Glucocorticoid Receptor Signaling

Our bones get more brittle with increasing age, and to add insult to injury, the most effective therapy for

another problem that is associated with getting older, rheumatoid arthritis, often adds to the problem by causing bone resorption. The Glucocorticoid steroids, are the best available anti-inflammatories, and are used widely in the treatment of arthritis, as well as other inflammatory conditions such as dermatitis and autoimmune diseases. The Glucocorticoids, secreted by the Adrenal Cortex are powerful antiinflammatory compounds due to their ability to inhibit all stages of the inflammatory response, from redness to wound healing to cell proliferation (Ref.1). They are powerful anti-inflammatory compounds that have the ability to inhibit all stages of the inflammatory response. They also have an essential role in cell metabolism and got the nomenclature, from their effect of raising the level of blood sugar (glucose) by stimulating gluconeogenesis in the liver: the conversion of fat and protein into intermediate metabolites that are ultimately converted into glucose. Cortisol (or Hydrocortisone) is the most important human Glucocorticoid. It is essential for life and regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions. Corticosterone, another Glucocorticoid, helps in the regulation of the conversion of amino acids into carbohydrates and glycogen by the liver, and stimulates glycogen formation in the tissues. All the cellular responses to Glucocorticoids is attributed to their binding to the intracellular GR (Glucocorticoid Receptor) (Ref.2), that, in turn, translocates to the nucleus, that positively and negatively modulates gene expression through diverse mechanisms. The GR is the Glucocorticoid-activated member of the nuclear receptor superfamily of transcription factors. It mediates the immunosuppressive and anti-inflammatory activity of these ligands in multiple physiological systems, including the respiratory and central nervous systems. Belonging to the family of steroid hormones, Glucocorticoids are essential for development and survival of vertebrates (Ref.3). Unbound GR is associated within the cytoplasm in an inactive oligomeric complex with some regulatory proteins such as the HSP90 (Heat Shock Protein-90 KD) which binds as a dimmer to the C-terminal domain, the HSP70 (Heat Shock Protein-70 KD), the p59 immunophilin, FKBP52 and the small p23 phosphoprotein. GRs are composed of several conserved structural elements, including a COOH-terminal ligand-binding domain (which also contains residues required for dimmerization and hormone-dependent gene transactivation), a nearby hinge region containing nuclear localization signals, a central zinc-fingercontaining DNA-binding domain, and an NH2-terminal variable region important for ligand-independent gene transactivation. The interaction between HSP90 and GR is required to maintain the C-terminal domain in a favourable conformation for ligand binding (Ref.4). The Gucocorticoid hormone passes through the plasma membrane into the cytoplasm where it binds to the specific, high-affinity GR. The resulting complex is the non-DNA-binding oligomer of the GR in which the receptor is complexed with other proteins. Binding of hormone agonists releases GR from its interactions with the inhibitory complex, thus inducing a conformational change which results in unmasking of the receptor nuclear localization signal. Upon activation, GR thereby translocates to the nucleus and binds as a dimmer to DNA through its central domain, which is structurally characterized by a DNA binding motif (Ref.3). The stabilization and nuclear localization of GR is facilitated by its sumoylation by SUMO1 (Small Ubiquitin Related Modifier-1). The sumoylation process is catalyzed by the SUMO1-conjugating E2 enzyme Ubc9 (Ref.5). GR interacts either with DNA by targeting specific nucleotide palindromic sequences termed GRE (Glucocorticoid Response Elements) or nGRE (Negative GRE) (Ref.6). In particular, the dimmeric GR places its two DNA-binding fragments into adjacent major grooves of the DNA double helix in correspondence of appropriately spaced GRE half palindromes. Depending on the nature of the GRE, the overall process of GR binding can result in activation or repression of genes containing GR-binding sites (Ref.3). Although the activity of the GR is often thought of simply in terms of direct gene transactivation,

considerable cross-talk also occurs between the GR and a cohort of molecules to mediate their function as transcriptional regulators. GRs can interact with coactivator complexes including CBP (CREB-Binding Protein), p300, ACTR (Activator of Thyroid Hormone and Retinoid Receptors), SRC1 (Steroid Receptor Coactivator-1), and PCAF (p300/CBP Associated Factor) that possess HAT (Histone Acetyltransferase) activities, and the SWI/SNF complex which possesses ATPdependent chromatin remodeling activities (Ref.3 & 7). Acetylation of core histones alters nucleosomal packing to allow increased access of transacting factors and components of the basal transcriptional machinery to the local DNA. All these complexes may act in concert to relieve chromatin-mediated gene repression, with the TRAP (Thyroid Hormone Receptor Associated Protein)-GRIP (Glucocorticoid Receptor Interacting Proteins)-ARC (Activated Recruited Cofactor) complex functioning to recruit the core transcription machinery. The latter includes the TBP (TATA Box-Binding Protein), the TAFs (TBP Associated Factors), the general transcription factors TFIIA, TFIIB, TFIIE, TFIIF, TFIIH, and the enzyme, RNA Pol II (RNA PolymeraseII). The nuclear receptors can also interact with the corepressors NCoR (Nuclear Receptor Corepressor) and SMRT (Silencing Mediator of Retinoid and Thyroid Hormone Receptor) thus leading to the recruitment of the Sin3-HDAC (Histone Deacetylase) corepressor complex, possessing histone deacetylase functions. This corepressor complex can thereby inhibit gene transcription by counteracting the actions of the coactivator complexes containing histone acetyltransferase activities (Ref.2 & 8). Alternatively, GR can also modulate the expression of genes through a GRE-independent mechanism, which is mediated in part through proteinprotein interactions of GR with other sequence-specific DNAbinding factors or coactivators (Ref.9). The negative modulation of gene transcription operated by Glucocorticoids occurs through non genomic mechanisms (transrepression), mediated by inhibitory influences exerted by activated GR on the functions of several transcription factors. This contributes to the anti-inflammatory properties of the Glucocorticoids. Transrepression is due at least in part to direct, physical interactions between monomeric GR and transcription factors such as c-Jun-c-Fos and NFKappaB (Nuclear Factor-KappaB), that synergistically coordinate the transcriptional activation of many genes involved in inflammatory diseases such as Asthma (Ref.10). In particular, the three main domains of GR may contribute to interact with the p65 subunit of NF-KappaB and with both Jun and Fos components of Activator Protein-1. The resulting reciprocal antagonism of the transcription factors engaged in these protein-protein associations causes an impairment of their transcriptional properties. However, Activator Protein-1, consisting of c-Jun homodimmers can also enhance GRE-mediated transactivation. On the other hand, Glucocorticoid-activated GR increases DNA-binding activity of CEBP-Beta via post-translational mechanisms involving phosphorylation at Thr(235) (Ref.11). GR can interact as a monomer, via direct protein-protein interactions, with transcription factors such as NFKappaB and Activator Protein-1, activated by cytokines and other pro-inflammatory stimuli (Ref.4). The resulting mutual repression prevents both GR and the other transcription factors from binding to their respective DNA response elements. In addition, Glucocorticoids repress NF-KappaB-mediated activation of pro-inflammatory genes by reducing the levels of serine-2 phosphorylation of the carboxy-terminal domain of RNA Pol II, which is essential for the recruitment of this enzyme to the promoter region. Glucocorticoids also increase the transcription and synthesis of I-KappaB and thus may inhibit NFKappaB by promoting its retention in the cytosol. Other products of Glucocorticoid inducible genes responsible for NF-KappaB inhibition include the two recently discovered proteins GILZ (GlucocorticoidInduced Leucine Zipper) and GITR (Glucocorticoid-Induced Tumor Necrosis Factor Receptor FamilyRelated Gene), which play a crucial role in modulation of T-cell activation and apoptosis. GR can also cooperate with transcription factors, including octamer transcription factors Oct1 and Oct2; CREB (cAMP Response Element Binding Protein), and STAT5 (Signal Transducers and Activators of Transcription-5),

to activate transcription. Competition for limiting co-activators of transcription is an important determinant of the fate of the cross-talk between the GR and other transcription factors. Both Activating Protein-1 and the GR are co-activated by CBP-p300, and in fact overexpression of CBP or p300 reverses the antagonism between Activator Protein-1 and the GR. Similarly, overexpression of CBP or SRC1 reverses the transcriptional antagonism between the GR and NF-KappaB (Ref.8 & 12). Glucocorticoids downregulate cell proliferation by decreasing the expression of Cyclin-D1 and the phosphorylation of Rb (Retinoblastoma) protein and by activating p21(CIP1) (Cyclin Dependent Kinase Inhibitor-p21). The antiproliferative effect of Glucocorticoids is mediated by the GR and CEBP-Alpha, and both active transcription factors are required to induce the synthesis of p21(CIP1). In human cells, including lung fibroblasts, pulmonary and bronchial smooth-muscle cells, and peripheral-blood lymphocytes, the GR forms a complex with CEBP-Alpha, which then binds to the CCAAT DNA consensus sequence in the p21(CIP1) promoter (Ref.13). The Glucocorticoid signaling interacts with other signaling pathways activated by various cytokines, thus regulating diverse biological processes through modulating the expression of target genes. GR represses TGF- transcriptional activation of the PAI-1 (Plasminogen Activator Inhibitor-1) and other genes in a ligand-dependent manner. Glucocorticoids inhibit the TGF--induced expression of ECM (Extracellular Matrix) proteins including Fibronectin and Collagen, and proteinase inhibitors such as tissue inhibitors of Metalloproteinase. GR inhibits transcriptional activation by both Smad3 and Smad4 C-terminal activation domains (Ref.14). The MAPKs (Mitogen-Activated Protein Kinases) play a key role in inflammatory cell types through transducing the response from proinflammatory cytokine receptors to the transcriptional apparatus. MAPK subgroups such as JNK regulate activation of the AP-1 complex required for proinflammatory gene expression. The MAPK p38 subgroup regulates the stability of mRNAs that encode the proinflammatory molecules TNFAlpha, IL-6, IL-8, and VEGF (Vascular Endothelial Growth Factor). Negative regulation of the MAPK family by Glucocorticoids may be an additional mechanism by which the GR exerts its antiinflammatory effects (Ref.15). The MAPK subgroups JNK, ERK1, ERK2, and p38 are all targets of negative regulation by activated GRs. For example, Glucocorticoids destabilize the mRNA of the proinflammatory enzyme COX2 (Cyclooxygenase-2) by inhibiting the activity of p38 (Ref.16). The GR represses the MAPK family by inhibiting the phosphorylation step required for their activation. The defined molecular mechanism behind this inhibition has not been fully characterized and may be cell type and stimulus specific (Ref.9). The therapeutic and prophylactic use of Glucocorticoids is widespread due to their powerful antiinflammatory, antiproliferative and immunomodulatory activity (Ref.17). These are widely prescribed anti-inflammatory drugs, used to treat a wide variety of inflammatory diseases, including allergies, asthma, rheumatoid arthritis, and auto-immune diseases. Glucocorticoids enhance the production of other anti-inflammatory molecules such as IL-1RA (Interleukin-1 Receptor Antagonist), IL-10 (Interleukin-10), secretory leukocyte inhibitory protein and neutral endopetidase (Ref.2). Glucocorticoids are important mediators of the immune system and modulate the biological activities of inflammatory cytokines. The very effective control of airway inflammation exerted by Glucocorticoids in asthma is largely mediated by inhibition of the transcriptional activity of several different genes encoding pro-inflammatory proteins such as cytokines (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-11, IL-13, TNF-Alpha, GMCSF, IFN-Gamma), chemokines (IL-8, RANTES, MIP-1a, MCP-1, MCP-3, MCP-4, Eotaxin), adhesion molecules (ICAM1, VCAM1, E-Selectin), and mediator-synthesizing enzymes (i-NOS, COX2, cytoplasmic PLA2) (Ref.9, 10 & 16). Glucocorticoids, acting through the GR, potently modulate immune function and are a mainstay of therapy for treatment of inflammatory conditions including allergies, asthma, rheumatoid arthritis; autoimmune diseases, leukemias and lymphomas (Ref.3). Common

Glucocorticoids include prednisone, dexamethasone, and hydrocortisone. Hydrocortisone is used as an anti-inflammatory in the treatment of arthritis, as well as other inflammatory conditions such as dermatitis and autoimmune disease. While Glucocorticoids are widely used as drugs to treat various inflammatory conditions, prolonged Glucocorticoid use may have adverse side effects such as immunosuppression, fluid shifts, brain changes, and psychological changes. Physicians are therefore very cautious about prescribing these medications, especially for long periods of time. The search for novel Glucocorticoids with reduced side effects has been intensified by the discovery of new molecular details regarding the function of the Glucocorticoid receptor. These new insights may pave the way for novel, safer therapies that retain the efficacy of currently prescribed steroids (Ref.18). References: 1. Ashwell JD,Lu FW,Vacchio MS. Glucocorticoids in T cell development and function. Annu Rev Immunol. 2000;18:309-45. Review. 2. Schaaf MJ,Cidlowski JA. Molecular mechanisms of glucocorticoid action and resistance. J Steroid Biochem Mol Biol. 2002 Dec;83(1-5):37-48. Review. 3. Pelaia G,Vatrella A,Cuda G,Maselli R,Marsico SA. Molecular mechanisms of corticosteroid actions in chronic inflammatory airway diseases. Life Sci. 2003 Feb 21;72(14):1549-61. Review. 4. Davies TH,Ning YM,Sanchez ER. Differential control of Glucocorticoid receptor hormone-binding function by tetratricopeptide repeat (TPR) proteins and the immunosuppressive ligand FK506. Biochemistry. 2005 Feb 15;44(6):2030-8. 5. Tian S,Poukka H,Palvimo JJ,Janne OA. Small ubiquitin-related modifier-1 (SUMO-1) modification of the Glucocorticoid receptor. Biochem J. 2002 Nov 1;367(Pt 3):907-11. 6. Ruegg J,Holsboer F,Turck C,Rein T. Cofilin 1 is revealed as an inhibitor of Glucocorticoid receptor by analysis of hormone-resistant cells. Mol Cell Biol. 2004 Nov;24(21):9371-82. 7. Grenier J,Trousson A,Chauchereau A,Amazit L,Lamirand A,Leclerc P,Guiochon-Mantel A,Schumacher M,Massaad C. Selective recruitment of p160 coactivators on Glucocorticoid-regulated promoters in Schwann cells. Mol Endocrinol. 2004 Dec;18(12):2866-79. 8. Schoneveld OJ,Gaemers IC,Lamers WH. Mechanisms of Glucocorticoid signalling. Biochim Biophys Acta. 2004 Oct 21;1680(2):114-28. Review. 9. Stellato C. Post-transcriptional and nongenomic effects of Glucocorticoids. Proc Am Thorac Soc. 2004;1(3):255-63. Review. 10. Bladh LG,Liden J,Pazirandeh A,Rafter I,Dahlman-Wright K,Nilsson S,Okret S. Identification of target genes involved in the antiproliferative effect of Glucocorticoids reveals a role for nuclear factor-(kappa)B repression. Mol Endocrinol. 2005 Mar;19(3):632-43.

11. Berg T,Didon L,Barton J,Andersson O,Nord M. Glucocorticoids increase C/EBPbeta activity in the lung epithelium via phosphorylation. Biochem Biophys Res Commun. 2005 Aug 26;334(2):638-45. 12. Cascallana JL,Bravo A,Donet E,Leis H,Lara MF,Paramio JM,Jorcano JL,Perez P. Ectoderm-targeted overexpression of the Glucocorticoid receptor induces hypohidrotic ectodermal dysplasia. Endocrinology. 2005 Jun;146(6):2629-38. 13. Roth M,Johnson PR,Borger P,Bihl MP,Rudiger JJ,King GG,Ge Q,Hostettler K,Burgess JK,Black JL,Tamm M. Dysfunctional interaction of C/EBPalpha and the Glucocorticoid receptor in asthmatic bronchial smooth-muscle cells. N Engl J Med. 2004 Aug 5;351(6):560-74. 14. Li G,Wang S,Gelehrter TD. Identification of Glucocorticoid receptor domains involved in transrepression of transforming growth factor-beta action. J Biol Chem. 2003 Oct 24;278(43):41779-88. 15. Bruna A,Nicolas M,Munoz A,Kyriakis JM,Caelles C. Glucocorticoid receptor-JNK interaction mediates inhibition of the JNK pathway by Glucocorticoids. EMBO J. 2003 Nov 17;22(22):6035-44. 16. Brewer JA,Khor B,Vogt SK,Muglia LM,Fujiwara H,Haegele KE,Sleckman BP,Muglia LJ. T-cell glucocorticoid receptor is required to suppress COX-2-mediated lethal immune activation. Nat Med. 2003 Aug 31 [Epub ahead of print] 17. Miner JN,Hong MH,Negro-Vilar A. New and improved Glucocorticoid receptor ligands. Expert Opin Investig Drugs. 2005 Dec;14(12):1527-45. 18. Rosen J,Miner JN. The search for safer Glucocorticoid receptor ligands. Endocr Rev. 2005 May;26(3):452-64.

Development_Glucocorticoid receptor signaling

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Object list (links open in MetaCore):

p23 co-chaperone, NCOA2 (GRIP1/TIF2), GCR-beta, GCR-alpha, GCR-alpha, c-Jun/c-Fos, TGF-beta receptor type I, HSP90, NF-kB, Oct-1, FKBP4, SMAD3, C/EBPbeta, HSP70, PAI1, E2I, p300, NCOA1 (SRC1), MMP-13, SUMO-1, NFKBIA, CBP, glucocorticoids, Oct-2, STAT5

Description:
Glucocorticoid receptor signaling Glucocorticoids contribute to the maintenance of basal and stress-related homeostasis in all higher organisms. Glucocorticoids and their synthetic derivatives work through the nuclear Receptor subfamily 3 group C member 1 (glucocorticoid receptor) ( GCR ). GCR is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. GCR mediates transactivation of target genes by binding glucocorticoid response elements in their promoter region. The GCR gene encodes two splicing variants, GCR-alpha and GCR-beta [1], [2]. The GCR must be bound to the protein chaperone Heat shock protein 90kDa ( HSP90 ) in order to acquire the high affinity steroid binding conformation [3]. Unligated cytoplasmic GCR exists as a heteromeric complex that contains a dimer of HSP90, an immunophilin protein of the FK506 binding protein family (for example, FK506 binding protein 4, 59kDa ( FKBP4 )), and Prostaglandin E synthase 3 ( p23 co-chaperone ). Other immunophilins or heat shock proteins (for example, HSP70 ) that are found associated with unliganded steroid receptors are likely to

be involved in the maturation of the receptor to its hormone-binding conformation. Also, probably HSP90 and HSP70 play role in regulation of nuclear trafficking of GCR [4]. GCR is covalently modified by SMT3 suppressor of mif two 3 homolog 1 ( SUMO-1 ). Sumoylation influences GCR function. SUMO-1 overexpression induces GCR degradation. Also SUMO-1 stimulates the transactivation capacity of GCR [5], [6]. GCR sumoylation may also regulate negatively transcriptional activity of Jun oncogene ( c-Jun ) [5]. Ubiquitinconjugating enzyme E2I ( E2I ) binds SUMO and can interact with SUMO noncovalently. The noncovalent interaction promotes the formation of short SUMO chains on targets and so promotes its activity [7]. Also E2I binds to GCR. E2I displays no intrinsic transactivation activity. However, it modifies both the absolute amount of induced gene product, and the fold induction by GCR. With high concentrations of GCR, added E2I also reduces the EC50 of agonists and increases the partial agonist activity of antagonists [8] GCR interacts with Nuclear receptor coactivator 1 and 2 ( NCOA1 (SRC1) and ( NCOA2 (GRIP1/TIF2) ), that acts as corepressors [9]. GCR and corepressor NCOA2 inhibit Activator protein 1 ( AP-1 ) and so induce AP-1 -mediated gene expression, for example Matrix metallopeptidase 13 ( MMP-13 ). The repression is not dependent on AP-1 subunits composition, for example Jun oncogene/v-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Jun/c-Fos ) [10], [11]. GCR inhibits Transforming growth factor beta ( TGF-beta ) signaling by directly targeting the transcriptional activation function of SMAD family member 3 ( SMAD3 ) [12], [11] in conjunction with NCOA1 and NCOA2 [9]. Thus, for example, GCR can prevent TGF -dependent SMAD3 -mediated Serpin peptidase inhibitor clade E member 1 ( PAI1 ) expression [12]. Also GCR-alpha inhibits gene expression via supression of Nuclear factor kappaB ( NF-kB ) activity [11]. GCR-alpha binding to NF-kB leads to inactivation of both proteins [13]. GCRalpha also can induce transcription of Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha ( NFKBIA ), a NF-kB inhibitor [14], [15], [16]. GCR can interact productively with the POU class 2 homeobox 1 and 2 ( Oct-1 and Oct-2 ) proteins to recruit them to DNA and this contributes to activation of transcription by Oct from glucocorticoid-responsive promoters [17], [18]. Activated GCR forms a complex with Signal transducer and activator of transcription 5 ( STAT5 ) and enhances STAT5 -mediated transcriptional induction [19]. GCR increases DNAbinding activity of CCAAT/enhancer binding protein beta ( C/EBPbeta ) [20]. GCR interacts with CREB binding protein ( CBP ) and E1A binding protein p300 ( p300 ) and competes with their transcription factors [21], [15]. GCR-beta has been shown to inhibit the effects of hormone-activated GCR-alpha on a glucocorticoid-responsive reporter gene in a concentration-dependent manner due to competition for glucocorticoid response element target sites [22].

References:

1. Yudt MR, Cidlowski JA The glucocorticoid receptor: coding a diversity of proteins and responses through a single gene. Molecular endocrinology (Baltimore, Md.) 2002 Aug;16(8):1719-26 2. Chrousos GP, Kino T Intracellular glucocorticoid signaling: a formerly simple system turns stochastic. Science's STKE : signal transduction knowledge environment 2005 Oct 4;2005(304):pe48 3. Xu M, Dittmar KD, Giannoukos G, Pratt WB, Simons SS Jr Binding of hsp90 to the glucocorticoid receptor requires a specific 7-amino acid sequence at the amino terminus of the hormone-binding domain. The Journal of biological chemistry 1998 May 29;273(22):13918-24 4. Defranco DB Role of molecular chaperones in subnuclear trafficking of glucocorticoid receptors. Kidney international 2000 Apr;57(4):1241-9 5. Tian S, Poukka H, Palvimo JJ, Janne OA Small ubiquitin-related modifier-1 (SUMO-1) modification of the glucocorticoid receptor. The Biochemical journal 2002 Nov 1;367(Pt 3):907-11 6. Le Drean Y, Mincheneau N, Le Goff P, Michel D Potentiation of glucocorticoid receptor transcriptional activity by sumoylation. Endocrinology 2002 Sep;143(9):3482-9 7. Knipscheer P, van Dijk WJ, Olsen JV, Mann M, Sixma TK Noncovalent interaction between Ubc9 and SUMO promotes SUMO chain formation. The EMBO journal 2007 Jun 6;26(11):2797-807 8. Kaul S, Blackford JA Jr, Cho S, Simons SS Jr Ubc9 is a novel modulator of the induction properties of glucocorticoid receptors. The Journal of biological chemistry 2002 Apr 12;277(15):12541-9 9. Li G, Heaton JH, Gelehrter TD ROLE OF STEROID RECEPTOR COACTIVATORS IN GLUCOCORTICOID AND TGF{beta} REGULATION OF PAI-1 GENE EXPRESSION. Molecular endocrinology (Baltimore, Md.) 2006 Jan 19; 10. Rogatsky I, Zarember KA, Yamamoto KR Factor recruitment and TIF2/GRIP1 corepressor activity at a collagenase-3 response element that mediates regulation by phorbol esters and hormones. The EMBO journal 2001 Nov 1;20(21):6071-83 11. Pelaia G, Vatrella A, Cuda G, Maselli R, Marsico SA Molecular mechanisms of corticosteroid actions in chronic inflammatory airway diseases. Life sciences 2003 Feb 21;72(14):1549-61 12. Song CZ, Tian X, Gelehrter TD Glucocorticoid receptor inhibits transforming growth factor-beta signaling by directly targeting the transcriptional activation function of Smad3. Proceedings of the National Academy of Sciences of the United States of America 1999 Oct 12;96(21):11776-81 13. McKay LI, Cidlowski JA Cross-talk between nuclear factor-kappa B and the steroid hormone receptors: mechanisms of mutual antagonism. Molecular endocrinology (Baltimore, Md.) 1998 Jan;12(1):45-56

14. Deroo BJ, Archer TK Glucocorticoid receptor activation of the I kappa B alpha promoter within chromatin. Molecular biology of the cell 2001 Nov;12(11):3365-74 15. Almawi WY, Melemedjian OK Molecular mechanisms of glucocorticoid antiproliferative effects: antagonism of transcription factor activity by glucocorticoid receptor. Journal of leukocyte biology 2002 Jan;71(1):9-15 16. Luecke HF, Yamamoto KR The glucocorticoid receptor blocks P-TEFb recruitment by NFkappaB to effect promoterspecific transcriptional repression. Genes & development 2005 May 1;19(9):1116-27 17. Prefontaine GG, Lemieux ME, Giffin W, Schild-Poulter C, Pope L, LaCasse E, Walker P, Hache RJ Recruitment of octamer transcription factors to DNA by glucocorticoid receptor. Molecular and cellular biology 1998 Jun;18(6):3416-30 18. Wang JM, Prefontaine GG, Lemieux ME, Pope L, Akimenko MA, Hache RJ Developmental effects of ectopic expression of the glucocorticoid receptor DNA binding domain are alleviated by an amino acid substitution that interferes with homeodomain binding. Molecular and cellular biology 1999 Oct;19(10):7106-22 19. Engblom D, Kornfeld JW, Schwake L, Tronche F, Reimann A, Beug H, Hennighausen L, Moriggl R, Schutz G Direct glucocorticoid receptor-Stat5 interaction in hepatocytes controls body size and maturation-related gene expression. Genes & development 2007 May 15;21(10):1157-62 20. Berg T, Didon L, Barton J, Andersson O, Nord M Glucocorticoids increase C/EBPbeta activity in the lung epithelium via phosphorylation. Biochemical and biophysical research communications 2005 Aug 26;334(2):638-45 21. Almlof T, Wallberg AE, Gustafsson JA, Wright AP Role of important hydrophobic amino acids in the interaction between the glucocorticoid receptor tau 1-core activation domain and target factors. Biochemistry 1998 Jun 30;37(26):9586-94 22. Bamberger CM, Bamberger AM, de Castro M, Chrousos GP Glucocorticoid receptor beta, a potential endogenous inhibitor of glucocorticoid action in humans. The Journal of clinical investigation 1995 Jun;95(6):2435-41