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Glucocorticoid receptor - Wikipedia, the free encyclopedia

Glucocorticoid receptor

From Wikipedia, the free encyclopedia


Nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)
Crystallographic structures of the glucocorticoid receptor DNA binding domain (DBD, left, PDB 1R4O bound to DNA) and ligand binding domain [LBD, right, 1M2Z bound to dexamethasone (white sticks) and the TIF2 coactivator protein (red)]. Dashed yellow lines represent hydrogen bonding interactions between the receptor and ligand. The 2D structure of dexamethasone is also depicted in the lower right hand side of the picture for reference.
Available structures: 1gdc, 1glu, 1m2z, 1nhz, 1p93, 1r4o, 1r4r, 1rgd, 2gda
Identifiers
Symbol(s) NR3C1; GCCR; GCR; GR; GRL
External IDs OMIM: 138040 MGI: 95824 HomoloGene: 30960
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 2908 14815
Ensembl ENSG00000113580 ENSMUSG00000024431
Uniprot P04150 Q05DD1
Refseq NM_000176 (mRNA)
NP_000167 (protein)		 NM_008173 (mRNA)
NP_032199 (protein)
Location Chr 5: 142.64 - 142.8 Mb Chr 18: 39.54 - 39.62 Mb
Pubmed search [1] [2]

The glucocorticoid receptor (GR, or GCR) also known as NR3C1 (nuclear receptor subfamily 3, group C, member 1) is a ligand-activated transcription factor that binds with high affinity to cortisol and other glucocorticoids.[1]

The GR is expressed in almost every cell in the body and regulates either directly or indirectly genes controlling a wide variety of processes including the development, metabolism, and immune response of the organism.

The GR protein is encoded by gene NR3C1 on chromosome 5 (5q31).

Contents

[edit] Structure

Like the other steroid receptors,[2] the glucocorticoid receptor is modular in structure[3] and contains the following domains (labeled A - F):

[edit] Ligand binding and response

In the absence of hormone, the glucocorticoid receptor (GR) resides in the cytosol complexed with a variety of proteins including heat shock protein 90 (hsp90), the heat shock protein 70 (hsp70) and the protein FKBP52 (FK506-binding protein 52).[4] The endogenous glucocortiod hormone cortisol diffuses through the cell membrane into the cytoplasm and binds to the glucocorticoid receptor (GR) resulting in release of the heat shock proteins. The resulting activated form GR has two principle mechanisms of action, transactivation and transrepression[5][6], described below.

[edit] Transactivation

A direct mechanism of action involves homodimerization of the receptor, translocation via active transport into the nucleus, and binding to specific DNA responsive elements activating gene transcription. This mechanism of action is referred to as transactivation. The biologic response depends on the cell type.

[edit] Transrepression

In the absence of activated GR, other transcription factors such as NF-κB or AP-1 themselves are able to transactivate target genes. However activated GR can complex with these other transcription factors and prevent them from binding their target genes and hence repress the expression of genes that are normally upregulated by NF-κB or AP-1. This indirect mechanism of action is referred to as transrepression.

[edit] Agonists and antagonists

Dexamethasone is an agonist, and RU486 and cyproterone are antagonists of the GR. Also, progesterone and DHEA have antagonist effects on the GR.

The GR is abnormal in familial glucocorticoid resistance.[7]

[edit] References

  1. ^ Lu NZ, Wardell SE, Burnstein KL, Defranco D, Fuller PJ, Giguere V, Hochberg RB, McKay L, Renoir JM, Weigel NL, Wilson EM, McDonnell DP, Cidlowski JA (2006). "International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors". Pharmacol Revl 58 (4): 782–97. doi:10.1124/pr.58.4.9. PMID 17132855. 
  2. ^ Kumar R, Thompson EB (1999). "The structure of the nuclear hormone receptors". Steroids 64 (5): 310–9. doi:10.1016/S0039-128X(99)00014-8. PMID 10406480. 
  3. ^ Kumar R, Thompson EB (2005). "Gene regulation by the glucocorticoid receptor: structure:function relationship". J. Steroid Biochem. Mol. Biol. 94 (5): 383–94. doi:10.1016/j.jsbmb.2004.12.046. PMID 15876404. 
  4. ^ Pratt WB, Morishima Y, Murphy M, Harrell M (2006). "Chaperoning of glucocorticoid receptors". Handb Exp Pharmacol 172: 111–38. PMID 16610357. 
  5. ^ Buckingham JC (2006). "Glucocorticoids: exemplars of multi-tasking". Br J Pharmacol 147 (Supplement 1): S258–68. doi:10.1038/sj.bjp.0706456. PMID 16402112. 
  6. ^ Hayashi R, Wada H, Ito K, Adcock IM (2004). "Effects of glucocorticoids on gene transcription". Eur J Pharmacol 500 (1-3): 51–62. doi:10.1016/j.ejphar.2004.07.011. PMID 15464020. 
  7. ^ Mendonca B, Leite M, de Castro M, Kino T, Elias L, Bachega T, Arnhold I, Chrousos G, Latronico A (2002). "Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene". J Clin Endocrinol Metab 87 (4): 1805–9. doi:10.1210/jc.87.4.1805. PMID 11932321. 

[edit] Further reading

  • Adcock IM, Ito K (2000). "Molecular mechanisms of corticosteroid actions.". Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace / Fondazione clinica del lavoro, IRCCS [and] Istituto di clinica tisiologica e malattie apparato respiratorio, Università di Napoli, Secondo ateneo 55 (3): 256–66. PMID 10948677. 
  • Chikanza IC (2002). "Mechanisms of corticosteroid resistance in rheumatoid arthritis: a putative role for the corticosteroid receptor beta isoform.". Ann. N. Y. Acad. Sci. 966: 39–48. PMID 12114257. 
  • Neeck G, Kluter A, Dotzlaw H, Eggert M (2002). "Involvement of the glucocorticoid receptor in the pathogenesis of rheumatoid arthritis.". Ann. N. Y. Acad. Sci. 966: 491–5. PMID 12114309. 
  • Yudt MR, Cidlowski JA (2003). "The glucocorticoid receptor: coding a diversity of proteins and responses through a single gene.". Mol. Endocrinol. 16 (8): 1719–26. PMID 12145329. 
  • Torrego A, Pujols L, Picado C (2003). "[Response to glucocorticoid treatment in asthma. The role of alpha and beta isoforms of the glucocorticoid receptor]". Arch. Bronconeumol. 38 (9): 436–40. PMID 12237016. 
  • Bray PJ, Cotton RG (2003). "Variations of the human glucocorticoid receptor gene (NR3C1): pathological and in vitro mutations and polymorphisms.". Hum. Mutat. 21 (6): 557–68. doi:10.1002/humu.10213. PMID 12754700. 
  • Kino T, Pavlakis GN (2004). "Partner molecules of accessory protein Vpr of the human immunodeficiency virus type 1.". DNA Cell Biol. 23 (4): 193–205. doi:10.1089/104454904773819789. PMID 15142377. 
  • Lu NZ, Cidlowski JA (2004). "The origin and functions of multiple human glucocorticoid receptor isoforms.". Ann. N. Y. Acad. Sci. 1024: 102–23. doi:10.1196/annals.1321.008. PMID 15265776. 
  • Kino T, Chrousos GP (2004). "Human immunodeficiency virus type-1 accessory protein Vpr: a causative agent of the AIDS-related insulin resistance/lipodystrophy syndrome?". Ann. N. Y. Acad. Sci. 1024: 153–67. doi:10.1196/annals.1321.013. PMID 15265780. 
  • Andersen JL, Planelles V (2005). "The role of Vpr in HIV-1 pathogenesis.". Curr. HIV Res. 3 (1): 43–51. PMID 15638722. 
  • Le Rouzic E, Benichou S (2006). "The Vpr protein from HIV-1: distinct roles along the viral life cycle.". Retrovirology 2: 11. doi:10.1186/1742-4690-2-11. PMID 15725353. 
  • Muthumani K, Choo AY, Premkumar A, et al. (2006). "Human immunodeficiency virus type 1 (HIV-1) Vpr-regulated cell death: insights into mechanism.". Cell Death Differ. 12 Suppl 1: 962–70. doi:10.1038/sj.cdd.4401583. PMID 15832179. 
  • Zhou J, Cidlowski JA (2005). "The human glucocorticoid receptor: one gene, multiple proteins and diverse responses.". Steroids 70 (5-7): 407–17. doi:10.1016/j.steroids.2005.02.006. PMID 15862824. 
  • Chrousos GP, Kino T (2006). "Intracellular glucocorticoid signaling: a formerly simple system turns stochastic.". Sci. STKE 2005 (304): pe48. doi:10.1126/stke.3042005pe48. PMID 16204701. 
  • Plotkin LL, Labutin AL, Lebedev LV, et al. (1975). "[Balloon probe for the removal of emboli and thrombi]". Meditsinskaia tekhnika (3): 42–3. PMID 1152650. 
  • Subramaniam M, Colvard D, Keeting PE, et al. (1993). "Glucocorticoid regulation of alkaline phosphatase, osteocalcin, and proto-oncogenes in normal human osteoblast-like cells.". J. Cell. Biochem. 50 (4): 411–24. doi:10.1002/jcb.240500410. PMID 1469072. 
  • Scherrer LC, Pratt WB (1992). "Association of the transformed glucocorticoid receptor with a cytoskeletal protein complex.". J. Steroid Biochem. Mol. Biol. 41 (3-8): 719–21. PMID 1562545. 
  • Cadepond F, Gasc JM, Delahaye F, et al. (1992). "Hormonal regulation of the nuclear localization signals of the human glucocorticosteroid receptor.". Exp. Cell Res. 201 (1): 99–108. PMID 1612132. 
  • Hurley DM, Accili D, Stratakis CA, et al. (1991). "Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance.". J. Clin. Invest. 87 (2): 680–6. PMID 1704018. 
  • Encío IJ, Detera-Wadleigh SD (1991). "The genomic structure of the human glucocorticoid receptor.". J. Biol. Chem. 266 (11): 7182–8. PMID 1707881. 

[edit] See also

Chrousos Syndrome or Sporadic /Familial Glucocorticoid (Cortisol) Resistance


[edit] External links

v • d • e
Corticosteroids - glucocorticoid/receptor and mineralocorticoid/receptor
(A07EA, C05AA, D07, D10AA, H02, R01AD, R03BA, S01BA, S02B, and S03B)
Endogenous
Others
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v • d • e
Transcription factors and intracellular receptors
(1) Basic domains
(1.1) Basic leucine zipper (bZIP)
Activating transcription factor (AATF, 1, 2, 3, 4, 5, 6, 7) • AP-1 (c-Fos, FOSB, FOSL1, FOSL2, c-Jun, JUNB, JUND) • BACH (1, 2) • BATF • BLZF1 • C/EBP (α, β, γ, δ, ε, ζ) • CREB (1, 3, L1) • CREM • DBP • DDIT3 • GABPA • HLF • MAF (B, F, G, K) • NFE (2, L1, L2) • NRL • NRF1 • XBP1
(1.2) Basic helix-loop-helix (bHLH)
ATOH1 • AhR • AHRR • ARNT • ASCL1 • BHLHB2 • BMAL (ARNTL, ARNTL2) • CLOCK • EPAS1 • HAND (1, 2) • HES (5, 6) • HEY (1, 2, L) • HES1 • HIF (1A, 3A) • ID (1, 2, 3, 4) • LYL1 • MXD4 • MYCL1 • MYCN • Myogenic regulatory factors (MyoD, Myogenin, MYF5, MYF6) • Neurogenins • NeuroD (1, 2) • NPAS (1, 2, 3) • OLIG (1, 2) • Scleraxis • TAL1 • Twist • USF1
(1.3) bHLH-ZIP
MAX • MITF • MNT • MLX • MXI1 • Myc • SREBP (1, 2)
(1.6) Basic helix-span-helix (bHSH)
(2) Zinc finger
DNA-binding domains
(2.1) Nuclear receptor (Cys4)
subfamily 1 (Thyroid hormone (α, β), CAR, FXR, LXR (α, β), PPAR (α, β/δ, γ), PXR, RAR (α, β, γ), ROR (α, β, γ), Rev-ErbA (α, β), VDR) • subfamily 2 (COUP-TF (I, II), Ear-2, HNF4 (α, γ), PNR, RXR (α, β, γ), Testicular receptor (2, 4), TLX) • subfamily 3 (Steroid hormone (Estrogen (α, β), Estrogen related (α, β, γ), Androgen, Glucocorticoid, Mineralocorticoid, Progesterone)) • subfamily 4 NUR (NGFIB, NOR1, NURR1) • subfamily 5 (LRH-1, SF1) • subfamily 6 (GCNF) • subfamily 0 (DAX1, SHP)
(2.2) Other Cys4
GATA (1, 2, 3, 4, 5, 6) • MTA (1, 2, 3)
(2.3) Cys2His2
ATBF1 • BCL(6, 11A, 11B) • CTCF • E4F1 • EGR (2, 3) • ERV3 • General transcription factors (TFIIA, TFIIB, TFIID, TFIIE, TFIIF: 1, 2, TFIIH: 1, 2, 4, 2I, 3A, 3C1, 3C2) • GFI1 • GLI-Krüppel family (1, 2, 3, YY1) • HIC (1, 2) • HIVEP (1, 2, 3) • IKZF (1, 2, 3) • ILF (2, 3) • KLF (2, 4, 5, 6, 9, 10, 11, 12, 13) • MTF1 • MYT1 • OSR1 • Sp1 • zinc finger ((3, 7, 9, 10, 19, 22, 24, 33B, 34, 35, 41, 43, 44, 51, 74, 143, 146, 148, 165, 202, 217, 219, 238, 239, 259, 267, 268, 281, 295, 318, 330, 346, 350, 365, 366, 384, 451, 452, 471, 593, 638, 649, 655) • Zbtb7 (7A) • ZBT (16, 17, 33)
(2.4) Cys6
(2.5) Alternating composition
AIRE • DIDO1 • GRLF1 • ING (1, 2, 4) • JARID (1A, 1B, 1C, 1D, 2) • JMJD1B
(3) Helix-turn-helix
domains
ARX • CDX (1, 2) • CRX • CUTL1 • DLX (3, 4, 5) • EMX2 • EN (1, 2) • FHL (1, 2, 3) • HESX1 • HHEX • HLX • Homeobox (A1, A3, A4, A5, A7, A9, A10, A11, A13, B1, B2, B3, B4, B5, B6, B7, B8, B9, B13, C4, C5, C6, C8, C9, C10, C11, C13, D1, D3, D4, D8, D9, D10, D11, D12, D13) • HOPX • MEIS (1, 2) • MEOX2 • MNX1 • MSX (1, 2) • NANOG • NKX (2-1, 2-5, 3-1) • PHF (3, 6, 10, 17) • POU domain (PIT-1, BRN-3: 1, 2, Octamer transcription factor: 1, 2, 3/4, 6, 7) • OTX (1, 2) • PDX1
(3.2) Paired box
PAX (1, 2, 3, 4, 5, 6, 7, 8, 9)
E2F (1, 2, 3, 4, 5) • FOX proteins (C1, C2, E1, G1, H1, K2, L2, M1, N3, O1A, , O3A, O4, P1, P2, P3)
HSF (1, 2, 4)
(3.5) Tryptophan clusters
ELF (4, 5) • EGF • ELK (1, 3, 4) • ERF • ERG • ETS (1, 2) • ETV (1, 4, 5, 6) • FLI1 • Interferon regulatory factors (1, 2, 3, 4, 5, 6, 7, 8) • MYB • MYBL2
(3.6) TEA domain
transcriptional enhancer factor 1, 2
(4) β-Scaffold factors with
minor groove contacts
(4.1) Rel homology region
NF-κB (NFKB1, NFKB2, REL, RELA, RELB) • NFAT (C1, C2, C3, C4, 5)
(4.2) STAT
STAT (1, 2, 3, 4, 5, 6)
(4.3) p53
(4.4) MADS box
Mef2 (A, B, C, D) • SRF
HNF (1A, 1B) • LEF1 • SOX (2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 15, 18) • SRY • SSRP1
(4.10) Cold-shock domain
(4.11) Runt
(0) Other
transcription factors
(0.2) HMGI(Y)
HMGA (1, 2) • HBP1
Rb • RBL1 • RBL2
(0.5) AP-2/EREBP-related factors
Apetala 2 • EREBP • B3
(0.6) Miscellaneous
ARID (1A, 1B, 2, 3A, 3B, 4A) • CAP • IFI (16, 35) • MLL (2, 3, T1) • MNDA • NFI (A, B, C, X) • NFY (A, B, C) • Rho/Sigma • R-SMAD
Languages


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