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Abrogation of glucocorticoid receptor dimerization correlates with dissociated glucocorticoid behavior of compound A

Steven Robertson, Fatima Allie-Reid, Wim Vanden Berghe UGent, Koch Visser, Anke Binder, Donita Africander, Michael Vismer, Karolien De Bosscher UGent, Janet Hapgood and Guy Haegeman, et al. (2010) JOURNAL OF BIOLOGICAL CHEMISTRY. 285(11). p.8061-8075
abstract
Compound A (CpdA), a dissociated glucocorticoid receptor modulator, decreases corticosteroid-binding globulin (CBG), adrenocorticotropic hormone (ACTH), and luteneinizing hormone levels in rats. Whether this is due to transcriptional regulation by CpdA is not known. Using promoter reporter assays we show that CpdA, like dexamethasone (Dex), directly transrepresses these genes. Results using a rat Cbg proximal-promoter reporter construct in BWTG3 and HepG2 cell lines support a glucocorticoid receptor (GR)-dependent transrepression mechanism for CpdA. However, CpdA, unlike Dex, does not result in transactivation via glucocorticoid-responsive elements within a promoter reporter construct even when GR is co-transfected. The inability of CpdA to result in transactivation via glucocorticoid-responsive elements is confirmed on the endogenous tyrosine aminotransferase gene, whereas transrepression ability is confirmed on the endogenous CBG gene. Consistent with a role for CpdA in modulating GR activity, whole cell binding assays revealed that CpdA binds reversibly to the GR, but with lower affinity than Dex, and influences association of [H-3] Dex, but has no effect on dissociation. In addition, like Dex, CpdA causes nuclear translocation of the GR, albeit to a lesser degree. Several lines of evidence, including fluorescence resonance energy transfer, co-immunoprecipitation, and nuclear immunofluorescence studies of nuclear localization-deficient GR show that CpdA, unlike Dex, does not elicit ligand-induced GR dimerization. Comparison of the behavior of CpdA in the presence of wild type GR to that of Dex with a dimerization-deficient GR mutant (GR(dim)) strongly supports the conclusion that loss of dimerization is responsible for the dissociated behavior of CpdA.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
TRANSCRIPTIONAL ACTIVATION, PROOPIOMELANOCORTIN GENE, MOLECULAR-MECHANISMS, AZIRIDINE PRECURSOR, IN-VIVO, RESONANCE ENERGY-TRANSFER, PROTEIN-PROTEIN INTERACTIONS, FACTOR-KAPPA-B, CORTICOSTEROID-BINDING GLOBULIN, GONADOTROPIN-RELEASING-HORMONE
journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
J. Biol. Chem.
volume
285
issue
11
pages
8061 - 8075
Web of Science type
Article
Web of Science id
000275413800024
JCR category
BIOCHEMISTRY & MOLECULAR BIOLOGY
JCR impact factor
5.328 (2010)
JCR rank
50/284 (2010)
JCR quartile
1 (2010)
ISSN
0021-9258
DOI
10.1074/jbc.M109.087866
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1150809
handle
http://hdl.handle.net/1854/LU-1150809
date created
2011-02-15 11:02:39
date last changed
2011-02-22 11:30:55
@article{1150809,
  abstract     = {Compound A (CpdA), a dissociated glucocorticoid receptor modulator, decreases corticosteroid-binding globulin (CBG), adrenocorticotropic hormone (ACTH), and luteneinizing hormone levels in rats. Whether this is due to transcriptional regulation by CpdA is not known. Using promoter reporter assays we show that CpdA, like dexamethasone (Dex), directly transrepresses these genes. Results using a rat Cbg proximal-promoter reporter construct in BWTG3 and HepG2 cell lines support a glucocorticoid receptor (GR)-dependent transrepression mechanism for CpdA. However, CpdA, unlike Dex, does not result in transactivation via glucocorticoid-responsive elements within a promoter reporter construct even when GR is co-transfected. The inability of CpdA to result in transactivation via glucocorticoid-responsive elements is confirmed on the endogenous tyrosine aminotransferase gene, whereas transrepression ability is confirmed on the endogenous CBG gene. Consistent with a role for CpdA in modulating GR activity, whole cell binding assays revealed that CpdA binds reversibly to the GR, but with lower affinity than Dex, and influences association of [H-3] Dex, but has no effect on dissociation. In addition, like Dex, CpdA causes nuclear translocation of the GR, albeit to a lesser degree. Several lines of evidence, including fluorescence resonance energy transfer, co-immunoprecipitation, and nuclear immunofluorescence studies of nuclear localization-deficient GR show that CpdA, unlike Dex, does not elicit ligand-induced GR dimerization. Comparison of the behavior of CpdA in the presence of wild type GR to that of Dex with a dimerization-deficient GR mutant (GR(dim)) strongly supports the conclusion that loss of dimerization is responsible for the dissociated behavior of CpdA.},
  author       = {Robertson, Steven and Allie-Reid, Fatima and Vanden Berghe, Wim and Visser, Koch and Binder, Anke and Africander, Donita and Vismer, Michael and De Bosscher, Karolien and Hapgood, Janet and Haegeman, Guy and Louw, Ann},
  issn         = {0021-9258},
  journal      = {JOURNAL OF BIOLOGICAL CHEMISTRY},
  keyword      = {TRANSCRIPTIONAL ACTIVATION,PROOPIOMELANOCORTIN GENE,MOLECULAR-MECHANISMS,AZIRIDINE PRECURSOR,IN-VIVO,RESONANCE ENERGY-TRANSFER,PROTEIN-PROTEIN INTERACTIONS,FACTOR-KAPPA-B,CORTICOSTEROID-BINDING GLOBULIN,GONADOTROPIN-RELEASING-HORMONE},
  language     = {eng},
  number       = {11},
  pages        = {8061--8075},
  title        = {Abrogation of glucocorticoid receptor dimerization correlates with dissociated glucocorticoid behavior of compound A},
  url          = {http://dx.doi.org/10.1074/jbc.M109.087866},
  volume       = {285},
  year         = {2010},
}

Chicago
Robertson, Steven, Fatima Allie-Reid, Wim Vanden Berghe, Koch Visser, Anke Binder, Donita Africander, Michael Vismer, et al. 2010. “Abrogation of Glucocorticoid Receptor Dimerization Correlates with Dissociated Glucocorticoid Behavior of Compound A.” Journal of Biological Chemistry 285 (11): 8061–8075.
APA
Robertson, S., Allie-Reid, F., Vanden Berghe, W., Visser, K., Binder, A., Africander, D., Vismer, M., et al. (2010). Abrogation of glucocorticoid receptor dimerization correlates with dissociated glucocorticoid behavior of compound A. JOURNAL OF BIOLOGICAL CHEMISTRY, 285(11), 8061–8075.
Vancouver
1.
Robertson S, Allie-Reid F, Vanden Berghe W, Visser K, Binder A, Africander D, et al. Abrogation of glucocorticoid receptor dimerization correlates with dissociated glucocorticoid behavior of compound A. JOURNAL OF BIOLOGICAL CHEMISTRY. 2010;285(11):8061–75.
MLA
Robertson, Steven, Fatima Allie-Reid, Wim Vanden Berghe, et al. “Abrogation of Glucocorticoid Receptor Dimerization Correlates with Dissociated Glucocorticoid Behavior of Compound A.” JOURNAL OF BIOLOGICAL CHEMISTRY 285.11 (2010): 8061–8075. Print.