RBCC Red Blood Cell Collection

NR3C1 (GRL) [Confidence: low (only semi-automatic identification from reviews)]
Glucocorticoid receptor; GR (Nuclear receptor subfamily 3 group C member 1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P04150
ID GCR_HUMAN Reviewed; 777 AA.
AC P04150; A0ZXF9; B0LPG8; D3DQF4; P04151; Q53EP5; Q6N0A4;
DT 01-NOV-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1986, sequence version 1.
DT 22-JAN-2014, entry version 201.
DE RecName: Full=Glucocorticoid receptor;
DE Short=GR;
DE AltName: Full=Nuclear receptor subfamily 3 group C member 1;
GN Name=NR3C1; Synonyms=GRL;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS ALPHA AND BETA).
RC TISSUE=Fibroblast;
RX PubMed=2867473; DOI=10.1038/318635a0;
RA Hollenberg S.M., Weinberger C., Ong E.S., Cerelli G., Oro A., Lebo R.,
RA Thompson E.B., Rosenfeld M.G., Evans R.M.;
RT "Primary structure and expression of a functional human glucocorticoid
RT receptor cDNA.";
RL Nature 318:635-641(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS ALPHA AND BETA).
RX PubMed=1707881;
RA Encio I.J., Detera-Wadleigh S.D.;
RT "The genomic structure of the human glucocorticoid receptor.";
RL J. Biol. Chem. 266:7182-7188(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=20843780; DOI=10.1093/nar/gkq750;
RA Wang W., Shen P., Thiyagarajan S., Lin S., Palm C., Horvath R.,
RA Klopstock T., Cutler D., Pique L., Schrijver I., Davis R.W.,
RA Mindrinos M., Speed T.P., Scharfe C.;
RT "Identification of rare DNA variants in mitochondrial disorders with
RT improved array-based sequencing.";
RL Nucleic Acids Res. 39:44-58(2011).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 10).
RX PubMed=17404046; DOI=10.1196/annals.1397.037;
RA Turner J.D., Schote A.B., Keipes M., Muller C.P.;
RT "A new transcript splice variant of the human glucocorticoid receptor:
RT identification and tissue distribution of hGR Delta 313-338, an
RT alternative exon 2 transactivation domain isoform.";
RL Ann. N. Y. Acad. Sci. 1095:334-341(2007).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ALPHA-2).
RC TISSUE=Osteosarcoma;
RA Munroe D.G., Pang J., Taylor G.R., Lau C., Plante R.K., Zhou L.;
RT "Alternative splicing within the DNA binding domain creates a novel
RT isoform of the human glucocorticoid receptor.";
RL Submitted (SEP-1993) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ALPHA).
RC TISSUE=Kidney;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ALPHA).
RC TISSUE=Uterine endothelium;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LYS-23 AND VAL-65.
RG NIEHS SNPs program;
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G;);
RL Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ALPHA).
RC TISSUE=Placenta;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [13]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-394.
RX PubMed=2026589;
RA Leclerc S., Xie B.X., Roy R., Govindan M.V.;
RT "Purification of a human glucocorticoid receptor gene promoter-binding
RT protein. Production of polyclonal antibodies against the purified
RT factor.";
RL J. Biol. Chem. 266:8711-8719(1991).
RN [14]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-394.
RX PubMed=1958537; DOI=10.1016/0960-0760(91)90197-D;
RA Govindan M.V., Pothier F., Leclerc S., Palaniswami R., Xie B.;
RT "Human glucocorticoid receptor gene promotor-homologous down
RT regulation.";
RL J. Steroid Biochem. Mol. Biol. 40:317-323(1991).
RN [15]
RP DOMAINS.
RX PubMed=3841189; DOI=10.1038/318670a0;
RA Weinberger C., Hollenberg S.M., Rosenfeld M.G., Evans R.M.;
RT "Domain structure of human glucocorticoid receptor and its
RT relationship to the v-erb-A oncogene product.";
RL Nature 318:670-672(1985).
RN [16]
RP ALTERNATIVE SPLICING (ISOFORMS GP-P; GP-A ALPHA AND GP-A BETA).
RX PubMed=8358712;
RA Moalli P.A., Pillay S., Krett N.L., Rosen S.T.;
RT "Alternatively spliced glucocorticoid receptor messenger RNAs in
RT glucocorticoid-resistant human multiple myeloma cells.";
RL Cancer Res. 53:3877-3879(1993).
RN [17]
RP INTERACTION WITH TADA2L AND THE ADA COMPLEX, AND MUTAGENESIS OF
RP PHE-191; ILE-193; LEU-194; LEU-197; TRP-213; LEU-224; LEU-225; PHE-235
RP AND LEU-236.
RX PubMed=9154805;
RA Henriksson A., Almloef T., Ford J., McEwan I.J., Gustafsson J.-A.,
RA Wright A.P.H.;
RT "Role of the Ada adaptor complex in gene activation by the
RT glucocorticoid receptor.";
RL Mol. Cell. Biol. 17:3065-3073(1997).
RN [18]
RP INTERACTION WITH THE SMARCA4 COMPLEX; NCOA1; NCOA2 AND THE
RP CREBBP/EP300 COMPLEX.
RX PubMed=9590696; DOI=10.1038/30032;
RA Fryer C.J., Archer T.K.;
RT "Chromatin remodelling by the glucocorticoid receptor requires the
RT BRG1 complex.";
RL Nature 393:88-91(1998).
RN [19]
RP INTERACTION WITH BAG1.
RX PubMed=10477749; DOI=10.1083/jcb.146.5.929;
RA Schneikert J., Huebner S., Martin E., Cato A.B.C.;
RT "A nuclear action of the eukaryotic cochaperone RAP46 in
RT downregulation of glucocorticoid receptor activity.";
RL J. Cell Biol. 146:929-940(1999).
RN [20]
RP ALTERNATIVE SPLICING (ISOFORMS ALPHA-2 AND BETA-2).
RX PubMed=10566686; DOI=10.1210/jc.84.11.4283;
RA Rivers C., Levy A., Hancock J., Lightman S., Norman M.;
RT "Insertion of an amino acid in the DNA-binding domain of the
RT glucocorticoid receptor as a result of alternative splicing.";
RL J. Clin. Endocrinol. Metab. 84:4283-4286(1999).
RN [21]
RP TISSUE SPECIFICITY.
RX PubMed=10902803; DOI=10.1210/jc.85.7.2519;
RA Kayes-Wandover K.M., White P.C.;
RT "Steroidogenic enzyme gene expression in the human heart.";
RL J. Clin. Endocrinol. Metab. 85:2519-2525(2000).
RN [22]
RP INTERACTION WITH NCOA6.
RX PubMed=10866662; DOI=10.1128/MCB.20.14.5048-5063.2000;
RA Mahajan M.A., Samuels H.H.;
RT "A new family of nuclear receptor coregulators that integrates nuclear
RT receptor signaling through CBP.";
RL Mol. Cell. Biol. 20:5048-5063(2000).
RN [23]
RP EFFECT ON EXPANDED POLYGLUTAMINE PROTEIN.
RX PubMed=10639135; DOI=10.1073/pnas.97.2.657;
RA Diamond M.I., Robinson M.R., Yamamoto K.R.;
RT "Regulation of expanded polyglutamine protein aggregation and nuclear
RT localization by the glucocorticoid receptor.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:657-661(2000).
RN [24]
RP GLUCOCORTICOID-MEDIATED DOWN-REGULATION.
RX PubMed=11555652; DOI=10.1074/jbc.M106033200;
RA Wallace A.D., Cidlowski J.A.;
RT "Proteasome-mediated glucocorticoid receptor degradation restricts
RT transcriptional signaling by glucocorticoids.";
RL J. Biol. Chem. 276:42714-42721(2001).
RN [25]
RP REDUCTION OF CELL DEATH IN RESPONSE TO CORTICOSTEROIDS.
RX PubMed=11238589; DOI=10.1084/jem.193.5.585;
RA Strickland I., Kisich K., Hauk P.J., Vottero A., Chrousos G.P.,
RA Klemm D.J., Leung D.Y.M.;
RT "High constitutive glucocorticoid receptor beta in human neutrophils
RT enables them to reduce their spontaneous rate of cell death in
RT response to corticosteroids.";
RL J. Exp. Med. 193:585-593(2001).
RN [26]
RP ALTERNATIVE INITIATION, AND MUTAGENESIS OF MET-1 AND MET-27.
RX PubMed=11435610; DOI=10.1210/me.15.7.1093;
RA Yudt M.R., Cidlowski J.A.;
RT "Molecular identification and characterization of A and B forms of the
RT glucocorticoid receptor.";
RL Mol. Endocrinol. 15:1093-1103(2001).
RN [27]
RP SUMOYLATION, AND MUTAGENESIS OF LYS-277; LYS-293 AND LYS-703.
RX PubMed=12144530; DOI=10.1042/BJ20021085;
RA Tian S., Poukka H., Palvimo J.J., Jaenne O.A.;
RT "Small ubiquitin-related modifier-1 (SUMO-1) modification of the
RT glucocorticoid receptor.";
RL Biochem. J. 367:907-911(2002).
RN [28]
RP PHOSPHORYLATION AT SER-203 AND SER-211.
RX PubMed=12000743; DOI=10.1074/jbc.M110530200;
RA Wang Z., Frederick J., Garabedian M.J.;
RT "Deciphering the phosphorylation 'code' of the glucocorticoid receptor
RT in vivo.";
RL J. Biol. Chem. 277:26573-26580(2002).
RN [29]
RP INTERACTION WITH PELP1.
RX PubMed=12415108; DOI=10.1073/pnas.192569699;
RA Wong C.-W., McNally C., Nickbarg E., Komm B.S., Cheskis B.J.;
RT "Estrogen receptor-interacting protein that modulates its nongenomic
RT activity-crosstalk with Src/Erk phosphorylation cascade.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:14783-14788(2002).
RN [30]
RP REVIEW ON ALTERNATIVE SPLICING, ALTERNATIVE INITIATION, AND
RP POST-TRANSLATIONAL MODIFICATIONS.
RX PubMed=15265776; DOI=10.1196/annals.1321.008;
RA Lu N.Z., Cidlowski J.A.;
RT "The origin and functions of multiple human glucocorticoid receptor
RT isoforms.";
RL Ann. N. Y. Acad. Sci. 1024:102-123(2004).
RN [31]
RP INTERACTION WITH TGFB1I1.
RX PubMed=15211577; DOI=10.1002/jcb.20109;
RA Guerrero-Santoro J., Yang L., Stallcup M.R., DeFranco D.B.;
RT "Distinct LIM domains of Hic-5/ARA55 are required for nuclear matrix
RT targeting and glucocorticoid receptor binding and coactivation.";
RL J. Cell. Biochem. 92:810-819(2004).
RN [32]
RP INTERACTION WITH HEXIM1.
RX PubMed=15941832; DOI=10.1073/pnas.0409863102;
RA Shimizu N., Ouchida R., Yoshikawa N., Hisada T., Watanabe H.,
RA Okamoto K., Kusuhara M., Handa H., Morimoto C., Tanaka H.;
RT "HEXIM1 forms a transcriptionally abortive complex with glucocorticoid
RT receptor without involving 7SK RNA and positive transcription
RT elongation factor b.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:8555-8560(2005).
RN [33]
RP INTERACTION WITH UNC45A.
RX PubMed=16478993; DOI=10.1128/MCB.26.5.1722-1730.2006;
RA Chadli A., Graham J.D., Abel M.G., Jackson T.A., Gordon D.F.,
RA Wood W.M., Felts S.J., Horwitz K.B., Toft D.;
RT "GCUNC-45 is a novel regulator for the progesterone receptor/hsp90
RT chaperoning pathway.";
RL Mol. Cell. Biol. 26:1722-1730(2006).
RN [34]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [35]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [36]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-134; SER-226 AND
RP SER-267, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [37]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [38]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [39]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [40]
RP SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=21664385; DOI=10.1016/j.bbamcr.2011.05.014;
RA Psarra A.M., Sekeris C.E.;
RT "Glucocorticoids induce mitochondrial gene transcription in HepG2
RT cells: role of the mitochondrial glucocorticoid receptor.";
RL Biochim. Biophys. Acta 1813:1814-1821(2011).
RN [41]
RP SUBCELLULAR LOCATION, AND SUBUNIT.
RX PubMed=21730050; DOI=10.1074/jbc.M111.256610;
RA Gallo L.I., Lagadari M., Piwien-Pilipuk G., Galigniana M.D.;
RT "The 90-kDa heat-shock protein (Hsp90)-binding immunophilin FKBP51 is
RT a mitochondrial protein that translocates to the nucleus to protect
RT cells against oxidative stress.";
RL J. Biol. Chem. 286:30152-30160(2011).
RN [42]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [43]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 521-777 OF MUTANT SER-602 IN
RP COMPLEX WITH NCOA2; DEXAMETHASONE AND RU-486, AND MUTAGENESIS OF
RP ARG-585; ASP-590; PHE-602; PRO-625 AND ILE-628.
RX PubMed=12151000; DOI=10.1016/S0092-8674(02)00817-6;
RA Bledsoe R.K., Montana V.G., Stanley T.B., Delves C.J., Apolito C.J.,
RA McKee D.D., Consler T.G., Parks D.J., Stewart E.L., Willson T.M.,
RA Lambert M.H., Moore J.T., Pearce K.H., Xu H.E.;
RT "Crystal structure of the glucocorticoid receptor ligand binding
RT domain reveals a novel mode of receptor dimerization and coactivator
RT recognition.";
RL Cell 110:93-105(2002).
RN [44]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 500-777 OF MUTANT SER-602 IN
RP COMPLEX WITH COACTIVATOR PEPTIDE; DEXAMETHASONE AND WITH RU-486.
RX PubMed=12686538; DOI=10.1074/jbc.M212711200;
RA Kauppi B., Jakob C., Faernegaardh M., Yang J., Ahola H., Alarcon M.,
RA Calles K., Engstrom O., Harlan J., Muchmore S., Ramqvist A.-K.,
RA Thorell S., Oehman L., Greer J., Gustafsson J.-A., Carlstedt-Duke J.,
RA Carlquist M.;
RT "The three-dimensional structures of antagonistic and agonistic forms
RT of the glucocorticoid receptor ligand-binding domain: RU-486 induces a
RT transconformation that leads to active antagonism.";
RL J. Biol. Chem. 278:22748-22754(2003).
RN [45]
RP CHARACTERIZATION OF VARIANT GCRES VAL-641.
RX PubMed=1704018; DOI=10.1172/JCI115046;
RA Hurley D.M., Accili D., Stratakis C.A., Karl M., Vamvakopoulos N.,
RA Rorer E., Constantine K., Taylor S.I., Chrousos G.P.;
RT "Point mutation causing a single amino acid substitution in the
RT hormone binding domain of the glucocorticoid receptor in familial
RT glucocorticoid resistance.";
RL J. Clin. Invest. 87:680-686(1991).
RN [46]
RP VARIANTS TYR-421 AND PHE-753.
RX PubMed=8358735;
RA Powers J.H., Hillmann A.G., Tang D.C., Harmon J.M.;
RT "Cloning and expression of mutant glucocorticoid receptors from
RT glucocorticoid-sensitive and -resistant human leukemic cells.";
RL Cancer Res. 53:4059-4065(1993).
RN [47]
RP VARIANT SER-363.
RX PubMed=8445027; DOI=10.1210/jc.76.3.683;
RA Karl M., Lamberts S.W.J., Detera-Wadleigh S.D., Encio I.J.,
RA Stratakis C.A., Hurley D.M., Accili D., Chrousos G.P.;
RT "Familial glucocorticoid resistance caused by a splice site deletion
RT in the human glucocorticoid receptor gene.";
RL J. Clin. Endocrinol. Metab. 76:683-689(1993).
RN [48]
RP VARIANT GCRES ILE-729.
RX PubMed=7683692; DOI=10.1172/JCI116410;
RA Malchoff D.M., Brufsky A., Reardon G., McDermott P., Javier E.C.,
RA Bergh C.H., Rowe D., Malchoff C.D.;
RT "A mutation of the glucocorticoid receptor in primary cortisol
RT resistance.";
RL J. Clin. Invest. 91:1918-1925(1993).
RN [49]
RP VARIANT PHE-753.
RX PubMed=8316249; DOI=10.1210/me.7.5.631;
RA Ashraf J., Thompson E.B.;
RT "Identification of the activation-labile gene: a single point mutation
RT in the human glucocorticoid receptor presents as two distinct receptor
RT phenotypes.";
RL Mol. Endocrinol. 7:631-642(1993).
RN [50]
RP VARIANTS LYS-23 AND SER-363.
RX PubMed=9150737; DOI=10.1007/s004390050425;
RA Koper J.W., Stolk R.P., de Lange P., Huizenga N.A.T.M., Molijn G.-J.,
RA Pols H.A.P., Grobbee D.E., Karl M., de Jong F.H., Brinkmann A.O.,
RA Lamberts S.W.J.;
RT "Lack of association between five polymorphisms in the human
RT glucocorticoid receptor gene and glucocorticoid resistance.";
RL Hum. Genet. 99:663-668(1997).
RN [51]
RP VARIANTS LYS-23; VAL-65 AND SER-363.
RX PubMed=10391209; DOI=10.1038/10290;
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RT "Characterization of single-nucleotide polymorphisms in coding regions
RT of human genes.";
RL Nat. Genet. 22:231-238(1999).
RN [52]
RP ERRATUM.
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RL Nat. Genet. 23:373-373(1999).
RN [53]
RP VARIANTS LYS-23; LEU-29; PHE-112; ASN-233 AND SER-363.
RX PubMed=10898924;
RX DOI=10.1002/1096-8628(20000612)96:3<412::AID-AJMG33>3.0.CO;2-C;
RA Feng J., Zheng J., Bennett W.P., Heston L.L., Jones I.R., Craddock N.,
RA Sommer S.S.;
RT "Five missense variants in the amino-terminal domain of the
RT glucocorticoid receptor: no association with puerperal psychosis or
RT schizophrenia.";
RL Am. J. Med. Genet. 96:412-417(2000).
RN [54]
RP VARIANTS GCRES HIS-477 AND SER-679.
RX PubMed=11589680; DOI=10.1046/j.1365-2265.2001.01323.x;
RA Ruiz M., Lind U., Gaafvels M., Eggertsen G., Carlstedt-Duke J.,
RA Nilsson L., Holtmann M., Stierna P., Wikstroem A.-C., Werner S.;
RT "Characterization of two novel mutations in the glucocorticoid
RT receptor gene in patients with primary cortisol resistance.";
RL Clin. Endocrinol. (Oxf.) 55:363-371(2001).
RN [55]
RP VARIANT SER-363.
RX PubMed=11344238; DOI=10.1210/jc.86.5.2270;
RA Dobson M.G., Redfern C.P.F., Unwin N., Weaver J.U.;
RT "The N363S polymorphism of the glucocorticoid receptor: potential
RT contribution to central obesity in men and lack of association with
RT other risk factors for coronary heart disease and diabetes mellitus.";
RL J. Clin. Endocrinol. Metab. 86:2270-2274(2001).
RN [56]
RP CHARACTERIZATION OF VARIANT GCRES ASN-559.
RX PubMed=11701741; DOI=10.1210/jc.86.11.5600;
RA Kino T., Stauber R.H., Resau J.H., Pavlakis G.N., Chrousos G.P.;
RT "Pathologic human GR mutant has a transdominant negative effect on the
RT wild-type GR by inhibiting its translocation into the nucleus:
RT importance of the ligand-binding domain for intracellular GR
RT trafficking.";
RL J. Clin. Endocrinol. Metab. 86:5600-5608(2001).
RN [57]
RP VARIANT LYS-23.
RX PubMed=12351458; DOI=10.2337/diabetes.51.10.3128;
RA van Rossum E.F.C., Koper J.W., Huizenga N.A.T.M., Uitterlinden A.G.,
RA Janssen J.A.M.J.L., Brinkmann A.O., Grobbee D.E., de Jong F.H.,
RA van Duyn C.M., Pols H.A.P., Lamberts S.W.J.;
RT "A polymorphism in the glucocorticoid receptor gene, which decreases
RT sensitivity to glucocorticoids in vivo, is associated with low insulin
RT and cholesterol levels.";
RL Diabetes 51:3128-3134(2002).
RN [58]
RP VARIANT PSEUDOHERMAPHRODITISM ALA-571.
RX PubMed=11932321; DOI=10.1210/jc.87.4.1805;
RA Mendonca B.B., Leite M.V., de Castro M., Kino T., Elias L.L.K.,
RA Bachega T.A.S., Arnhold I.J.P., Chrousos G.P., Latronico A.C.;
RT "Female pseudohermaphroditism caused by a novel homozygous missense
RT mutation of the GR gene.";
RL J. Clin. Endocrinol. Metab. 87:1805-1809(2002).
RN [59]
RP VARIANT GCRES MET-747, AND ALTERED INTERACTION WITH THE COACTIVATOR
RP NCOA2.
RX PubMed=12050230; DOI=10.1210/jc.87.6.2658;
RA Vottero A., Kino T., Combe H., Lecomte P., Chrousos G.P.;
RT "A novel, C-terminal dominant negative mutation of the GR causes
RT familial glucocorticoid resistance through abnormal interactions with
RT p160 steroid receptor coactivators.";
RL J. Clin. Endocrinol. Metab. 87:2658-2667(2002).
RN [60]
RP VARIANT LYS-23.
RX PubMed=15276593; DOI=10.1016/j.amjmed.2004.01.027;
RA van Rossum E.F.C., Feelders R.A., van den Beld A.W.,
RA Uitterlinden A.G., Janssen J.A.M.J.L., Ester W., Brinkmann A.O.,
RA Grobbee D.E., de Jong F.H., Pols H.A.P., Koper J.W., Lamberts S.W.J.;
RT "Association of the ER22/23EK polymorphism in the glucocorticoid
RT receptor gene with survival and C-reactive protein levels in elderly
RT men.";
RL Am. J. Med. 117:158-162(2004).
RN [61]
RP VARIANT LYS-23.
RX PubMed=15292341; DOI=10.1210/jc.2003-031422;
RA van Rossum E.F.C., Voorhoeve P.G., te Velde S.J., Koper J.W.,
RA Delemarre-van de Waal H.A., Kemper H.C.G., Lamberts S.W.J.;
RT "The ER22/23EK polymorphism in the glucocorticoid receptor gene is
RT associated with a beneficial body composition and muscle strength in
RT young adults.";
RL J. Clin. Endocrinol. Metab. 89:4004-4009(2004).
CC -!- FUNCTION: Receptor for glucocorticoids (GC). Has a dual mode of
CC action: as a transcription factor that binds to glucocorticoid
CC response elements (GRE), both for nuclear and mitochondrial DNA,
CC and as a modulator of other transcription factors. Affects
CC inflammatory responses, cellular proliferation and differentiation
CC in target tissues. Could act as a coactivator for STAT5-dependent
CC transcription upon growth hormone (GH) stimulation and could
CC reveal an essential role of hepatic GR in the control of body
CC growth. Involved in chromatin remodeling. May play a negative role
CC in adipogenesis through the regulation of lipolytic and
CC antilipogenic genes expression.
CC -!- SUBUNIT: Heteromultimeric cytoplasmic complex with HSP90AA1,
CC HSPA1A/HSPA1B, and FKBP5 or another immunophilin such as PPID,
CC STIP1, or the immunophilin homolog PPP5C. Upon ligand binding
CC FKBP5 dissociates from the complex and FKBP4 takes its place,
CC thereby linking the complex to dynein and mediating transport to
CC the nucleus, where the complex dissociates. Directly interacts
CC with UNC45A. Binds to DNA as a homodimer, and as heterodimer with
CC NR3C2 or the retinoid X receptor. Binds STAT5A and STAT5B
CC homodimers and heterodimers. Interacts with NRIP1, POU2F1, POU2F2
CC and TRIM28. Interacts with several coactivator complexes,
CC including the SMARCA4 complex, CREBBP/EP300, TADA2L (Ada complex)
CC and p160 coactivators such as NCOA2 and NCOA6. Interaction with
CC BAG1 inhibits transactivation. Interacts with HEXIM1, PELP1 and
CC TGFB1I1. Interacts with NCOA1, NCOA3, SMARCA4, SMARCC1, SMARCD1,
CC and SMARCE1.
CC -!- INTERACTION:
CC P59598:Asxl1 (xeno); NbExp=2; IntAct=EBI-493507, EBI-5743705;
CC P01730:CD4; NbExp=2; IntAct=EBI-493507, EBI-353826;
CC Q6ZU52:KIAA0408; NbExp=2; IntAct=EBI-493507, EBI-739493;
CC P06239:LCK; NbExp=3; IntAct=EBI-493507, EBI-1348;
CC Q62667:Mvp (xeno); NbExp=2; IntAct=EBI-493507, EBI-918333;
CC P82094:TMF1; NbExp=3; IntAct=EBI-493507, EBI-949763;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Mitochondrion. Nucleus.
CC Note=Cytoplasmic in the absence of ligand, nuclear after ligand-
CC binding.
CC -!- SUBCELLULAR LOCATION: Isoform Beta: Nucleus. Note=Localized
CC largely in the nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing, Alternative initiation; Named isoforms=10;
CC Comment=At least 4 isoforms, Alpha (shown here), Alpha-B, Beta
CC and Beta-B, are produced by alternative initiation at Met-1 and
CC Met-27. The existence of isoform Alpha and isoform Alpha-B has
CC been proved by mutagenesis. As the sequence environment of the 2
CC potential ATG initiator codons is the same for the other
CC alternatively spliced isoforms, alternative initiation of
CC translation could also occur on these transcripts. Additional
CC isoforms seem to exist;
CC Name=Alpha; Synonyms=Alpha-A;
CC IsoId=P04150-1; Sequence=Displayed;
CC Note=Predominant physiological form. Isoform Alpha-B is produced
CC by alternative initiation at Met-27 of isoform Alpha. Both
CC isoforms exhibit similar subcellular location and nuclear
CC translocation after ligand activation. Isoform Alpha-B appears
CC to be more susceptible to degradation, at least when expressed
CC in mammalian cells, but more effective in transcriptional
CC activation and not in transrepression;
CC Name=Beta; Synonyms=Beta-A;
CC IsoId=P04150-2; Sequence=VSP_003703;
CC Note=No hormone-binding activity. Widely expressed at low level;
CC Name=Alpha-2; Synonyms=Gamma;
CC IsoId=P04150-3; Sequence=VSP_007363;
CC Note=Due to a partial intron retention. Lower transcriptional
CC activity. Expressed at low level;
CC Name=Beta-2;
CC IsoId=P04150-6; Sequence=VSP_007363, VSP_003703;
CC Note=Due to a partial intron retention;
CC Name=GR-A alpha;
CC IsoId=P04150-5; Sequence=VSP_013340;
CC Note=Lacks exons 5, 6 and 7. Found in glucocorticoid-resistant
CC myeloma patients;
CC Name=GR-A beta;
CC IsoId=P04150-7; Sequence=VSP_013340, VSP_003703;
CC Note=Lacks exons 5, 6 and 7;
CC Name=GR-P;
CC IsoId=P04150-4; Sequence=Not described;
CC Note=Encoded by exons 2-7 plus several basepairs from the
CC subsequent intron region. Lacks the ligand binding domain.
CC Accounts for up to 10-20% of mRNAs;
CC Name=Alpha-B; Synonyms=Beta-B;
CC IsoId=P04150-8; Sequence=VSP_018773;
CC Note=Produced by alternative initiation at Met-27 of isoform
CC Alpha. Both isoforms exhibit similar subcellular location and
CC nuclear translocation after ligand activation. Isoform Alpha-B
CC appears to be more susceptible to degradation, at least when
CC expressed in mammalian cells, but more effective in
CC transcriptional activation and not in transrepression;
CC Name=Beta-B;
CC IsoId=P04150-9; Sequence=VSP_018773, VSP_003703;
CC Note=Produced by alternative initiation at Met-27 of isoform
CC Beta;
CC Name=10; Synonyms=hGRDelta313-338;
CC IsoId=P04150-10; Sequence=VSP_043908;
CC -!- TISSUE SPECIFICITY: Widely expressed. In the heart, detected in
CC left and right atria, left and right ventricles, aorta, apex,
CC intraventricular septum, and atrioventricular node as well as
CC whole adult and fetal heart.
CC -!- DOMAIN: Composed of three domains: a modulating N-terminal domain,
CC a DNA-binding domain and a C-terminal ligand-binding domain.
CC -!- PTM: Increased proteasome-mediated degradation in response to
CC glucocorticoids.
CC -!- PTM: Phosphorylated in the absence of hormone; becomes
CC hyperphosphorylated in the presence of glucocorticoid. The Ser-
CC 203-phosphorylated form is mainly cytoplasmic, and the Ser-211-
CC phosphorylated form is nuclear. Transcriptional activity
CC correlates with the amount of phosphorylation at Ser-211. May be
CC dephosphorylated by PPP5C, attenuates NR3C1 action.
CC -!- PTM: Sumoylated; this reduces transcription transactivation.
CC -!- PTM: Ubiquitinated; restricts glucocorticoid-mediated
CC transcriptional signaling (By similarity).
CC -!- POLYMORPHISM: Carriers of the 22-Glu-Lys-23 allele are relatively
CC more resistant to the effects of GCs with respect to the
CC sensitivity of the adrenal feedback mechanism than non-carriers,
CC resulting in a better metabolic health profile. Carriers have a
CC better survival than non-carriers, as well as lower serum CRP
CC levels. The 22-Glu-Lys-23 polymorphism is associated with a sex-
CC specific, beneficial body composition at young-adult age, as well
CC as greater muscle strength in males.
CC -!- DISEASE: Glucocorticoid resistance (GCRES) [MIM:138040]:
CC Hypertensive, hyperandrogenic disorder characterized by increased
CC serum cortisol concentrations. Inheritance is autosomal dominant.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- MISCELLANEOUS: High constitutive expression of isoform beta by
CC neutrophils may provide a mechanism by which these cells escape
CC glucocorticoid-induced cell death. Up-regulation by
CC proinflammatory cytokines such as IL8 further enhances their
CC survival in the presence of glucocorticoids during inflammation.
CC -!- MISCELLANEOUS: Can up- or down-modulate aggregation and nuclear
CC localization of expanded polyglutamine polypeptides derived from
CC AR and HD through specific regulation of gene expression.
CC Aggregation and nuclear localization of expanded polyglutamine
CC proteins are regulated cellular processes that can be modulated by
CC this receptor, a well-characterized transcriptional regulator.
CC -!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR3
CC subfamily.
CC -!- SIMILARITY: Contains 1 nuclear receptor DNA-binding domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/NR3C1";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/nr3c1/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Glucocorticoid receptor entry;
CC URL="http://en.wikipedia.org/wiki/Glucocorticoid_receptor";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; X03225; CAA26976.1; -; mRNA.
DR EMBL; X03348; CAA27054.1; -; mRNA.
DR EMBL; U80946; AAB64353.1; -; Genomic_DNA.
DR EMBL; U78506; AAB64353.1; JOINED; Genomic_DNA.
DR EMBL; U78507; AAB64353.1; JOINED; Genomic_DNA.
DR EMBL; U78508; AAB64353.1; JOINED; Genomic_DNA.
DR EMBL; U78509; AAB64353.1; JOINED; Genomic_DNA.
DR EMBL; U78510; AAB64353.1; JOINED; Genomic_DNA.
DR EMBL; U78511; AAB64353.1; JOINED; Genomic_DNA.
DR EMBL; U78512; AAB64353.1; JOINED; Genomic_DNA.
DR EMBL; U80947; AAB64354.1; -; Genomic_DNA.
DR EMBL; U78506; AAB64354.1; JOINED; Genomic_DNA.
DR EMBL; U78507; AAB64354.1; JOINED; Genomic_DNA.
DR EMBL; U78508; AAB64354.1; JOINED; Genomic_DNA.
DR EMBL; U78509; AAB64354.1; JOINED; Genomic_DNA.
DR EMBL; U78510; AAB64354.1; JOINED; Genomic_DNA.
DR EMBL; U78511; AAB64354.1; JOINED; Genomic_DNA.
DR EMBL; U78512; AAB64354.1; JOINED; Genomic_DNA.
DR EMBL; HQ205546; ADP91135.1; -; Genomic_DNA.
DR EMBL; HQ205547; ADP91138.1; -; Genomic_DNA.
DR EMBL; HQ205548; ADP91141.1; -; Genomic_DNA.
DR EMBL; HQ205549; ADP91144.1; -; Genomic_DNA.
DR EMBL; HQ205550; ADP91147.1; -; Genomic_DNA.
DR EMBL; HQ205551; ADP91150.1; -; Genomic_DNA.
DR EMBL; HQ205552; ADP91153.1; -; Genomic_DNA.
DR EMBL; HQ205553; ADP91156.1; -; Genomic_DNA.
DR EMBL; HQ205554; ADP91159.1; -; Genomic_DNA.
DR EMBL; HQ205555; ADP91162.1; -; Genomic_DNA.
DR EMBL; HQ205556; ADP91165.1; -; Genomic_DNA.
DR EMBL; HQ205557; ADP91168.1; -; Genomic_DNA.
DR EMBL; HQ205558; ADP91171.1; -; Genomic_DNA.
DR EMBL; HQ205559; ADP91174.1; -; Genomic_DNA.
DR EMBL; HQ205560; ADP91177.1; -; Genomic_DNA.
DR EMBL; HQ205561; ADP91180.1; -; Genomic_DNA.
DR EMBL; HQ205562; ADP91183.1; -; Genomic_DNA.
DR EMBL; HQ205563; ADP91186.1; -; Genomic_DNA.
DR EMBL; HQ205564; ADP91189.1; -; Genomic_DNA.
DR EMBL; HQ205565; ADP91192.1; -; Genomic_DNA.
DR EMBL; HQ205566; ADP91195.1; -; Genomic_DNA.
DR EMBL; HQ205567; ADP91198.1; -; Genomic_DNA.
DR EMBL; HQ205568; ADP91201.1; -; Genomic_DNA.
DR EMBL; HQ205569; ADP91204.1; -; Genomic_DNA.
DR EMBL; HQ205570; ADP91207.1; -; Genomic_DNA.
DR EMBL; HQ205571; ADP91210.1; -; Genomic_DNA.
DR EMBL; HQ205572; ADP91213.1; -; Genomic_DNA.
DR EMBL; HQ205573; ADP91216.1; -; Genomic_DNA.
DR EMBL; HQ205574; ADP91219.1; -; Genomic_DNA.
DR EMBL; HQ205575; ADP91222.1; -; Genomic_DNA.
DR EMBL; HQ205576; ADP91225.1; -; Genomic_DNA.
DR EMBL; HQ205577; ADP91228.1; -; Genomic_DNA.
DR EMBL; HQ205578; ADP91231.1; -; Genomic_DNA.
DR EMBL; HQ205579; ADP91234.1; -; Genomic_DNA.
DR EMBL; HQ205580; ADP91237.1; -; Genomic_DNA.
DR EMBL; HQ205581; ADP91240.1; -; Genomic_DNA.
DR EMBL; HQ205582; ADP91243.1; -; Genomic_DNA.
DR EMBL; HQ205583; ADP91246.1; -; Genomic_DNA.
DR EMBL; HQ205584; ADP91249.1; -; Genomic_DNA.
DR EMBL; HQ205585; ADP91252.1; -; Genomic_DNA.
DR EMBL; AM183262; CAJ65924.1; -; mRNA.
DR EMBL; U01351; AAA16603.1; -; mRNA.
DR EMBL; AK223594; BAD97314.1; -; mRNA.
DR EMBL; BX640610; CAE45716.1; -; mRNA.
DR EMBL; AY436590; AAQ97180.1; -; Genomic_DNA.
DR EMBL; EU332858; ABY87547.1; -; Genomic_DNA.
DR EMBL; AC005601; AAC34207.1; -; Genomic_DNA.
DR EMBL; AC004782; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC091925; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471062; EAW61872.1; -; Genomic_DNA.
DR EMBL; CH471062; EAW61873.1; -; Genomic_DNA.
DR EMBL; BC015610; AAH15610.1; -; mRNA.
DR EMBL; M69104; AAA88049.1; -; Genomic_DNA.
DR EMBL; AH002750; AAA53151.1; -; Genomic_DNA.
DR EMBL; S68378; AAB20466.1; -; Genomic_DNA.
DR PIR; A93370; QRHUGA.
DR PIR; B93370; QRHUGB.
DR RefSeq; NP_000167.1; NM_000176.2.
DR RefSeq; NP_001018084.1; NM_001018074.1.
DR RefSeq; NP_001018085.1; NM_001018075.1.
DR RefSeq; NP_001018086.1; NM_001018076.1.
DR RefSeq; NP_001018087.1; NM_001018077.1.
DR RefSeq; NP_001018661.1; NM_001020825.1.
DR RefSeq; NP_001019265.1; NM_001024094.1.
DR RefSeq; NP_001191187.1; NM_001204258.1.
DR RefSeq; NP_001191188.1; NM_001204259.1.
DR RefSeq; NP_001191189.1; NM_001204260.1.
DR RefSeq; NP_001191190.1; NM_001204261.1.
DR RefSeq; NP_001191191.1; NM_001204262.1.
DR RefSeq; NP_001191192.1; NM_001204263.1.
DR RefSeq; NP_001191193.1; NM_001204264.1.
DR RefSeq; NP_001191194.1; NM_001204265.1.
DR RefSeq; XP_005268476.1; XM_005268419.1.
DR RefSeq; XP_005268477.1; XM_005268420.1.
DR RefSeq; XP_005268478.1; XM_005268421.1.
DR RefSeq; XP_005268479.1; XM_005268422.1.
DR RefSeq; XP_005268480.1; XM_005268423.1.
DR RefSeq; XP_005268481.1; XM_005268424.1.
DR RefSeq; XP_005268482.1; XM_005268425.1.
DR UniGene; Hs.122926; -.
DR PDB; 1M2Z; X-ray; 2.50 A; A/D=521-777.
DR PDB; 1NHZ; X-ray; 2.30 A; A=500-777.
DR PDB; 1P93; X-ray; 2.70 A; A/B/C/D=500-777.
DR PDB; 3BQD; X-ray; 2.50 A; A=525-777.
DR PDB; 3CLD; X-ray; 2.84 A; A/B=521-777.
DR PDB; 3E7C; X-ray; 2.15 A; A/B=521-777.
DR PDB; 3H52; X-ray; 2.80 A; A/B/C/D=528-777.
DR PDB; 3K22; X-ray; 2.10 A; A/B=521-777.
DR PDB; 3K23; X-ray; 3.00 A; A/B/C=521-777.
DR PDB; 4HN5; X-ray; 1.90 A; A/B=417-506.
DR PDB; 4HN6; X-ray; 2.55 A; A/B=417-506.
DR PDBsum; 1M2Z; -.
DR PDBsum; 1NHZ; -.
DR PDBsum; 1P93; -.
DR PDBsum; 3BQD; -.
DR PDBsum; 3CLD; -.
DR PDBsum; 3E7C; -.
DR PDBsum; 3H52; -.
DR PDBsum; 3K22; -.
DR PDBsum; 3K23; -.
DR PDBsum; 4HN5; -.
DR PDBsum; 4HN6; -.
DR DisProt; DP00030; -.
DR ProteinModelPortal; P04150; -.
DR SMR; P04150; 418-777.
DR DIP; DIP-576N; -.
DR IntAct; P04150; 53.
DR MINT; MINT-150603; -.
DR STRING; 9606.ENSP00000231509; -.
DR BindingDB; P04150; -.
DR ChEMBL; CHEMBL2034; -.
DR DrugBank; DB00288; Amcinonide.
DR DrugBank; DB00443; Betamethasone.
DR DrugBank; DB01222; Budesonide.
DR DrugBank; DB01234; Dexamethasone.
DR DrugBank; DB00663; Flumethasone Pivalate.
DR DrugBank; DB00180; Flunisolide.
DR DrugBank; DB00588; Fluticasone Propionate.
DR DrugBank; DB00769; Hydrocortamate.
DR DrugBank; DB00741; Hydrocortisone.
DR DrugBank; DB00873; Loteprednol Etabonate.
DR DrugBank; DB00959; Methylprednisolone.
DR DrugBank; DB00834; Mifepristone.
DR DrugBank; DB00764; Mometasone.
DR DrugBank; DB00635; Prednisone.
DR GuidetoPHARMACOLOGY; 625; -.
DR PhosphoSite; P04150; -.
DR DMDM; 121069; -.
DR PaxDb; P04150; -.
DR PRIDE; P04150; -.
DR DNASU; 2908; -.
DR Ensembl; ENST00000231509; ENSP00000231509; ENSG00000113580.
DR Ensembl; ENST00000343796; ENSP00000343205; ENSG00000113580.
DR Ensembl; ENST00000394464; ENSP00000377977; ENSG00000113580.
DR Ensembl; ENST00000394466; ENSP00000377979; ENSG00000113580.
DR Ensembl; ENST00000415690; ENSP00000387672; ENSG00000113580.
DR Ensembl; ENST00000424646; ENSP00000405282; ENSG00000113580.
DR Ensembl; ENST00000503201; ENSP00000427672; ENSG00000113580.
DR Ensembl; ENST00000504572; ENSP00000422518; ENSG00000113580.
DR GeneID; 2908; -.
DR KEGG; hsa:2908; -.
DR UCSC; uc003lmz.3; human.
DR CTD; 2908; -.
DR GeneCards; GC05M142639; -.
DR HGNC; HGNC:7978; NR3C1.
DR HPA; CAB010435; -.
DR HPA; HPA004248; -.
DR MIM; 138040; gene+phenotype.
DR neXtProt; NX_P04150; -.
DR Orphanet; 786; Glucocorticoid resistance.
DR PharmGKB; PA181; -.
DR eggNOG; NOG270250; -.
DR HOGENOM; HOG000037950; -.
DR HOVERGEN; HBG007583; -.
DR KO; K05771; -.
DR OMA; QSTFDIL; -.
DR OrthoDB; EOG7B31M9; -.
DR PhylomeDB; P04150; -.
DR Reactome; REACT_71; Gene Expression.
DR SignaLink; P04150; -.
DR ChiTaRS; NR3C1; human.
DR EvolutionaryTrace; P04150; -.
DR GeneWiki; Glucocorticoid_receptor; -.
DR GenomeRNAi; 2908; -.
DR NextBio; 11517; -.
DR PRO; PR:P04150; -.
DR ArrayExpress; P04150; -.
DR Bgee; P04150; -.
DR CleanEx; HS_NR3C1; -.
DR Genevestigator; P04150; -.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0016020; C:membrane; IEA:Ensembl.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:ProtInc.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0004883; F:glucocorticoid receptor activity; TAS:ProtInc.
DR GO; GO:0043565; F:sequence-specific DNA binding; IEA:Ensembl.
DR GO; GO:0003700; F:sequence-specific DNA binding transcription factor activity; TAS:ProtInc.
DR GO; GO:0005496; F:steroid binding; IEA:UniProtKB-KW.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0030325; P:adrenal gland development; IEA:Ensembl.
DR GO; GO:0016568; P:chromatin modification; IEA:UniProtKB-KW.
DR GO; GO:0008211; P:glucocorticoid metabolic process; IEA:Ensembl.
DR GO; GO:0060603; P:mammary gland duct morphogenesis; IEA:Ensembl.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0031946; P:regulation of glucocorticoid biosynthetic process; IEA:Ensembl.
DR GO; GO:0006111; P:regulation of gluconeogenesis; IEA:Ensembl.
DR GO; GO:0006367; P:transcription initiation from RNA polymerase II promoter; TAS:Reactome.
DR Gene3D; 1.10.565.10; -; 1.
DR Gene3D; 3.30.50.10; -; 1.
DR InterPro; IPR001409; Glcrtcd_rcpt.
DR InterPro; IPR008946; Nucl_hormone_rcpt_ligand-bd.
DR InterPro; IPR000536; Nucl_hrmn_rcpt_lig-bd_core.
DR InterPro; IPR001723; Str_hrmn_rcpt.
DR InterPro; IPR001628; Znf_hrmn_rcpt.
DR InterPro; IPR013088; Znf_NHR/GATA.
DR Pfam; PF02155; GCR; 1.
DR Pfam; PF00104; Hormone_recep; 1.
DR Pfam; PF00105; zf-C4; 1.
DR PRINTS; PR00528; GLCORTICOIDR.
DR PRINTS; PR00398; STRDHORMONER.
DR PRINTS; PR00047; STROIDFINGER.
DR SMART; SM00430; HOLI; 1.
DR SMART; SM00399; ZnF_C4; 1.
DR SUPFAM; SSF48508; SSF48508; 1.
DR PROSITE; PS00031; NUCLEAR_REC_DBD_1; 1.
DR PROSITE; PS51030; NUCLEAR_REC_DBD_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative initiation; Alternative splicing;
KW Chromatin regulator; Complete proteome; Cytoplasm; Disease mutation;
KW DNA-binding; Isopeptide bond; Lipid-binding; Metal-binding;
KW Mitochondrion; Nucleus; Phosphoprotein; Polymorphism;
KW Pseudohermaphroditism; Receptor; Reference proteome; Steroid-binding;
KW Transcription; Transcription regulation; Ubl conjugation; Zinc;
KW Zinc-finger.
FT CHAIN 1 777 Glucocorticoid receptor.
FT /FTId=PRO_0000019937.
FT DNA_BIND 421 486 Nuclear receptor.
FT ZN_FING 421 441 NR C4-type.
FT ZN_FING 457 481 NR C4-type.
FT REGION 1 420 Modulating.
FT REGION 487 527 Hinge.
FT REGION 528 777 Steroid-binding.
FT COMPBIAS 399 418 Glu/Pro/Ser/Thr-rich (PEST region).
FT MOD_RES 113 113 Phosphoserine (By similarity).
FT MOD_RES 134 134 Phosphoserine.
FT MOD_RES 141 141 Phosphoserine (By similarity).
FT MOD_RES 203 203 Phosphoserine.
FT MOD_RES 211 211 Phosphoserine.
FT MOD_RES 226 226 Phosphoserine.
FT MOD_RES 267 267 Phosphoserine.
FT CROSSLNK 277 277 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT CROSSLNK 293 293 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT CROSSLNK 419 419 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin)
FT (Probable).
FT VAR_SEQ 1 26 Missing (in isoform Alpha-B and isoform
FT Beta-B).
FT /FTId=VSP_018773.
FT VAR_SEQ 313 338 Missing (in isoform 10).
FT /FTId=VSP_043908.
FT VAR_SEQ 451 451 G -> GR (in isoform Alpha-2 and isoform
FT Beta-2).
FT /FTId=VSP_007363.
FT VAR_SEQ 491 674 Missing (in isoform GR-A alpha and
FT isoform GR-A beta).
FT /FTId=VSP_013340.
FT VAR_SEQ 728 777 VVENLLNYCFQTFLDKTMSIEFPEMLAEIITNQIPKYSNGN
FT IKKLLFHQK -> NVMWLKPESTSHTLI (in isoform
FT Beta, isoform Beta-B, isoform Beta-2 and
FT isoform GR-A beta).
FT /FTId=VSP_003703.
FT VARIANT 23 23 R -> K (in dbSNP:rs6190).
FT /FTId=VAR_014140.
FT VARIANT 29 29 F -> L.
FT /FTId=VAR_015628.
FT VARIANT 65 65 F -> V (in dbSNP:rs6192).
FT /FTId=VAR_014622.
FT VARIANT 112 112 L -> F.
FT /FTId=VAR_015629.
FT VARIANT 233 233 D -> N.
FT /FTId=VAR_015630.
FT VARIANT 363 363 N -> S (may increase sensitivity to
FT exogenously administered glucocorticoids;
FT may contribute to central obesity in men
FT and show lack of association with other
FT risk factors for coronary heart disease
FT and diabetes mellitus; dbSNP:rs6195).
FT /FTId=VAR_004675.
FT VARIANT 421 421 C -> Y (in a glucocorticoid resistant
FT leukemia cell line).
FT /FTId=VAR_015631.
FT VARIANT 477 477 R -> H (in GCRES).
FT /FTId=VAR_013472.
FT VARIANT 559 559 I -> N (in GCRES; interferes with
FT translocation to the nucleus and thereby
FT strongly reduces transcription
FT activation. Is equally impaired in
FT nuclear export. Acts as dominant negative
FT mutant).
FT /FTId=VAR_015632.
FT VARIANT 571 571 V -> A (in pseudohermaphroditism; female
FT with hypokalemia due to glucocorticoid
FT resistance; 6-fold reduction in binding
FT affinity compared with the wild-type
FT receptor).
FT /FTId=VAR_025014.
FT VARIANT 641 641 D -> V (in GCRES).
FT /FTId=VAR_004676.
FT VARIANT 679 679 G -> S (in GCRES; has 50% binding
FT affinity).
FT /FTId=VAR_013473.
FT VARIANT 729 729 V -> I (in GCRES).
FT /FTId=VAR_004677.
FT VARIANT 747 747 I -> M (in GCRES; alters interaction with
FT NCOA2 and strongly reduces transcription
FT activation; acts as dominant negative
FT mutant).
FT /FTId=VAR_015633.
FT VARIANT 753 753 L -> F (in two glucocorticoid resistant
FT leukemia cell lines lacking the normal
FT allele).
FT /FTId=VAR_004678.
FT MUTAGEN 1 1 M->T: Abolishes expression of A-type
FT isoforms.
FT MUTAGEN 27 27 M->T: Abolishes expression of B-type
FT isoforms.
FT MUTAGEN 191 191 F->D: Reduces transactivation by the ADA
FT complex.
FT MUTAGEN 193 193 I->D: Reduces transactivation by the ADA
FT complex.
FT MUTAGEN 194 194 L->A: Strongly reduces transactivation by
FT the ADA complex; when associated with V-
FT 224 and F-225.
FT MUTAGEN 197 197 L->E: Reduces transactivation by the ADA
FT complex.
FT MUTAGEN 213 213 W->A: Strongly reduces transactivation by
FT the ADA complex.
FT MUTAGEN 224 224 L->V: Strongly reduces transactivation by
FT the ADA complex; when associated with A-
FT 194 and F-225.
FT MUTAGEN 225 225 L->F: Strongly reduces transactivation by
FT the ADA complex; when associated with A-
FT 194 and V-224.
FT MUTAGEN 235 235 F->L: Strongly reduces transactivation by
FT the ADA complex; when associated with V-
FT 236.
FT MUTAGEN 236 236 L->V: Strongly reduces transactivation by
FT the ADA complex; when associated with L-
FT 235.
FT MUTAGEN 277 277 K->R: Strongly reduces sumoylation.
FT Almost complete loss of sumoylation; when
FT associated with R-293.
FT MUTAGEN 293 293 K->R: Strongly reduces sumoylation.
FT Almost complete loss of sumoylation; when
FT associated with R-277.
FT MUTAGEN 585 585 R->A: Reduces activation mediated by
FT ligand binding domain; when associated
FT with A-590.
FT MUTAGEN 590 590 D->A: Reduces activation mediated by
FT ligand binding domain; when associated
FT with A-585.
FT MUTAGEN 602 602 F->S: Increases solubility. No effect on
FT transactivation by dexamethasone.
FT MUTAGEN 625 625 P->A: Decreases transactivation by
FT dexamethasone by 95%.
FT MUTAGEN 628 628 I->A: Decreases dimerization and
FT transactivation by dexamethasone; when
FT associated with S-602.
FT MUTAGEN 703 703 K->R: Slightly reduces sumoylation.
FT CONFLICT 399 399 R -> G (in Ref. 6; BAD97314).
FT CONFLICT 754 754 A -> T (in Ref. 6; BAD97314).
FT TURN 422 424
FT STRAND 430 432
FT STRAND 435 437
FT HELIX 439 449
FT STRAND 458 461
FT TURN 467 472
FT HELIX 474 484
FT TURN 525 527
FT HELIX 532 538
FT STRAND 550 552
FT HELIX 556 580
FT TURN 582 586
FT HELIX 589 615
FT STRAND 616 619
FT STRAND 621 624
FT STRAND 627 629
FT HELIX 631 634
FT HELIX 639 656
FT HELIX 660 671
FT STRAND 673 676
FT HELIX 683 703
FT STRAND 704 706
FT HELIX 708 710
FT HELIX 711 741
FT TURN 743 745
FT HELIX 751 766
FT STRAND 769 771
SQ SEQUENCE 777 AA; 85659 MW; C5C90C9A5DD16AAB CRC64;
MDSKESLTPG REENPSSVLA QERGDVMDFY KTLRGGATVK VSASSPSLAV ASQSDSKQRR
LLVDFPKGSV SNAQQPDLSK AVSLSMGLYM GETETKVMGN DLGFPQQGQI SLSSGETDLK
LLEESIANLN RSTSVPENPK SSASTAVSAA PTEKEFPKTH SDVSSEQQHL KGQTGTNGGN
VKLYTTDQST FDILQDLEFS SGSPGKETNE SPWRSDLLID ENCLLSPLAG EDDSFLLEGN
SNEDCKPLIL PDTKPKIKDN GDLVLSSPSN VTLPQVKTEK EDFIELCTPG VIKQEKLGTV
YCQASFPGAN IIGNKMSAIS VHGVSTSGGQ MYHYDMNTAS LSQQQDQKPI FNVIPPIPVG
SENWNRCQGS GDDNLTSLGT LNFPGRTVFS NGYSSPSMRP DVSSPPSSSS TATTGPPPKL
CLVCSDEASG CHYGVLTCGS CKVFFKRAVE GQHNYLCAGR NDCIIDKIRR KNCPACRYRK
CLQAGMNLEA RKTKKKIKGI QQATTGVSQE TSENPGNKTI VPATLPQLTP TLVSLLEVIE
PEVLYAGYDS SVPDSTWRIM TTLNMLGGRQ VIAAVKWAKA IPGFRNLHLD DQMTLLQYSW
MFLMAFALGW RSYRQSSANL LCFAPDLIIN EQRMTLPCMY DQCKHMLYVS SELHRLQVSY
EEYLCMKTLL LLSSVPKDGL KSQELFDEIR MTYIKELGKA IVKREGNSSQ NWQRFYQLTK
LLDSMHEVVE NLLNYCFQTF LDKTMSIEFP EMLAEIITNQ IPKYSNGNIK KLLFHQK
//

MIM 138040
*RECORD*
*FIELD* NO
138040
*FIELD* TI
+138040 GLUCOCORTICOID RECEPTOR; GCCR
;;GCR; GRL;;
NUCLEAR RECEPTOR SUBFAMILY 3, GROUP C, MEMBER 1; NR3C1
read moreGLUCOCORTICOID RECEPTOR DEFICIENCY, INCLUDED;;
GCCR DEFICIENCY, INCLUDED;;
GCR DEFICIENCY, INCLUDED;;
GRL DEFICIENCY, INCLUDED;;
GLUCOCORTICOID RESISTANCE, INCLUDED;;
CORTISOL RESISTANCE FROM GLUCOCORTICOID RECEPTOR DEFECT, INCLUDED;;
PSEUDOHERMAPHRODITISM, FEMALE, WITH HYPOKALEMIA, DUE TO GLUCOCORTICOID
RESISTANCE, INCLUDED;;
BODY COMPOSITION, BENEFICIAL, INCLUDED
*FIELD* TX

CLINICAL FEATURES

Vingerhoeds et al. (1976) reported a case of cortisol resistance. High
levels of cortisol (without stigmata of Cushing syndrome), resistance of
the hypothalamic-pituitary-adrenal axis to dexamethasone, and an
affinity defect of the glucocorticoid receptor characterized the
disorder. Chrousos et al. (1982) restudied the family reported by
Vingerhoeds et al. (1976). A man who was presumably homozygous had
mineralocorticoid excess resulting in hypertension, hypokalemia, and
metabolic alkalosis. One of his brothers, who had severe hypertension
and died of a cerebrovascular accident at age 54, may also have been
homozygous. Another brother and his son were apparently heterozygous;
they showed slightly elevated 24-hour mean plasma cortisol levels and
increased urinary free cortisol. Lipsett et al. (1986) provided further
follow-up on the 4-generation family originally reported by Vingerhoeds
et al. (1976). Autosomal dominant inheritance of glucocorticoid
resistance was clearly demonstrated. Lipsett et al. (1986) believed that
a mutation in the glucocorticoid receptor was responsible, although
other explanations could be invoked. The single homozygote in the family
was the proband; the other persons with elevated plasma cortisol levels
and increased urinary free cortisol represented heterozygotes. The
parents of the proband descended from families with consanguinity that
occurred before the 16th century. The 2 parental families had lived in
close proximity for many generations. This cortisol resistance is
probably the rarest cause of treatable hypertension yet described.
Affected mother and son with decreased glucocorticoid receptors were
reported by Iida et al. (1985).

Bronnegard et al. (1986) described a woman with receptor-mediated
resistance to cortisol as indicated by elevated 24-hour mean plasma
cortisol levels and increased free urinary cortisol. Plasma ACTH
concentrations were normal but she was resistant to adrenal suppression
by dexamethasone. No stigmata of Cushing syndrome were present. The
patient had symptoms of pronounced fatigue. Menopause had occurred at
age 43. The patient's only child, a son, aged 29 years, had periods of
inexplicable fatigue that had made him stay home from school and work.
Because of the extreme fatigue that led to the mother's working only
half-time, Addison's disease was suspected, but rather than
hypocortisolism, elevation of urinary cortisol values was found.
Bronnegard et al. (1986) found that the end-organ insensitivity to
cortisol was not due to decreased concentration or ligand affinity of
the receptor. Rather the woman and her son showed an increased
thermolability of the cortisol receptor, a phenomenon also observed with
the androgen receptor in patients with the testicular feminization
syndrome (300068).

Lamberts et al. (1986) described cortisol resistance in a 26-year-old
woman with hirsutism, mild virilization, and menstrual difficulties.
They thought that the abnormality was autosomal dominant because her
father and 2 brothers had increased plasma cortisol concentrations that
did not suppress normally in response to dexamethasone. No hypertension
or hypokalemic alkalosis was present. The proband had male-pattern scalp
baldness. Nawata et al. (1987) studied a 27-year-old woman with the
syndrome of glucocorticoid resistance. She was initially thought to have
Cushing disease, based on high plasma ACTH and serum cortisol levels,
increased urinary cortisol secretion, resistance to adrenal suppression
with dexamethasone, and bilateral adrenal hyperplasia by computed
tomography and scintigraphy; however, she had no clinical signs or
symptoms of Cushing syndrome. Laboratory studies indicated that the
patient's glucocorticoid resistance was due to a decrease in the
affinity of the receptor for glucocorticoids and a decrease in the
binding of the GCCR complex to DNA.

Charmandari et al. (2008) reviewed the clinical aspects, molecular
mechanisms, and implications of primary generalized glucocorticoid
resistance. They noted that the clinical spectrum is broad, ranging from
asymptomatic to severe cases of hyperandrogenism, fatigue, and/or
mineralocorticoid excess. Mutations in the GCCR gene resulting in the
disorder impair glucocorticoid signal transduction and reduce tissue
sensitivity to glucocorticoids. A consequent increase in the activity of
the hypothalamic-pituitary-adrenal axis compensates for the reduced
sensitivity of peripheral tissues to glucocorticoids at the expense of
ACTH hypersecretion-related pathology. The study of functional defects
of GCCR mutants highlighted the importance of integrated cellular and
molecular signaling mechanisms for maintaining homeostasis and
preserving normal physiology.

- Corticotrophinomas

As cortisol resistance can be caused by genetic abnormalities in the GRL
gene, Huizenga et al. (1998) investigated whether the insensitivity of
corticotropinomas to cortisol is also caused by de novo GRL mutations.
Except for 1 silent point mutation, they did not identify mutations in
the GRL gene in leukocytes or corticotropinomas from 22 patients with
Cushing disease. Of the 22 patients, 18 were heterozygous for at least 1
polymorphism, and 6 of the 18 had loss of heterozygosity (LOH) in the
tumor DNA. They concluded that LOH at the GRL locus is a relatively
frequent phenomenon in pituitary adenomas of patients with Cushing
disease and that this may explain the relative resistance of the adenoma
cells to the inhibitory feedback action of cortisol on ACTH secretion.

EVOLUTION

Examples of resistance to cortisol are known; the guinea pig is a
'corticoresistant' species (Vingerhoeds et al., 1976).

Two New World primates, the squirrel monkey and the marmoset, have
markedly elevated plasma cortisol levels without physiologic evidence of
glucocorticoid hormone excess. Chrousos et al. (1982) showed that their
hypothalamic-pituitary-adrenal axis is resistant to suppression by
dexamethasone. They studied glucocorticoid receptors in circulating
monocytes and cultured skin fibroblasts of New and Old World monkeys and
found that, although the receptor content was the same in all species,
the 2 New World species had markedly decreased binding affinity for
dexamethasone. The presumed mutation must have occurred after
bifurcation of the Old and New World primates (about 60 Myr ago) and
before diversion of the 2 New World species (about 15 Myr ago). A
difference between the disorder in man with an affinity defect of the
glucocorticoid receptor and the state in New World monkeys is that in
the severe form of the human disease, sodium-retaining corticoids
(corticosterone and deoxycorticosterone) are elevated many-fold,
producing hypertension and hypokalemic alkalosis. The mineralocorticoid
overproduction, which does not occur in the New World monkeys, is
probably due to corticotropin hyperstimulation of the adrenal cortex.

CLONING

Glucocorticoid hormones, like other classes of steroid hormones, exert
their cellular action by complexing with a specific cytoplasmic receptor
which in turn translocates to the nucleus and binds to specific sites on
chromatin. The glucocorticoid receptor was the first transcription
factor to be isolated and studied in detail (Muller and Renkawitz,
1991). The glucocorticoid receptor (GCCR) is crucial to gene expression.
It is a 94-kD polypeptide and according to one model is thought to have
distinct steroid-binding and DNA-binding domains. Weinberger et al.
(1985) used expression cloning techniques to select human glucocorticoid
receptor cDNA.

Hollenberg et al. (1985) identified cDNAs encoding the human
glucocorticoid receptor (symbolized hGR by them). These DNAs predicted 2
protein forms of 777 (alpha) and 742 (beta) amino acids, which differ in
their carboxy termini. The proteins contain a
cysteine/lysine/arginine-rich region which may define the DNA-binding
domain.

Weinberger et al. (1985, 1987) pointed out that the glucocorticoid
receptor that they cloned is related to the erb-A family of oncogenes
(see 190120 and 190160). Cloned members of the erb oncogene family
showed a strong relatedness to the DNA-binding domain of the
glucocorticoid receptor. A short region of GRL was homologous to certain
homeotic proteins of Drosophila. Carlstedt-Duke et al. (1987) analyzed
the domain structure of the rat liver GCR protein. The steroid-binding
domain, defined by a unique tryptic cleavage, corresponded to the
COOH-terminal protein with the domain border in the region of residue
518. The DNA-binding domain, defined by a region with chymotryptic
cleavage sites, was immediately adjacent to the steroid-binding domain
with its border in the region of residues 410-414.

GENE FUNCTION

Of the 2 isoforms of the glucocorticoid receptor generated by
alternative splicing, GR-alpha is a ligand-activated transcription
factor that, in the hormone-bound state, modulates the expression of
glucocorticoid-responsive genes by binding to a specific glucocorticoid
response element (GRE) DNA sequence. In contrast, GR-beta does not bind
glucocorticoids and is transcriptionally inactive. Bamberger et al.
(1995) demonstrated that GR-beta is able to inhibit the effects of
hormone-activated GR-alpha on a glucocorticoid-responsive reporter gene
in a concentration-dependent manner. The inhibitory effect appeared to
be due to competition for GRE target sites. Since RT-PCR analysis showed
expression of GR-beta mRNA in multiple human tissues, GR-beta may be a
physiologically and pathophysiologically relevant endogenous inhibitor
of glucocorticoid action and may participate in defining the sensitivity
of tissues to glucocorticoids.

Roux et al. (1996) found that mutation of isoleucine-747 to threonine in
the C-terminal portion of the ligand-binding domain of NR3C1 alters the
specificity of the ligand for transactivation. Whereas natural
glucocorticoids such as cortisol or corticosterone were completely
inactive, synthetic steroids like dexamethasone efficiently stimulated
I747T mutant NR3C1-mediated transactivation. The basis for the inability
of cortisol to activate I747T was predicted from the canonical
3-dimensional structure of nuclear receptor ligand-binding domains
because isoleucine-747 is in the direct vicinity of residues that
contribute to the ligand-binding pocket.

Using oligonucleotide-directed mutagenesis, Lind et al. (1996), found
functional substitutions of residue 736 with serine (cys736 to ser) and
threonine (cys736 to thr). The cys736-to-ser protein showed reduced
sensitivity to all hormones tested in transactivation assays and a
reduced hormone binding affinity. A correspondence between sensitivity
to hormone in transactivation assays and hormone-binding affinity was
also observed for the cys736-to-thr protein. The authors concluded that
very conservative substitutions of cys736, including serine and
threonine, cause variable effects on hormone binding that distinguish
between different glucocorticoid steroid hormones.

Diamond et al. (2000) showed, in diverse cell types, that
glucocorticoids can up- or down-modulate aggregation and nuclear
localization of expanded polyglutamine polypeptides derived from the
androgen receptor (AR; 313700) or huntingtin (HTT; 613004) through
specific regulation of gene expression. Wildtype glucocorticoid
receptor, as well as C-terminal deletion derivatives, suppressed the
aggregation and nuclear localization of these polypeptides, whereas
mutations within the DNA-binding domain and the N terminus of GCR
abolished this activity. Surprisingly, deletion of a transcriptional
regulatory domain within the GCR N terminus markedly increased
aggregation and nuclear localization of the expanded polyglutamine
proteins. Thus, aggregation and nuclear localization of expanded
polyglutamine proteins are regulated cellular processes that can be
modulated by a well-characterized transcriptional regulator, the GCR.
The findings suggested approaches to study the molecular pathogenesis
and selective neuronal degeneration of polyglutamine expansion diseases.

Welch and Diamond (2001) used wildtype GR and a mutated form of GR
(GR-delta-109-317) to study expanded polyglutamine AR protein in
different cell contexts. The authors found that wildtype GR promoted
soluble forms of the AR protein and prevented nuclear aggregation in NIH
3T3 cells and cultured neurons. In contrast, GR-delta-108-317 decreased
polyglutamine protein solubility, and caused formation of nuclear
aggregates in nonneuronal cells. Nuclear aggregates recruited the
heat-shock protein hsp72 more rapidly than cytoplasmic aggregates, and
were associated with decreased cell viability. Limited proteolysis and
chemical crosslinking suggested unique soluble forms of the expanded AR
protein may underlie these distinct biological activities. The authors
hypothesized that unique protein associations or conformations of
expanded polyglutamine proteins may determine subsequent cellular
effects such as nuclear localization and cellular toxicity.

Webster et al. (2003) reported that 2 proteins that comprise a lethal
factor of Bacillus anthracis selectively and specifically repress
glucocorticoid receptor and other nuclear hormone receptors, including
progesterone receptor (PGR; 607311). This was, it seemed, the first
report of a bacterial product interfering with nuclear hormone receptor
function. It provides a previously uncharacterized explanation of how
such agents might contribute to the pathogenesis of bacterial
infections, and may have implications for development of new treatments
and prevention of the toxic effects of anthrax.

Glucocorticoid response units are complex and are often located at
distant sites relative to the transcription start site in a gene. In
their review, Schoneveld et al. (2004) discussed the interaction of GCCR
with other transcription factors and the utilization of several GREs for
the regulation of gene expression. They also discussed other factors
that may influence the activity of the glucocorticoid response unit,
such as higher order chromatin structure and nuclear organization.

Revest et al. (2005) found that the effects of stress-related
glucocorticoid receptor signaling in mouse hippocampus were mediated by
the MAPK pathway and Egr1 (128990).

Hagendorf et al. (2005) investigated whether chronic hypercortisolism,
chronic hypocortisolism, or acute, relative hypocortisolism influences
the expression levels of GCCR splice variants in mononuclear leukocytes.
They found a significant correlation between the expression levels of
the 3 GCCR splice variants and between the mRNA levels and the number of
receptors per cell. The authors concluded that Cushing syndrome is
accompanied by a reversible decrease in GCCR affinity, possibly related
to an increased GCCR-beta expression, which may be a compensatory
mechanism to glucocorticoid excess. In chronic hypocortisolism, adaptive
changes in GCCR status seem to occur at the level of glucocorticoid
receptor number.

Using structural, biochemical, and cell-based assays, Meijsing et al.
(2009) showed that glucocorticoid receptor binding sequences, differing
by as little as a single basepair, differentially affect glucocorticoid
receptor conformation and regulatory activity. Meijsing et al. (2009)
proposed that DNA is a sequence-specific allosteric ligand of
glucocorticoid receptor that tailors the activity of the receptor toward
specific target genes.

Lamia et al. (2011) showed that 2 circadian coregulators, cryptochrome-1
(CRY1; 601933) and cryptochrome-2 (CRY2; 603732), interact with
glucocorticoid receptor in a ligand-dependent fashion and globally alter
the transcriptional response to glucocorticoids in mouse embryonic
fibroblasts: cryptochrome deficiency vastly decreases gene repression
and approximately doubles the number of dexamethasone-induced genes,
suggesting that cryptochromes broadly oppose glucocorticoid receptor
activation and promote repression. In mice, genetic loss of Cry1 and/or
2 results in glucose intolerance and constitutively high levels of
circulating corticosterone, suggesting reduced suppression of the
hypothalamic-pituitary-adrenal axis coupled with increased
glucocorticoid transactivation in the liver. Genomically, Cry1 and Cry2
associate with a glucocorticoid response element in the
phosphoenolpyruvate carboxykinase-1 (PCK1; 614168) promoter in a
hormone-dependent manner, and dexamethasone-induced transcription of the
Pck1 gene was strikingly increased in cryptochrome-deficient livers.
Lamia et al. (2011) concluded that their results revealed a specific
mechanism through which cryptochromes couple the activity of clock and
receptor target genes to complex genomic circuits underpinning normal
metabolic homeostasis.

Zhang et al. (2013) demonstrated that the RNA-binding protein ZFP36L2
(612053) is a transcriptional target of the GR receptor in burst-forming
unit-erythroid (BFU-E) progenitors and is required for BFU-E self
renewal. ZFP36L2 is normally downregulated during erythroid
differentiation from the BFU-E stage, but its expression is maintained
by all tested GR agonists that stimulate BFU-E self-renewal, and the GR
binds to several potential enhancer regions of ZFP36L2. Knockdown of
ZFP36L2 in cultured BFU-E cells did not affect the rate of cell division
but disrupted glucocorticoid-induced BFU-E self-renewal, and knockdown
of ZFP36L2 in transplanted erythroid progenitors prevented expansion of
erythroid lineage progenitors normally seen following induction of
anemia by phenylhydrazine treatment. ZFP36L2 preferentially binds to
mRNAs that are induced or maintained at high expression levels during
terminal erythroid differentiation and negatively regulates their
expression levels. ZFP36L2 therefore functions as part of a molecular
switch promoting BFU-E self-renewal and a subsequent increase in the
total numbers of colony-forming unit-erythroid (CFU-E) progenitors and
erythroid cells that are generated.

- Glucocorticoid Receptor-Beta

Oakley et al. (1996) examined the expression, biochemical properties,
and physiologic function of GR-beta. They found that the GR-beta message
has a widespread tissue distribution. Although the GRL gene had
previously been reported to consist of 10 exons (Encio and
Detera-Wadleigh, 1991), Oakley et al. (1996) suggested that the GRL
sequences formerly identified as exon 9-alpha, intron J, and exon 9-beta
comprise 1 large terminal exon (exon 9) of approximately 4.1 kb and that
the GRL gene is organized into 9 rather than 10 exons. They demonstrated
that GR-beta resides primarily in the nucleus of transfected cells
independent of hormone treatment. Oakley et al. (1996) showed that
dominant-negative activity occurs in cells that have endogenous GR-alpha
receptors. In addition, they demonstrated that the repression of
GR-alpha activity occurs with the simple promoter pGRE2CAT, indicating
that the repression is a general phenomenon of glucocorticoid-responsive
promoters and that GRE-mediated transcription is actually inhibited.

Corticosteroids have specific effects on cardiac structure and function
mediated by mineralocorticoid and glucocorticoid receptors (MR and GR,
respectively). Aldosterone and corticosterone are synthesized in rat
heart. To see whether they might also be synthesized in the human
cardiovascular system, Kayes-Wandover and White (2000) examined the
expression of genes for steroidogenic enzymes as well as genes for GR,
MR, and 11-hydroxysteroid dehydrogenase (HSD11B2; 614232), which
maintains the specificity of MR. Human samples were from left and right
atria, left and right ventricles, aorta, apex, intraventricular septum,
and atrioventricular node, as well as whole adult and fetal heart. Using
RT-PCR, mRNAs encoding CYP11A (118485), CYP21 (613815), CYP11B1
(610613), GR, MR, and HSD11B2 were detected in all samples except
ventricles, which did not express CYP11B1. CYP11B2 (124080) mRNA was
detected in the aorta and fetal heart, but not in any region of the
adult heart, and CYP17 (609300) was not detected in any cardiac sample.
Levels of steroidogenic enzyme gene expression were typically 0.1% those
in the adrenal gland. The authors concluded that these findings are
consistent with autocrine or paracrine roles for corticosterone and
deoxycorticosterone, but not cortisol or aldosterone, in the normal
adult human heart.

Neutrophils are markedly less sensitive to glucocorticoids than are T
lymphocytes. Using immunofluorescence, Western blot, and RNA dot blot
analyses, Strickland et al. (2001) showed that GR-alpha and GR-beta are
both expressed on mononuclear cells and neutrophils, with GR-beta
expression somewhat greater than GR-alpha on neutrophils. IL8 (146930)
stimulation of neutrophils resulted in a significant increase in GR-beta
but not GR-alpha expression in neutrophils. Unlike human neutrophils,
mouse neutrophils do not express GR-beta. Transfection of GR-beta into
mouse neutrophils led to a significant reduction in the cell death rate
when exposed to dexamethasone. Strickland et al. (2001) concluded that
the high constitutive and proinflammatory cytokine-inducible
upregulation of GR-beta in neutrophils enhances their survival during
glucocorticoid treatment of inflammation. They proposed that this
knowledge may help in the development of novel antiinflammatory
strategies.

Inflammatory responses in many cell types are coordinately regulated by
the opposing actions of NF-kappa-B (164011) and the glucocorticoid
receptor. Webster et al. (2001) reported the identification of a tumor
necrosis factor (TNF)-responsive NF-kappa-B DNA-binding site 5-prime to
the GCCR promoter that leads to a 1.5-fold increase in GR-alpha mRNA and
a 2.0-fold increase in GR-beta mRNA in HeLaS3 cells, which endogenously
express both glucocorticoid receptor isoforms. However, TNF-alpha
(191160) treatment disproportionately increased the steady-state levels
of the GR-beta protein isoform over GR-alpha, making GR-beta the
predominant endogenous receptor isoform. Similar results were observed
following treatment of human lymphoid cells with TNF-alpha or
interleukin-1 (IL1; see 147760). The increase in GR-beta protein
expression correlated with the development of glucocorticoid resistance.

- Glucocorticoid Receptor-Gamma

Rivers et al. (1999) described GR-gamma, a novel variant of GCCR in
which, as a result of alternative splicing, 3 bases are retained from
the intron separating exons 3 and 4. These 3 bases code for an
additional amino acid (arginine) in the DNA-binding domain of the
receptor. Insertion of arginine at this site had previously been shown
to decrease transcriptional activation by the GR to 48% that of GR-alpha
(Ray et al., 1996). Analysis of cDNA from different tissues showed that
GR-gamma is widely expressed at a relatively high level (between 3.8%
and 8.7% of total GR).

BIOCHEMICAL FEATURES

Bledsoe et al. (2002) reported the crystal structure of the human GR
ligand-binding domain (LBD; residues 521 to 777) bound to dexamethasone
and a coactivator motif (the third LXXLL motif) derived from
transcriptional intermediary factor-2 (TIF2; 601993). Despite structural
similarity to other steroid receptors, the GR LBD adopts a surprising
dimer configuration involving formation of an intermolecular beta sheet.
Functional studies demonstrated that the dimer interface is important
for GR-mediated activation. The structure also revealed an additional
charge clamp that determines the binding selectivity of a coactivator
and a distinct ligand-binding pocket that explains its selectivity for
endogenous steroid hormones.

GENE STRUCTURE

Breslin et al. (2001) isolated and characterized a novel human GCCR gene
sequence (GR 1Ap/e), which is distinct from previously identified human
GCCR promoter and coding sequences. The 2,056-bp GR 1Ap/e sequence is
approximately 31 kbp upstream of the human GCCR coding sequence. This
sequence contains a novel promoter of 1,075 bp and untranslated exon
sequence of 981 bp. Alternative splicing produces 3 different GR
1A-containing transcripts, 1A1, 1A2, and 1A3. GCCR transcripts
containing exon 1A1, 1A2, 1B, and 1C are expressed at various levels in
many cancer cell lines, while the exon 1A3-containing GR transcript is
expressed most abundantly in blood cell cancer cell lines.
Glucocorticoid hormone treatment causes an upregulation of exon
1A3-containing GCCR transcripts in CEM-C7 T-lymphoblast cells and a
downregulation of exon 1A3-containing transcripts in IM-9 B-lymphoma
cells. Much of the basal promoter-activating function is found in the
+41/+269 sequence, which contains 2 deoxyribonuclease I footprints (FP5
and FP6). FP5 is an interferon regulatory factor-binding element, and it
contributes significantly to basal transcription rate, but it is not
activated by steroid. FP6 resembles a glucocorticoid response element
and can bind GR-beta.

Bray and Cotton (2003) stated that the NR3C1 gene contains 10 exons that
code for a 777-amino acid protein.

MAPPING

Gehring et al. (1984, 1985) achieved mapping of GRL to chromosome 5 by
study of hybrids of a human lymphoblastic cell line (that is
glucocorticoid-sensitive and contains glucocorticoid receptors of
wildtype characteristics) and a mouse lymphoma cell line (that is
resistant to lysis by glucocorticoids because of a mutant receptor that
exhibits abnormal DNA binding).

Weinberger et al. (1985) used a cDNA clone in connection with a panel of
somatic hybrid cells with various rearrangements involving chromosome 5
to assign GCCR to 5q11-q13. However, Francke and Foellmer (1989)
demonstrated by in situ hybridization that the GRL gene is located on
5q31-q32. The new assignment is consistent with linkage to a DNA marker
that maps to the same region (Giuffra et al., 1988) and also with
human/mouse comparative mapping data. From family linkage studies,
Giuffra et al. (1988) likewise concluded that the GRL locus is located
toward the end of the long arm of chromosome 5.

Hollenberg et al. (1985) confirmed the assignment of a glucocorticoid
receptor gene to chromosome 5 by Southern analysis of a hybrid cell line
containing only chromosome 5. In addition, 2 fragments (formed with
EcoRI and Hind III) were found in total human DNA and not in the hybrid
line. To map these, Hollenberg et al. (1985) used a dual-laser
fluorescence-activated cell sorter and spot-blotting. This confirmed the
assignment to chromosome 5 and in addition showed hGR sequences on
chromosome 16. The assignment to chromosome 16 was confirmed by Southern
analysis of DNA from a mouse erythroleukemia cell line containing human
chromosome 16. They concluded that both the alpha and beta receptor
proteins are probably encoded by a single gene on chromosome 5 and
generated by alternative splicing. In addition they concluded that a
gene on chromosome 16 contains homology to the glucocorticoid receptor
gene, at least between nucleotides 570 and 1,640. This could be the
receptor gene for a related steroid, a processed gene or pseudogene, or
a gene with other function that shares a domain with the GRL gene. See
138060.

Theriault et al. (1989) used in situ hybridization with a biotinylated
cDNA probe to localize the human GRL gene to human chromosome 5q31. The
assignment was confirmed by hybridization to chromosomes from an
individual with a balanced reciprocal translocation (5;8)(q31;q13).
Using chromosome-5-linked DNA probes to study somatic cell hybrids
retaining partial chromosome 5 and clinical samples from patients with
acquired deletions of 5q, Huebner et al. (1990) concluded that the GRL
gene is telomeric to CSF2 (138960) and centromeric to CSF1R
(164770)/PDGFRB (173410), near ECGF (131220).

HETEROGENEITY

Huizenga et al. (2000) described 5 patients with biochemical and
clinical cortisol resistance. They found alterations in receptor number
or ligand affinity and/or the ability of dexamethasone to inhibit
mitogen-induced cell proliferation. To investigate the molecular defects
leading to the clinical and biochemical pictures in these patients, they
screened the GCCR gene using PCR-SSCP sequence analysis. No GCCR gene
alterations were found in these patients. The authors concluded that
alterations somewhere in the cascade of events starting with ligand
binding to the GCCR protein, and finally resulting in the regulation of
the expression of glucocorticoid-responsive genes, or postreceptor
defects or interactions with other nuclear factors, form the
pathophysiologic basis of cortisol resistance in these patients.

MOLECULAR GENETICS

Bray and Cotton (2003) reported that a total of 15 missense, 3 nonsense,
3 frameshift, 1 splice site, and 2 alternatively spliced mutations had
been reported in the NR3C1 gene associated with glucocorticoid
resistance, as well as 16 polymorphisms.

Stevens et al. (2004) tested the potential involvement of the GCCR gene
in mediating glucocorticoid sensitivity using haplotype analysis and a
low-dose dexamethasone suppression test. Linkage disequilibrium across
the GCCR gene was determined in 216 Caucasians from the United Kingdom,
and 116 had a 0.25-mg overnight dexamethasone suppression test. Very
strong linkage disequilibrium was observed across the GCCR gene, with
only 4 haplotypes accounting for 95% of those observed. Haplotype
pattern mining and linear regression analyses independently identified a
3-marker haplotype across intron B to be significantly associated with
low postdexamethasone cortisol (P = 0.03). Carriage of this haplotype
occurred in 41% of the individuals with low postdexamethasone cortisol
versus 23% in the combined other quartiles. The authors concluded that a
3-point haplotype within intron B is associated with enhanced
sensitivity to glucocorticoids and that this haplotype may help
predetermine variation in clinical response to glucocorticoid therapy
and also assist the understanding of diseases related to glucocorticoid
production.

Van den Akker et al. (2006) studied the effect of the GCCR haplotype
characterized by the GR-9-beta polymorphism on GCCR transactivation and
transrepression. The 53 persons carrying the GR-9-beta haplotype without
ER22/23EK (138040.0011) had no significant differences in their BMI,
waist-to-hip ratio, fat spectrum, and insulin sensitivity or in their
cortisol response to dexamethasone and levels of C-reactive protein,
compared with 113 noncarriers. Ex vivo, GCCR-induced upregulation of
GCCR-induced leucine zipper mRNA via transactivation did not
significantly differ in GR-9-beta homozygotes, whereas the
downregulation of IL2 (147680) expression via transrepression was
decreased. Van den Akker et al. (2006) concluded that persons carrying
the GR-9-beta haplotype seem to have a decreased GCCR transrepression
with normal transactivation.

DeRijk et al. (2006) studied the role of a GCCR common polymorphism
(I180V) in the neuroendocrine response to a psychosocial stressor and in
electrolyte regulation. Carriers of the 180V allele showed higher saliva
(P less than 0.01), plasma cortisol (P less than 0.01), and heart rate
responses (P less than 0.05) to the Trier Social Stress Test than
noncarriers (I180I). In vitro testing of the 180V allele revealed a mild
loss of function using cortisol as a ligand, compared with the 180I
allele. DeRijk et al. (2006) concluded that cortisol and heart rate
responses to a psychosocial stressor are enhanced in carriers of the
180V variant.

ANIMAL MODEL

Pepin et al. (1992) developed transgenic mice in which antisense RNA
complementary to the 3-prime noncoding region of the glucocorticoid
receptor mRNA led to reduced glucocorticoid receptor capacity and
function, predominantly in neuronal tissue. Montkowski et al. (1995)
demonstrated that the transgenic mice have profound behavioral changes
and elevated plasma corticotropin concentrations in response to stress.
Treatment with moclobemide, an inhibitor of monoamine oxidase type A
(309850), reversed the behavioral deficits in this mouse model.

Since the glucocorticoid receptor can influence transcription both
through DNA-binding-dependent and -independent mechanisms, Reichardt et
al. (1998) attempted to separate these modes of action by introducing
the arg458-to-thr point mutation into the glucocorticoid receptor by
gene targeting using the Cre/loxP system. This mutation impairs
dimerization and therefore GRE-dependent transactivation, while
functions that require cross-talk with other transcription factors, such
as transrepression of AP-1-driven genes, remain intact. In contrast to
GR-/- mice, these mutants, termed GR-dim, are viable, revealing the in
vivo relevance of DNA-binding-independent activities of the
glucocorticoid receptor. The GR-dim/dim mice lose the ability to
transactivate gene transcription by cooperative DNA binding but retain
the repressing function of the corticosteroid receptor. Furthermore, the
development and function of the adrenal medulla are not impaired in
these mice.

The glucocorticoid receptor controls transcription of target genes both
directly by interaction with DNA regulatory elements and indirectly by
cross-talk with other transcription factors. In response to various
stimuli, including stress, glucocorticoids coordinate metabolic,
endocrine, immune, and nervous system responses and ensure an adequate
profile of transcription. In the brain, glucocorticoid receptor has been
thought to modulate emotional behavior, cognitive functions, and
addictive states. These aspects could not be studied in the absence of
functional glucocorticoid receptor because inactivation of the Grl1 gene
in mice causes lethality at birth. Therefore, Tronche et al. (1999)
generated tissue-specific mutations of this gene using the
Cre/loxP-recombination system. This allowed them to generate viable
adult mice with loss of glucocorticoid receptor function in selected
tissues. Loss of glucocorticoid receptor function in the nervous system
impaired regulation of the hypothalamus-pituitary-adrenal axis,
resulting in increased glucocorticoid levels that lead to symptoms
reminiscent of those observed in Cushing syndrome. Conditional
mutagenesis of glucocorticoid receptor in the nervous system provided
genetic evidence for the importance of glucocorticoid receptor signaling
in emotional behavior because mutant animals showed an impaired
behavioral response to stress and displayed reduced anxiety.

Using a tandem array of mouse mammary tumor virus reporter elements and
a form of glucocorticoid receptor labeled with green fluorescent
protein, McNally et al. (2000) observed targeting of the receptor to
response elements in mouse cells. Photobleaching experiments provided
direct evidence that the hormone-occupied receptor undergoes rapid
exchange between chromatin and the nucleoplasmic compartment. Thus,
McNally et al. (2000) concluded that the interaction of regulatory
proteins with target sites in chromatin is a more dynamic process than
had been believed.

Brewer et al. (2003) used Lck (153390) promoter-driven, Cre
recombinase-mediated excision of exon 2 of the Gccr gene to generate
healthy mice lacking Gccr only in T cells and thymus to avoid perinatal
mortality and to maintain systemic corticosterone responses. Gccr was
dispensable for T-cell development, but administration of a T-cell
stimulus or superantigen to mutant mice, but not control mice, resulted
in high mortality that could not be rescued by dexamethasone or
anti-Ifng (147570). Microarray and ribonuclease protection analyses
suggested that endogenous glucocorticoids are required for
transcriptional suppression of Ifng, but not Tnf or Il2 (147680), in T
cells. Inhibition of Cox2 (600262) protected mice from lethality without
affecting Ifng levels. Histologic analysis revealed that T-cell
stimulation in mutant mice caused significant damage to the
gastrointestinal tract, particularly the cecum, but little or no damage
in other tissues. Brewer et al. (2003) concluded that Gccr function in T
cells is essential for survival during polyclonal T-cell activation.
Furthermore, they suggested that Cox2 inhibition may be useful for
treatment of glucocorticoid insufficiency or resistance in patients with
toxic shock syndrome (see 607395), graft-versus-host disease (GVHD; see
614395), or other T-cell activating processes.

Tronche et al. (2004) found that mice with targeted disruption of Gccr
in hepatocytes showed dramatically reduced body size due to impaired
Stat5 (601511)-dependent growth hormone signaling. Mice with a mutant
Gccr deficient in DNA binding but still able to interact with Stat5
showed normal body size and normal levels of Stat5-dependent
transcription. Tronche et al. (2004) concluded that GCCR acts as a
coactivator for STAT5-dependent transcription upon growth hormone
stimulation.

Wei et al. (2004) showed that the glucocorticoid receptor modulates the
range and stability of emotions, features of emotional responsiveness.
They generated transgenic mice overexpressing Gccr specifically in
forebrain. These mice displayed a significant increase in anxiety-like
and depressive-like behaviors relative to wildtype, and were also
supersensitive to antidepressants and showed enhanced sensitization to
cocaine. Thus, mice overexpressing Gccr in forebrain have a consistently
wider than normal range of reactivity in both positive and negative
emotionality tests. This phenotype is associated, in specific brain
regions, with increased expression of genes relevant to emotionality:
corticotropin-releasing hormone (122560), 5-hydroxytryptamine receptor
1A (109760), and transporters of serotonin (182138), norepinephrine
(163970), and dopamine (126455). Thus, Gccr overexpression in forebrain
causes higher 'emotional lability' secondary to a unique pattern of
molecular regulation. Wei et al. (2004) concluded that natural
variations in GCCR gene expression can contribute to the fine tuning of
emotional stability or lability and may play a role in bipolar disorder
(see 125480).

Barik et al. (2013) bred mice with selective inactivation of the gene
encoding the glucocorticoid receptor along the dopamine pathway, and
exposed them to repeated aggressions. Glucocorticoid receptor in
dopaminoceptive but not dopamine-releasing neurons specifically promoted
social aversion as well as dopaminergic neurochemical and
electrophysiologic neuroadaptations. Anxiety and fear memories remained
unaffected. Acute inhibition of the activity of dopamine-releasing
neurons fully restored social interaction in socially defeated wildtype
mice. Barik et al. (2013) concluded that their data suggested a
glucocorticoid receptor-dependent neuronal dichotomy for the regulation
of emotional and social behaviors, and clearly implicated the
glucocorticoid receptor as a link between stress resiliency and
dopaminergic tone.

Niwa et al. (2013) described an underlying mechanism in which
glucocorticoids link adolescent stressors to epigenetic controls in
neurons. In a mouse model of this phenomenon, a mild isolation stress
affects the mesocortical projection of dopaminergic neurons in which DNA
hypermethylation of the tyrosine hydoxylase (191290) gene is elicited,
but only when combined with a relevant genetic risk for neuropsychiatric
disorders. These molecular changes were associated with several
neurochemical and behavioral deficits that occur in this mouse model,
all of which were blocked by a glucocorticoid receptor antagonist. Niwa
et al. (2013) concluded that the biology and phenotypes of the mouse
models resemble those of psychotic depression.

*FIELD* AV
.0001
GLUCOCORTICOID RESISTANCE, FAMILIAL
NR3C1, ASP641VAL

In the kindred originally reported by Vingerhoeds et al. (1976) and
studied by Chrousos et al. (1982, 1983) and Lipsett et al. (1985),
Hurley et al. (1991) sequenced the glucocorticoid receptor from 3
affected members. A change at nucleotide 2054 predicted substitution of
valine for aspartic acid at amino acid residue 641. The propositus was
homozygous while the other relatives were heterozygous for the mutation.
The point mutation was in the steroid-binding domain of the receptor.

.0002
GLUCOCORTICOID RESISTANCE, FAMILIAL
NR3C1, IVS6DS, 4-BP DEL

In all 3 affected members of a Dutch kindred, Karl et al. (1993) found
that 1 NR3C1 allele had a 4-bp deletion that removed the donor splice
site affecting the last 2 bases of the exon and the first 2 nucleotides
of intron 6. The father and 3 of 5 children were affected. Affected
members had hypercortisolism and approximately half of normal
glucocorticoid receptors. The proband was a daughter with manifestations
of hyperandrogenism. Furthermore, in the proband, in 1 of her affected
brothers, and in her unaffected sister, Karl et al. (1993) found a
single nucleotide substitution (1220A-G; asn363 to ser; 138040.0007) in
exon 2 of the NR3C1 allele. Transfection studies indicated that the
amino acid substitution did not alter the function of the glucocorticoid
receptor. The presence of the null allele in this family was apparently
compensated for by increased cortisol production at the expense of
concurrent hyperandrogenism.

.0003
GLUCOCORTICOID RESISTANCE, CELLULAR
NR3C1, LEU753PHE

Ashraf and Thompson (1993) showed that 2 glucocorticoid-resistant cell
lines were hemizygous for a leu753-to-phe mutation. Both were derived
from a wildtype cell line heterozygous for this mutation; the resistant
cell lines had suffered the loss of the normal allele.

.0004
REMOVED FROM DATABASE
.0005
REMOVED FROM DATABASE
.0006
REMOVED FROM DATABASE
.0007
GLUCOCORTICOID RECEPTOR POLYMORPHISM
NR3C1, ASN363SER

Koper et al. (1997) identified a polymorphism, located at nucleotide
position 1220 (AAT to AGT), that results in an asparagine-to-serine
change in codon 363 (N363S) of the NR3C1 protein. Huizenga et al. (1998)
investigated whether this polymorphism is associated with altered
sensitivity to glucocorticoids. In a group of 216 elderly persons, they
identified 13 heterozygotes for the N363S polymorphism by PCR/SSCP
analysis. Thus, they found the polymorphism in 6.0% of the studied
population. Huizenga et al. (1998) concluded that individuals carrying
this polymorphism were clinically healthy, but had a higher sensitivity
to exogenously administered glucocorticoids, with respect to both
cortisol suppression and insulin response. Huizenga et al. (1998)
speculated that life-long exposure to the mutated allele may be
accompanied by an increased body mass index and a lowered bone mineral
density in the lumbar spine with no effect on blood pressure.

Dobson et al. (2001) investigated the association between the 363S
allele and risk factors for coronary heart disease and diabetes mellitus
in a population of European origin living in the northeast of the United
Kingdom. Blood samples from 135 males and 240 females were characterized
for 363 allele status. The overall frequency of the 363S allele was
3.0%; 23 heterozygotes (7 males and 16 females) but no 363S homozygotes
were identified. These data showed a significant association of the 363S
allele with increased waist-to-hip ratio in males but not in females.
This allele was not associated with blood pressure, body mass index,
serum cholesterol, triglycerides, low-density lipoprotein and
high-density lipoprotein cholesterol levels, or glucose tolerance
status. The authors concluded that this GR polymorphism may contribute
to central obesity in men.

Russcher et al. (2005) examined the effects of the N363S polymorphism on
glucocorticoid sensitivity at the level of gene expression in functional
assays. The N363S polymorphism, associated with increased glucocorticoid
sensitivity, resulted in a significantly increased transactivating
capacity, both in vitro and ex vivo. The N363S polymorphism did not seem
to influence the transrepressing capacity of the glucocorticoid
receptor.

In a population of 295 South Asians living in the United Kingdom
consisting of 35% people of Indian origin, 42% of Pakistani origin, and
19% Bangladeshi origin, Syed et al. (2004) detected a prevalence of 0.3%
of the 363S allele (2 heterozygous subjects). Both subjects had raised
body mass index and central obesity. The authors concluded that given
its prevalence, the N363S polymorphism is unlikely to be an important
factor in obesity and/or dysmetabolic traits in people of South Asian
origin living in the United Kingdom.

Majnik et al. (2006) found that the carrier frequency of the N363S
variant in patients with bilateral adrenal incidentalomas was markedly
and significantly higher than that in control subjects (20.5 vs 7.8%, P
less than 0.05), but not in those with unilateral adrenal incidentalomas
(7.1%) or in patients with type 2 diabetes (13.0%).

Jewell and Cidlowski (2007) studied the biologic relevancy of the N363S
variant on GCCR function. Functional assays with reporter gene systems
and homologous downregulation revealed only minor differences between
the wildtype human GCCR and N363S receptors in both transiently and
stably expressing cell lines. However, examination of the 2 receptors by
human gene microarray analysis revealed a unique gene expression profile
for N363S. Jewell and Cidlowski (2007) noted that several of the
regulated genes supported a potential role for the N363S polymorphism in
human diseases.

.0008
GLUCOCORTICOID RESISTANCE, GENERALIZED
NR3C1, ILE559ASN

Karl et al. (1996) reported a patient with sporadic generalized
glucocorticoid resistance who, at age 33, presented with infertility and
hypertension. The patient's clinical and biochemical picture was more
severe than would be expected from the loss of 1 GCCR allele activity.
Two years after initiation of an effective dexamethasone regimen, this
patient developed full-blown Cushing syndrome secondary to an
ACTH-secreting pituitary tumor, with a further 8-fold increase in serum
cortisol. The patient had a heterozygous missense mutation in exon 4 of
the glucocorticoid receptor gene resulting in a nonconservative
ile559-to-asn (I559N) amino acid substitution. This allele had
negligible ligand binding, was transcriptionally extremely weak, and
exerted a trans-dominant-negative effect on the transactivational
activity of the wildtype GCCR, causing severe glucocorticoid resistance
in the heterozygous state (Kino et al., 2001).

To further elucidate the mechanism of trans-dominance of the I559N
mutant receptor and its clinical manifestations, Kino et al. (2001)
examined its trafficking in living cells using N-terminal fusion of
green fluorescent protein (GFP) to wildtype and I559N mutant
glucocorticoid receptor. The chimeric mutant protein product was
predominantly localized in the cytoplasm, and only high doses or
prolonged glucocorticoid treatment triggered complete nuclear import
that took 180 minutes, versus 12 minutes for the wildtype construct.
Furthermore, the mutant construct inhibited nuclear import of the
wildtype, suggesting that its trans-dominant activity on the wildtype
receptor is probably exerted at the process of nuclear translocation.

.0009
GLUCOCORTICOID RESISTANCE, FAMILIAL
NR3C1, ILE747MET

Vottero et al. (2002) reported a French kindred with familial
glucocorticoid resistance in which affected members had a heterozygous
T-to-G transversion at nucleotide 2373 of exon 9-alpha of the GCCR gene,
causing substitution of ile747 to met (I747M). This mutation was located
close to helix 12, at the C terminus of the ligand-binding domain, which
has a pivotal role in the formation of activation function (AF)-2, a
subdomain that interacts with p160 coactivators. The affinity of the
mutant GCCR for dexamethasone was decreased by about 2-fold, and its
transcriptional activity on the glucocorticoid-responsive mouse mammary
tumor virus promoter was compromised by 20- to 30-fold. In addition, the
mutant GCCR functioned as a dominant-negative inhibitor of wildtype
receptor-induced transactivation. The mutant GR through its intact AF-1
domain bound to a p160 coactivator, but failed to do so through its AF-2
domain. Overexpression of a p160 coactivator restored the
transcriptional activity and reversed the negative transdominant
activity of the mutant GCCR. The authors concluded that the mutant
receptor has an ineffective AF-2 domain, which leads to an abnormal
interaction with p160 coactivators and a distinct nuclear distribution
of both.

.0010
PSEUDOHERMAPHRODITISM, FEMALE, WITH HYPOKALEMIA, DUE TO GLUCOCORTICOID
RESISTANCE
NR3C1, VAL571ALA

Mendonca et al. (2002) reported a female patient with ambiguous
genitalia, the child of second-cousin parents, who had been treated as a
21-hydroxylase deficiency (201910) case since the age of 5 years. She
had very high levels of plasma ACTH and high levels of cortisol,
androstenedione, and 17-hydroxyprogesterone. Her cortisol and
17-hydroxyprogesterone levels were not compatible with the diagnosis of
classic congenital adrenal hyperplasia; furthermore, cortisol was not
properly suppressed after dexamethasone administration. Her laboratory
evaluation indicated a diagnosis of glucocorticoid resistance. A
homozygous T-to-C substitution at nucleotide 1844 in exon 5 of the GR
gene was identified in the patient, which caused a valine-to-alanine
substitution at amino acid 571 (V571A) in the ligand domain of the
receptor. Her parents and an older sister were heterozygous for this
mutation. The ala571 allele had a 6-fold reduction in binding affinity
compared with the wildtype receptor. Mendonca et al. (2002) concluded
that this was the first reported case of female pseudohermaphroditism
caused by a novel GR gene mutation and that this phenotype indicates
that pre- and postnatal virilization can occur in females with the
glucocorticoid resistance syndrome.

.0011
GLUCOCORTICOID RESISTANCE, RELATIVE
BODY COMPOSITION, BENEFICIAL, INCLUDED
NR3C1, 198G-A, 200G-A

Koper et al. (1997) identified a polymorphism consisting of 2 linked
point mutations in the glucocorticoid receptor gene. The first mutation,
a G-to-A transition in codon 22, is silent, with both GAG and GAA coding
for glutamic acid (E). The second mutation changes codon 23 from
arginine (R) to lysine (K) (AGG-AAG). Van Rossum et al. (2002) found an
association of this polymorphism with relative resistance to
glucocorticoids, and in a population-based study in the elderly observed
that carriers of the ER22/23EK polymorphism had better insulin
sensitivity and lower total and low density lipoprotein cholesterol
levels. They also found the frequency of the 22/23EK allele to be higher
in the elder half of the studied population, which suggested a survival
advantage. In a separate population of 402 elderly Dutch men, van Rossum
et al. (2004) found that after 4 years of follow-up 19.2% of the
noncarriers had died, whereas none of the 21 ER22/23EK carriers had
died. ER22/23EK carriers also had lower serum C-reactive protein
(123260) levels, possibly reflecting improved cardiovascular status.

Van Rossum et al. (2004) investigated the association of the ER22/23EK
polymorphism with differences in body composition and muscle strength in
a cohort of 350 subjects who were followed from age 13 to 36 years. They
identified 27 (8%) heterozygous ER22/23EK carriers. In males at 36 years
of age, they found that ER22/23EK carriers were taller, had more lean
body mass, greater thigh circumference, and more muscle strength in arms
and legs. They observed no differences in body mass index or fat mass.
In females, waist and hip circumferences tended to be smaller in
ER22/23EK carriers at the age of 36 years, but no differences in body
mass index were found. The authors concluded that the ER22/23EK
polymorphism is associated with a sex-specific, beneficial body
composition at young adult age, as well as greater muscle strength in
males.

Russcher et al. (2005) examined the effects of the ER22/23EK
polymorphism on glucocorticoid sensitivity at the level of gene
expression in functional assays. The ER22/23EK polymorphism produced a
significant reduction of transactivating capacity in both transfection
experiments and in peripheral blood mononuclear lymphocytes of carriers
of this polymorphism. The ER22/23EK polymorphism did not seem to
influence the transrepressing capacity of the glucocorticoid receptor.

Finken et al. (2007) tested the effects of the R23K (ER22/23EK) and
N363S (138040.0007) polymorphisms in the GCCR gene, associated with
decreased and increased sensitivity to cortisol, respectively, on linear
growth and the adult metabolic profile in a cohort of 249 men and women
born less than 32 weeks' gestation and followed up prospectively from
birth until 19 years of age. The 23K variant, present in 24 individuals,
was associated with lower fasting insulin levels and a lower homeostatic
model assessment for insulin resistance index, as well as with a taller
stature from the age of 1 year. Carriers of the 23K variant showed
complete catch-up growth between the ages of 3 months and 1 year, and
attained height was similar to the population reference mean, whereas
stature in noncarriers was on average 0.5 standard deviation below this
mean. Finken et al. (2007) concluded that carriers of the 23K variant
are, at least in part, protected against postnatal growth failure and
insulin resistance after preterm birth.

.0012
GLUCOCORTICOID RESISTANCE, GENERALIZED
NR3C1, LEU773PRO

In a 29-year-old woman with generalized glucocorticoid resistance who
presented with a long-standing history of fatigue, anxiety,
hyperandrogenism, and hypertension, Charmandari et al. (2005) found a
heterozygous T-to-C transition at nucleotide position 2318 in exon 9 of
the GR-alpha gene, which resulted in substitution of leucine by proline
at amino acid position 773 (L773P) in the ligand-binding domain of the
receptor. Compared with the wildtype receptor, the mutant L773P GR-alpha
demonstrated a 2-fold reduction in the ability to transactivate the
glucocorticoid-inducible mouse mammary tumor virus promoter, exerted a
dominant-negative effect on the wildtype receptor, had a 2.6-fold
reduction in the affinity for ligand, showed delayed nuclear
translocation (30 vs 12 min), and, although it preserved its ability to
bind to DNA, displayed an abnormal interaction with the GR-interacting
protein-1 coactivator (NCOA2; 601993) in vitro. The authors concluded
that the C terminus of the ligand-binding domain of GR-alpha is
important in conferring transactivational activity by altering multiple
functions of this composite transcription factor.

.0013
GLUCOCORTICOID RESISTANCE, GENERALIZED
NR3C1, ARG477HIS

In a 41-year-old woman with primary cortisol resistance, Ruiz et al.
(2001) identified heterozygosity for a 1430G-A transition in exon 4 of
the NR3C1 gene, resulting in an arg477-to-his (R477H) substitution in
the second zinc finger in the DNA-binding domain of the receptor. The
mutant showed no transactivating capacity.

Charmandari et al. (2006) studied the mechanisms through which the R477H
and G779S (138040.0014) mutations in the DNA- and ligand-binding
domains, respectively, affect glucocorticoid signal transduction and
concluded that the mutants cause generalized glucocorticoid resistance
by affecting different functions of the glucocorticoid receptor, which
span the cascade of the GR signaling system.

.0014
GLUCOCORTICOID RESISTANCE, GENERALIZED
NR3C1, GLY679SER

In a 31-year-old woman with primary cortisol resistance, Ruiz et al.
(2001) identified heterozygosity for a 2035G-A transition in exon 8 of
the NR3C1 gene, resulting in a gly679-to-ser (G679S) substitution in the
ligand-binding domain of the receptor. The mutant showed reduced
transactivation capacity compared to wildtype.

See 138040.0013 and Charmandari et al. (2006).

.0015
GLUCOCORTICOID RESISTANCE, GENERALIZED
NR3C1, PHE737LEU

In a boy with generalized glucocorticoid resistance, Charmandari et al.
(2007) identified a 2209T-C transition in exon 9 of the GR-alpha gene,
resulting in a phe737-to-leu (F737L) substitution within helix 11 of the
ligand-binding domain of the protein. Compared to wildtype, the mutant
receptor demonstrated decreased affinity for the ligand, marked delay in
nuclear translocation, and/or abnormal interaction with the
GR-interacting protein-1 coactivator (NCOA2; 601993). Charmandari et al.
(2007) concluded that these findings confirm the importance of the C
terminus of the ligand-binding domain of the receptor in conferring
transactivational activity.

*FIELD* SA
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79. Wei, Q.; Lu, X.-Y.; Liu, L.; Schafer, G.; Shieh, K.-R.; Burke,
S.; Robinson, T. E.; Watson, S. J.; Seasholtz, A. F.; Akil, H.: Glucocorticoid
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80. Weinberger, C.; Evans, R.; Rosenfeld, M. G.; Hollenberg, S. M.;
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*FIELD* CS

Endocrine:
Hypertension

Misc:
Severe hypertension and hypokalemic alkalosis in homozygotes

Lab:
Glucocorticoid receptor defect;
Slightly elevated 24-hour mean plasma cortisol;
Increased urinary free cortisol

Inheritance:
Autosomal dominant (5q31-q32)

*FIELD* CN
Ada Hamosh - updated: 08/27/2013
Ada Hamosh - updated: 2/20/2013
Ada Hamosh - updated: 2/7/2012
Ada Hamosh - updated: 8/14/2009
John A. Phillips, III - updated: 1/8/2009
John A. Phillips, III - updated: 9/22/2008
John A. Phillips, III - updated: 5/2/2008
John A. Phillips, III - updated: 3/24/2008
John A. Phillips, III - updated: 9/28/2007
John A. Phillips, III - updated: 7/18/2007
John A. Phillips, III - updated: 7/17/2007
John A. Phillips, III - updated: 5/16/2007
John A. Phillips, III - updated: 5/14/2007
John A. Phillips, III - updated: 4/18/2007
Patricia A. Hartz - updated: 2/8/2006
John A. Phillips, III - updated: 8/1/2005
John A. Phillips, III - updated: 4/29/2005
Victor A. McKusick - updated: 10/7/2004
Patricia A. Hartz - updated: 5/11/2004
Paul J. Converse - updated: 9/5/2003
John A. Phillips, III - updated: 7/29/2003
Victor A. McKusick - updated: 7/11/2003
Victor A. McKusick - updated: 6/19/2003
John A. Phillips, III - updated: 1/31/2003
George E. Tiller - updated: 8/21/2002
Stylianos E. Antonarakis - updated: 7/29/2002
John A. Phillips, III - updated: 7/12/2002
John A. Phillips, III - updated: 6/11/2002
Paul J. Converse - updated: 10/18/2001
John A. Phillips, III - updated: 10/4/2001
Victor A. McKusick - updated: 6/18/2001
John A. Phillips, III - updated: 3/5/2001
John A. Phillips, III - updated: 2/9/2001
John A. Phillips, III - updated: 10/2/2000
Ada Hamosh - reorganized: 2/23/2000
Ada Hamosh - updated: 2/17/2000
Victor A. McKusick - updated: 2/9/2000
Victor A. McKusick - updated: 8/30/1999
John A. Phillips, III - updated: 6/24/1998
John A. Phillips, III - updated: 6/22/1998
Stylianos E. Antonarakis - updated: 6/4/1998
John A. Phillips, III - updated: 5/21/1998
John A. Phillips, III - updated: 3/7/1997
John A. Phillips, III - updated: 12/13/1996
Jon B. Obray - updated: 6/29/1996
Orest Hurko - updated: 5/8/1996

*FIELD* CD
Victor A. McKusick: 1/7/1987

*FIELD* ED
alopez: 08/27/2013
alopez: 2/25/2013
terry: 2/20/2013
terry: 6/4/2012
alopez: 2/8/2012
terry: 2/7/2012
mgross: 12/16/2011
carol: 9/23/2011
terry: 4/25/2011
terry: 3/25/2011
alopez: 3/24/2011
alopez: 3/23/2011
carol: 9/15/2009
alopez: 8/21/2009
terry: 8/14/2009
alopez: 1/8/2009
ckniffin: 12/3/2008
alopez: 9/22/2008
carol: 5/2/2008
carol: 3/24/2008
carol: 11/30/2007
alopez: 9/28/2007
alopez: 7/18/2007
alopez: 7/17/2007
alopez: 5/16/2007
alopez: 5/14/2007
alopez: 4/18/2007
carol: 12/13/2006
wwang: 6/22/2006
wwang: 2/14/2006
terry: 2/8/2006
alopez: 8/1/2005
alopez: 4/29/2005
tkritzer: 10/11/2004
terry: 10/7/2004
mgross: 5/11/2004
carol: 3/17/2004
alopez: 10/16/2003
mgross: 9/5/2003
alopez: 7/29/2003
cwells: 7/14/2003
terry: 7/11/2003
alopez: 6/24/2003
terry: 6/19/2003
terry: 6/16/2003
alopez: 1/31/2003
cwells: 8/21/2002
mgross: 7/29/2002
alopez: 7/12/2002
alopez: 6/11/2002
mgross: 10/18/2001
joanna: 10/10/2001
cwells: 10/9/2001
cwells: 10/4/2001
carol: 9/10/2001
mcapotos: 7/2/2001
mcapotos: 6/26/2001
terry: 6/18/2001
terry: 3/20/2001
mgross: 3/5/2001
alopez: 2/23/2001
terry: 2/9/2001
mgross: 10/11/2000
terry: 10/2/2000
carol: 2/23/2000
alopez: 2/17/2000
terry: 2/17/2000
carol: 2/17/2000
carol: 2/16/2000
terry: 2/9/2000
mgross: 9/24/1999
alopez: 8/30/1999
terry: 8/30/1999
dkim: 9/11/1998
dholmes: 7/2/1998
dholmes: 6/29/1998
dholmes: 6/24/1998
dholmes: 6/22/1998
carol: 6/9/1998
terry: 6/4/1998
dholmes: 5/21/1998
dholmes: 4/15/1998
alopez: 8/4/1997
jenny: 6/3/1997
jenny: 5/28/1997
mark: 3/27/1997
jenny: 3/7/1997
jenny: 2/25/1997
carol: 7/1/1996
carol: 6/29/1996
mark: 5/8/1996
terry: 5/7/1996
terry: 5/3/1996
mark: 7/18/1995
terry: 6/26/1995
mimadm: 9/24/1994
warfield: 4/8/1994
pfoster: 2/18/1994
carol: 11/12/1993