Development - Glucocorticoid receptor signaling

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]. Ubiquitin-conjugating 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) [11], [12] 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]. GCR-alpha 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 DNA-binding 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 [15], [21].

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 transforming growth factor beta regulation of plasminogen activator inhibitor gene expression. Molecular endocrinology (Baltimore, Md.) 2006 May;20(5):1025-34
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 promoter-specific 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