kaltsas G. Koch C. Kopp P. Korbonits M. McLachlan R. Morley J.E. Endotext. MDText.com, Inc. Copyright © 2000-2021, MDText.com, Inc., South Dartmouth (MA)2000Google Scholar). GR is a ubiquitously expressed nuclear hormone receptor that functions through ligand-induced translocation to the nucleus. There, GR regulates gene expression, resulting in critical physiological and pharmacological effects (see Fig. 1) that depend heavily on cellular and organismal context (4Arango-Lievano M. Lambert W.M. Jeanneteau F. Molecular biology of glucocorticoid signaling.Adv. Exp. Med. Biol. 2015; 872: 33-57Crossref PubMed Scopus (9) Google Scholar, 5Meijsing S.H. Mechanisms of glucocorticoid-regulated gene transcription.Adv. Exp. Med. Biol. 2015; 872: 59-81Crossref PubMed Scopus (23) Google Scholar, 6Oakley R.H. Cidlowski J.A. The biology of the glucocorticoid receptor: New signaling mechanisms in health and disease.J. Allergy Clin. Immunol. 2013; 132: 1033-1044Abstract Full Text Full Text PDF PubMed Scopus (471) Google Scholar, 7Whirledge S. DeFranco D.B. Glucocorticoid signaling in health and disease: Insights from tissue-specific GR Knockout mice.Endocrinology. 2018; 159: 46-64Crossref PubMed Scopus (44) Google Scholar). An example of this specificity is the indispensable role for GR signaling in lung development (8Gerber A.N. Glucocorticoids and the lung.Adv. Exp. Med. Biol. 2015; 872: 279-298Crossref PubMed Scopus (16) Google Scholar), where maturation and secretion of surfactant by cells unique to the lung require GR signaling (9Li A. Hardy R. Stoner S. Tuckermann J. Seibel M. Zhou H. Deletion of mesenchymal glucocorticoid receptor attenuates embryonic lung development and abdominal wall closure.PLoS One. 2013; 8: e63578Crossref PubMed Scopus (0) Google Scholar, 10Mendelson C.R. Role of transcription factors in fetal lung development and surfactant protein gene expression.Annu. Rev. Physiol. 2000; 62: 875-915Crossref PubMed Scopus (164) Google Scholar). Many other tissue types also perform unique responses to glucocorticoids, including the bone, nervous system, skeletal muscle, heart, and liver (11Bodine S.C. Furlow J.D. Glucocorticoids and skeletal muscle.Adv. Exp. Med. 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This, in collaboration with components of the core circadian clock, coordinates diverse physiological effects during health, including the regulation of metabolic and immune system homeostasis (16Magomedova L. Cummins C.L. Glucocorticoids and metabolic control.Handbook Exp. Pharmacol. 2016; 233: 73-93Crossref PubMed Scopus (0) Google Scholar, 17Rose A.J. Herzig S. Metabolic control through glucocorticoid hormones: An update.Mol. Cell Endocrinol. 2013; 380: 65-78Crossref PubMed Scopus (85) Google Scholar, 18Ronchetti S. Ricci E. Migliorati G. Gentili M. Riccardi C. How glucocorticoids Affect the Neutrophil Life.Int. J. Mol. Sci. 2018; 19: 4090Crossref PubMed Scopus (0) Google Scholar). These effects are altered by dynamic changes in corticosteroid hormone levels (19Vitousek M.N. Taff C.C. Ryan T.A. Zimmer C. Stress Resilience and the dynamic regulation of glucocorticoids.Integr. Comp. Biol. 2019; 59: 251-263PubMed Google Scholar, 20Russell G. Lightman S. The human stress response.Nat. Rev. Endocrinol. 2019; 15: 525-534Crossref PubMed Scopus (101) Google Scholar), which can rewire inflammation and metabolism as an adaptive response to stress. Beyond these crucial roles in normal physiology (21Katsu Y. Iguchi T. Subchapter 95D - Cortisol.in: Takei Y. Ando H. Tsutsui K. Handbook of Hormones. Academic Press, San Diego2016Google Scholar), likely through commandeering evolutionarily favorable stress response pathways (20Russell G. Lightman S. The human stress response.Nat. Rev. Endocrinol. 2019; 15: 525-534Crossref PubMed Scopus (101) Google Scholar), it has been recognized for more than 70 years that glucocorticoids have potent anti-inflammatory properties when used as drugs (22Gelfand M.L. Administration of cortisone by the aerosol method in the treatment of bronchial asthma.N. Engl. J. Med. 1951; 245: 293-294Crossref PubMed Google Scholar, 23Randolph T.G. Rollins J.P. The effect of cortisone on bronchial asthma.J. Allergy. 1950; 21: 288-295Abstract Full Text PDF PubMed Google Scholar). The range of diseases that are treated with glucocorticoids is extraordinarily diverse and includes asthma, rheumatoid arthritis, spinal cord injury, vasculitis, inflammatory bowel disease, sarcoidosis, and systemic lupus erythematous, among many others (24Vandewalle J. Luypaert A. De Bosscher K. Libert C. Therapeutic mechanisms of glucocorticoids.Trends Endocrinol Metabol. 2018; 29: 42-54Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 25Morand E.F. Corticosteroids in the treatment of rheumatologic diseases.Curr. Opin. Rheumatol. 2000; 12: 171-177Crossref PubMed Scopus (0) Google Scholar, 26Sellarés J. Francesqui J. Llabres M. Hernandez-Gonzalez F. Baughman R.P. Current treatment of sarcoidosis.Curr. Opin. Pulm. Med. 2020; 26: 591-597Crossref PubMed Scopus (0) Google Scholar, 27de Mattos B.R. Garcia M.P. Nogueira J.B. Paiatto L.N. Albuquerque C.G. Souza C.L. Fernandes L.G. Tamashiro W.M. Simioni P.U. Inflammatory bowel disease: An Overview of immune mechanisms and biological treatments.Mediators Inflamm. 2015; 2015: 493012Crossref PubMed Scopus (92) Google Scholar, 28Bracken M.B. Steroids for acute spinal cord injury.Cochrane Database Syst. Rev. 2012; 1: Cd001046Crossref PubMed Google Scholar, 29Kermani T.A. Dasgupta B. Current and emerging therapies in large-vessel vasculitis.Rheumatology (Oxford). 2018; 57: 1513-1524Crossref PubMed Scopus (10) Google Scholar). Oral corticosteroids are also effective in treating exacerbations of chronic obstructive pulmonary disease (COPD), which are frequently caused by viral infections (30Kunadharaju R. Sethi S. Treatment of acute exacerbations in chronic obstructive pulmonary disease.Clin. Chest Med. 2020; 41: 439-451Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). This role in resolving viral-induced inflammation in the lung has recently been extended to treating COVID-19 disease, where moderate doses of dexamethasone administered to patients with severe COVID-19 for up to 10 days reduced mortality (31Horby P. Lim W.S. Emberson J.R. Mafham M. Bell J.L. Linsell L. Staplin N. Brightling C. Ustianowski A. Elmahi E. Prudon B. Green C. Felton T. Chadwick D. Rege K. et al.Dexamethasone in Hospitalized patients with Covid-19 - Preliminary Report.N. Engl. J. Med. 2021; 384: 693-704Crossref PubMed Scopus (1713) Google Scholar). Thus, understanding the mechanisms of GR signaling is as relevant today as it was 50 years ago, when it was first recognized that hormone-regulated changes in cellular function are driven by direct effects of ligand-activated receptor on gene expression (32Baxter J.D. Rousseau G.G. Benson M.C. Garcea R.L. Ito J. Tomkins G.M. Role of DNA and specific cytoplasmic receptors in glucocorticoid action.Proc. Natl. Acad. Sci. U. S. A. 1972; 69: 1892-1896Crossref PubMed Google Scholar, 33Yu F.L. Feigelson P. Cortisone stimulation of nucleolar RNA polymerase activity.Proc. Natl. Acad. Sci. U. S. A. 1971; 68: 2177-2180Crossref PubMed Google Scholar). Here, we propose a parsimonious model for GR-mediated transcriptional repression built on concepts validated through unbiased genome-wide investigations. The highly inducible nature of glucocorticoid activity led to extensive use of GR signaling as a model system for pregenomics studies of eukaryotic transcription. This occurred in parallel with efforts to decipher the mechanistic basis for glucocorticoid effects on normal physiology and inflammation. Such studies, from the 1980s, 1990s, and early 2000s, defined a canonical pathway in which, following ligand binding and nuclear translocation, homodimeric GR binds to specific palindromic and near palindromic DNA sequences with high affinity (34La Baer J. Yamamoto K.R. Analysis of the DNA-binding affinity, sequence specificity and context dependence of the glucocorticoid receptor zinc finger region.J. Mol. Biol. 1994; 239: 664-688Crossref PubMed Scopus (43) Google Scholar, 35Beato M. Chalepakis G. Schauer M. Slater E.P. DNA regulatory elements for steroid hormones.J. Steroid Biochem. 1989; 32: 737-747Crossref PubMed Scopus (247) Google Scholar, 36Jantzen H.M. Strähle U. Gloss B. Stewart F. Schmid W. Boshart M. Miksicek R. Schütz G. Cooperativity of glucocorticoid response elements located far upstream of the tyrosine aminotransferase gene.Cell. 1987; 49: 29-38Abstract Full Text PDF PubMed Scopus (515) Google Scholar, 37Rusconi S. Yamamoto K.R. Functional dissection of the hormone and DNA binding activities of the glucocorticoid receptor.Embo J. 1987; 6: 1309-1315Crossref PubMed Google Scholar). Sequences with both palindromes and near palindromes, which comprise the canonical glucocorticoid response element (GRE), were found in the regulatory regions of numerous GR-induced genes, such as TAT, PEPCK, and others (35Beato M. Chalepakis G. Schauer M. Slater E.P. DNA regulatory elements for steroid hormones.J. Steroid Biochem. 1989; 32: 737-747Crossref PubMed Scopus (247) Google Scholar, 36Jantzen H.M. Strähle U. Gloss B. Stewart F. Schmid W. Boshart M. Miksicek R. Schütz G. Cooperativity of glucocorticoid response elements located far upstream of the tyrosine aminotransferase gene.Cell. 1987; 49: 29-38Abstract Full Text PDF PubMed Scopus (515) Google Scholar, 38Wang J.C. Stromstedt P.E. Sugiyama T. Granner D.K. The phosphoenolpyruvate carboxykinase gene glucocorticoid response unit: Identification of the functional domains of accessory factors HNF3 beta (hepatic nuclear factor-3 beta) and HNF4 and the necessity of proper alignment of their cognate binding sites.Mol. Endocrinol. 1999; 13: 604-618PubMed Google Scholar). Reporter analyses defined a functional requirement for these binding sites in mediating GR-driven transcription (36Jantzen H.M. Strähle U. Gloss B. Stewart F. Schmid W. Boshart M. Miksicek R. Schütz G. Cooperativity of glucocorticoid response elements located far upstream of the tyrosine aminotransferase gene.Cell. 1987; 49: 29-38Abstract Full Text PDF PubMed Scopus (515) Google Scholar, 39Imai E. Stromstedt P.E. Quinn P.G. Carlstedt-Duke J. Gustafsson J.A. Granner D.K. Characterization of a complex glucocorticoid response unit in the phosphoenolpyruvate carboxykinase gene.Mol. Cell Biol. 1990; 10: 4712-4719Crossref PubMed Google Scholar). Characterization of functional GREs within the context of immediate flanking DNA sequences indicated that GR functions in collaboration with other transcription factors (40Diamond M.I. Miner J.N. Yoshinaga S.K. Yamamoto K.R. Transcription factor interactions: Selectors of positive or negative regulation from a single DNA element.Science. 1990; 249: 1266-1272Crossref PubMed Google Scholar), in a process implicated in imparting tissue specificity to hormone responses (41Nitsch D. Boshart M. Schütz G. Activation of the tyrosine aminotransferase gene is dependent on synergy between liver-specific and hormone-responsive elements.Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 5479-5483Crossref PubMed Google Scholar). Moreover, coregulators that do not directly bind DNA, such as NCOA2 (also known as GRIP1), were shown to associate with specific surfaces of GR to enable formation of GR-nucleated multiprotein complexes (42Rogatsky I. Luecke H.F. Leitman D.C. Yamamoto K.R. Alternate surfaces of transcriptional coregulator GRIP1 function in different glucocorticoid receptor activation and repression contexts.Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16701-16706Crossref PubMed Scopus (169) Google Scholar, 43Hong H. Kohli K. Garabedian M.J. Stallcup M.R. GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors.Mol. Cell Biol. 1997; 17: 2735-2744Crossref PubMed Google Scholar). These recruit or interact with the more general components of the transcriptional apparatus (42Rogatsky I. Luecke H.F. Leitman D.C. Yamamoto K.R. Alternate surfaces of transcriptional coregulator GRIP1 function in different glucocorticoid receptor activation and repression contexts.Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16701-16706Crossref PubMed Scopus (169) Google Scholar), including chromatin remodeling machinery (44Ostlund Farrants A.K. Blomquist P. Kwon H. Wrange O. Glucocorticoid receptor-glucocorticoid response element binding stimulates nucleosome disruption by the SWI/SNF complex.Mol. Cell Biol. 1997; 17: 895-905Crossref PubMed Google Scholar), and ultimately RNA polymerase II (45Devine J.H. Hewetson A. Lee V.H. Chilton B.S. After chromatin is SWItched-on can it be RUSHed?.Mol. Cell Endocrinol. 1999; 151: 49-56Crossref PubMed Scopus (0) Google Scholar, 46McEwan I.J. Almlöf T. Wikström A.C. Dahlman-Wright K. Wright A.P. Gustafsson J.A. The glucocorticoid receptor functions at multiple steps during transcription initiation by RNA polymerase II.J. Biol. Chem. 1994; 269: 25629-25636Abstract Full Text PDF PubMed Google Scholar). In aggregate, these studies informed a model in which ligand-activated homodimeric GR interacts with high-affinity GREs located in regulatory regions of target genes, initiating multistep recruitment of additional proteins. This culminates in increased gene transcription in a process that depends on both the local features of the GRE and the overall cellular context (47Roesler W.J. Park E.A. Hormone response units: One plus one equals more than two.Mol. Cell Biochem. 1998; 178: 1-8Crossref PubMed Scopus (15) Google Scholar, 48Yamamoto K.R. Multilayered control of intracellular receptor function.Harvey lectures. 1995; 91: 1-19PubMed Google Scholar, 49Yamamoto K.R. Steroid receptor regulated transcription of specific genes and gene networks.Annu. Rev. Genet. 1985; 19: 209-252Crossref PubMed Google Scholar). This model was largely congruent with findings for other nuclear hormone receptors and shared many features with models for the activity of tissue-specific transcription factors that drive differentiation, such as MyoD (50Tapscott S.J. The circuitry of a master switch: Myod and the regulation of skeletal muscle gene transcription.Development. 2005; 132: 2685-2695Crossref PubMed Scopus (500) Google Scholar, 51Kushner P.J. Agard D. Feng W.J. Lopez G. Schiau A. Uht R. Webb P. Greene G. Oestrogen receptor function at classical and alternative response elements.Novartis Found. Symp. 2000; 230 (discussion 27-40): 20-26Crossref PubMed Google Scholar). A number of genes induced through the canonical GR signaling pathway, i.e., in association with high affinity GR:GRE interactions, were identified to have a role in the repression of inflammatory processes, e.g., TSCD22 (also known as GILZ), NFKBIA, and DUSP1 (52Scheinman R.I. Cogswell P.C. Lofquist A.K. Baldwin Jr., A.S. Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids.Science. 1995; 270: 283-286Crossref PubMed Google Scholar, 53Lasa M. Abraham S.M. Boucheron C. Saklatvala J. Clark A.R. Dexamethasone causes sustained expression of mitogen-activated protein kinase (MAPK) phosphatase 1 and phosphatase-mediated inhibition of MAPK p38.Mol. Cell Biol. 2002; 22: 7802-7811Crossref PubMed Scopus (310) Google Scholar, 54King E.M. Holden N.S. Gong W. Rider C.F. Newton R. Inhibition of NF-kappaB-dependent transcription by MKP-1: Transcriptional repression by glucocorticoids occurring via p38 MAPK.J. Biol. 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However, repressive effects of glucocorticoids on gene expression were too rapid to be solely attributable to secondary effects of GR-induced genes, and repression did not uniformly require protein synthesis (58van de Stolpe A. Caldenhoven E. Raaijmakers J.A. van der Saag P.T. Koenderman L. Glucocorticoid-mediated repression of intercellular adhesion molecule-1 expression in human monocytic and bronchial epithelial cell lines.Am. J. Respir. Cell Mol. Biol. 1993; 8: 340-347Crossref PubMed Google Scholar, 59Guertin M. Baril P. Bartkowiak J. Anderson A. Bélanger L. Rapid suppression of alpha 1-fetoprotein gene transcription by dexamethasone in developing rat liver.Biochemistry. 1983; 22: 4296-4302Crossref PubMed Google Scholar, 60Miesfeld R.L. Molecular genetics of corticosteroid action.Am. Rev. Respir. Dis. 1990; 141: S11-S17PubMed Google Scholar). Accordingly, numerous studies and models focused on alternate mechanisms encompassing what we will refer to as “primary” transcriptional repression, i.e., not requiring protein synthesis, as contributing to the effects of glucocorticoids on repressing gene expression and inflammatory processes (Fig. 2). Some studies suggested that GR interactions with DNA through canonical or semipalindromic GREs could result in “steric” inhibition of interactions between inflammatory factors and nearby DNA elements (35Beato M. Chalepakis G. Schauer M. Slater E.P. DNA regulatory elements for steroid hormones.J. Steroid Biochem. 1989; 32: 737-747Crossref PubMed Scopus (247) Google Scholar, 61Oro A.E. Hollenberg S.M. Evans R.M. Transcriptional inhibition by a glucocorticoid receptor-beta-galactosidase fusion protein.Cell. 1988; 55: 1109-1114Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 62Ray A. LaForge K.S. Sehgal P.B. On the mechanism for efficient repression of the interleukin-6 promoter by glucocorticoids: Enhancer, TATA box, and RNA start site (Inr motif) occlusion.Mol. Cell Biol. 1990; 10: 5736-5746Crossref PubMed Google Scholar). Other studies suggested that inductive transcriptional complexes nucleated by GR included cofactors that were recruited from other active enhancers and promoters (63Hoeck W. Hofer P. Groner B. Overexpression of the glucocorticoid receptor represses transcription from hormone responsive and non-responsive promoters.J. Steroid Biochem. Mol. Biol. 1992; 41: 283-289Crossref PubMed Scopus (0) Google Scholar). This competition consequently resulted in reduced expression of a subset of genes that are regulated by these cofactors (64Meyer M.E. Gronemeyer H. Turcotte B. Bocquel M.T. Tasset D. Chambon P. Steroid hormone receptors compete for factors that mediate their enhancer function.Cell. 1989; 57: 433-442Abstract Full Text PDF PubMed Scopus (424) Google Scholar, 65Wieland S. Döbbeling U. Rusconi S. Interference and synergism of glucocorticoid receptor and octamer factors.Embo J. 1991; 10: 2513-2521Crossref PubMed Google Scholar). Determinants of the GRE itself were also implicated (66Sakai D.D. Helms S. Carlstedt-Duke J. Gustafsson J.A. Rottman F.M. Yamamoto K.R. Hormone-mediated repression: A negative glucocorticoid response element from the bovine prolactin gene.Genes Dev. 1988; 2: 1144-1154Crossref PubMed Google Scholar), and GR interactions with specific DNA sequences known as negative GREs (67Dostert A. Heinzel T. Negative glucocorticoid receptor response elements and their role in glucocorticoid action.Curr. Pharm. Des. 2004; 10: 2807-2816Crossref PubMed Scopus (170) Google Scholar), which differ from canonical high-affinity GR binding sequences, were reported to result in repression rather than induction (67Dostert A. Heinzel T. Negative glucocorticoid receptor response elements and their role in glucocorticoid action.Curr. Pharm. Des. 2004; 10: 2807-2816Crossref PubMed Scopus (170) Google Scholar, 68Chandran U.R. Warren B.S. Baumann C.T. Hager G.L. DeFranco D.B. The glucocorticoid receptor is tethered to DNA-bound Oct-1 at the mouse gonadotropin-releasing hormone distal negative glucocorticoid response element.J. Biol. Chem. 1999; 274: 2372-2378Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). However, the dominant model that emerged was centered on the notion of repressive tethering or protein–protein interactions between GR and other transcription factors that resulted in reduced gene expression (69De Bosscher K. Van Craenenbroeck K. Meijer O.C. Haegeman G. Selective transrepression versus transactivation mechanisms by glucocorticoid receptor modulators in stress and immune systems.Eur. J. Pharmacol. 2008; 583: 290-302Crossref PubMed Scopus (60) Google Scholar, 70Barnes P.J. Molecular mechanisms of antiasthma therapy.Ann. Med. 1995; 27: 531-535Crossref PubMed Google Scholar, 71Ray A. Prefontaine K.E. Physical association and functional antagonism between the p65 subunit of transcription factor NF-kappa B and the glucocorticoid receptor.Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 752-756Crossref PubMed Google Scholar). In this model (see Fig. 2), without binding directly to DNA, GR associates or tethers with NF-κB or AP-1 (72Heck S. Kullmann M. Gast A. Ponta H. Rahmsdorf H.J. Herrlich P. Cato A.C. A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP-1.Embo J. 1994; 13: 4087-4095Crossref PubMed Scopus (0) Google Scholar, 73Caldenhoven E. Liden J. Wissink S. Van de Stolpe A. Raaijmakers J. Koenderman L. Okret S. Gustafsson J.A. Van der Saag P.T. Negative cross-talk between RelA and the glucocorticoid receptor: A possible mechanism for the antiinflammatory action of glucocorticoids.Mol. Endocrinol. 1995; 9: 401-412Crossref PubMed Google Scholar), resulting in repression of their activity in a process typically attributed to recruitment of transcriptional corepressors such as NCOR1 and HDAC2 (74Ito K. Jazrawi E. Cosio B. Barnes P.J. Adcock I.M. p65-activated histone acetyltransferase activity is repressed by glucocorticoids: mifepristone fails to recruit HDAC2 to the p65-HAT complex.J. Biol. Chem. 2001; 276: 30208-30215Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). This model was ostensibly supported by studies of mutations that prevented GR dimerization and/or limited GR-mediated transcriptional induction. For example, largely based on reporter assays, GR dimerization mutants enabled transcriptional repression in response to glucocorticoids (72Heck S. Kullmann M. Gast A. Ponta H. Rahmsdorf H.J. Herrlich P. Cato A.C. A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP-1.Embo J. 1994; 13: 4087-4095Crossref PubMed Scopus (0) Google Scholar, 75Bledsoe R.K. Montana V.G. Stanley T.B. Delves C.J. Apolito C.J. McKee D.D. Consler T.G. Parks D.J. Stewart E.L. Willson T.M. Lambert M.H. Moore J.T. Pearce K.H. Xu H.E. Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition.Cell. 2002; 110: 93-105Abstract Full Text Full Text PDF PubMed Scopus (614) Google Scholar). These presumptive monomeric forms of GR failed to bind DNA in biochemical assays and did not efficiently induce gene transcription through canonical GREs (72Heck S. Kullmann M. Gast A. Ponta H. Rahmsdorf H.J. Herrlich P. Cato A.C. A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP-1.Embo J. 1994; 13: 4087-4095Crossref PubMed Scopus (0) Google Scholar). However, GR dimerization mutants were known to support transactivation by GR in some contexts (76Rogatsky I. Wang J.C. Derynck M.K. Nonaka D.F. Khodabakhsh D.B. Haqq C.M. Darimont B.D. Garabedian M.J. Yamamoto K.R. Target-specific utilization of transcriptional regulatory surfaces by the glucocorticoid receptor.Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 13845-13850Crossref PubMed Scopus (200) Google Scholar), thus the available data were not necessarily supportive of tethering-based repression (77Newton R. Holden N.S. Separating transrepression and transactivation: A distressing divorce for the glucocorticoid receptor?.Mol. Pharmacol. 2007; 72: 799-809Crossref PubMed Scopus (244) Google Scholar). Nevertheless, canonical DNA binding and classical transcriptional induction came to be viewed as largely dispensable for GR-mediated repression (78Reichardt H.M. Kaestner K.H. Tuckermann J. Kretz O. Wessely O. Bock R. Gass P. Schmid W. Herrlich P. Angel P. Schütz G. DNA binding of the glucocorticoid receptor is not essential for survival.Cell. 1998; 93: 531-541Abstract Full Text Full Text PDF PubMed Scopus (868) Google Scholar, 79Tuckermann J.P. Reichardt H.M. Arribas R. Richter K.H. Schütz G. Angel P. The DNA binding-independent function of the glucocorticoid receptor mediates repression of AP-1-dependent genes in skin.J. Cell Biol. 1999; 147: 1365-1370Crossref PubMed Scopus (161) Google Scholar). This model formed the basis for extensive attempts to develop improved GR ligands with reduced side effects (80Schacke H. Berger M. Rehwinkel H. Asadullah K. Selective glucocorticoid receptor agonists (SEGRAs): Novel ligands with an improved therapeutic index.Mol. Cell Endocrinol. 2007; 275: 109-117Crossref PubMed Scopus (179) Google Scholar), none of which have resulted in clinically used drugs. As we will discuss below, although it is increasingly recognized that the bifurcated model is overly simplistic, the model continues to be incorporated in currently and serves as a conceptual framework for understanding GR signaling (81V" @default.
• W3155381855 created "2021-04-26" @default.
• W3155381855 creator A5011679004 @default.
• W3155381855 creator A5027692415 @default.
• W3155381855 creator A5068506060 @default.
• W3155381855 date "2021-01-01" @default.
• W3155381855 modified "2023-10-14" @default.
• W3155381855 title "Repression of transcription by the glucocorticoid receptor: A parsimonious model for the genomics era" @default.
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