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

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dc.contributor.authorRobertson, Steven
dc.contributor.authorAllie-Reid, Fatima
dc.contributor.authorVanden Berghe, Wim
dc.contributor.authorVisser, Koch
dc.contributor.authorBinder, Anke
dc.contributor.authorAfricander, Donita
dc.contributor.authorVismer, Michael
dc.contributor.authorDe Bosscher, Karolien
dc.contributor.authorHapgood, Janet
dc.contributor.authorHaegeman, Guy
dc.contributor.authorLouw, Ann
dc.contributor.otherA-7620-2012
dc.date.accessioned2012-02-03T13:30:17Z
dc.date.available2012-02-03T13:30:17Z
dc.date.issued2010-03
dc.descriptionThe original publication is available at http://www.jbc.orgen_ZA
dc.descriptionThis article was published based on a PhD in 2011 see http://hdl.handle.net/10019.1/6885en_ZA
dc.description.abstractCompound 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 [3H]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 (GRdim) strongly supports the conclusion that loss of dimerization is responsible for the dissociated behavior of CpdA.en_ZA
dc.description.versionPost-printen_ZA
dc.format.extent15 p. : ill.
dc.identifier.citationRobertson, S. et al. 2010. Abrogation of glucocorticoid receptor dimerization correlates with dissociated glucocorticoid behavior of compound A. Journal of biological chemistry, 285(11), 8061-8075, doi:10.1074/jbc.M109.087866.en_ZA
dc.identifier.issn1083-351X
dc.identifier.issn0021-9258 (print)
dc.identifier.otherdoi:10.1074/jbc.M109.087866
dc.identifier.urihttp://hdl.handle.net/10019.1/19557
dc.language.isoen_ZAen_ZA
dc.publisherHighWire Pressen_ZA
dc.rights.holderThe American Society for Biochemisty and Molecular Biologyen_ZA
dc.subjectCompound A (CpdA)en_ZA
dc.subjectGlucocorticoid receptorsen_ZA
dc.subjectCpdAen_ZA
dc.subjectHormone levelsen_ZA
dc.subjectRodentsen_ZA
dc.subjectCell bindingen_ZA
dc.titleAbrogation of glucocorticoid receptor dimerization correlates with dissociated glucocorticoid behavior of compound Aen_ZA
dc.typeArticleen_ZA
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