Inhibition of corticosteroid-binding globulin gene expression by glucocorticoids involves C/EBPβ

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dc.contributor.authorVerhoog, Nicoletteen_ZA
dc.contributor.authorAllie-Reid, Fatimaen_ZA
dc.contributor.authorBerghe, Wim Vandenen_ZA
dc.contributor.authorSmith, Carineen_ZA
dc.contributor.authorHaegeman, Guyen_ZA
dc.contributor.authorHapgood, Janeten_ZA
dc.contributor.authorLouw, Annen_ZA
dc.date.accessioned2015-11-18T07:08:43Z
dc.date.available2015-11-18T07:08:43Z
dc.date.issued2014en_ZA
dc.description.abstractCorticosteroid-binding globulin (CBG), a negative acute phase protein produced primarily in the liver, is responsible for the transport of glucocorticoids (GCs). It also modulates the bioavailability of GCs, as only free or unbound steroids are biologically active. Fluctuations in CBG levels therefore can directly affect GC bioavailability. This study investigates the molecular mechanism whereby GCs inhibit the expression of CBG. GCs regulate gene expression via the glucocorticoid receptor (GR), which either directly binds to DNA or acts indirectly via tethering to other DNA-bound transcription factors. Although no GC-response elements (GRE) are present in the Cbg promoter, putative binding sites for C/EBPβ, able to tether to the GR, as well as HNF3α involved in GR signaling, are present. C/EBPβ, but not HNF3α, was identified as an important mediator of DEX-mediated inhibition of Cbg promoter activity by using specific deletion and mutant promoter reporter constructs of Cbg . Furthermore, knockdown of C/EBPβ protein expression reduced DEX-induced repression of CBG mRNA, confirming C/EBPβ’s involvement in GC-mediated CBG repression. Chromatin immunoprecipitation (ChIP) after DEX treatment indicated increased co-recruitment of C/EBPβ and GR to the Cbg promoter, while C/EBPβ knockdown prevented GR recruitment. Together, the results suggest that DEX repression of CBG involves tethering of the GR to C/EBPβ.en_ZA
dc.identifier.apacitationVerhoog, N., Allie-Reid, F., Berghe, W. V., Smith, C., Haegeman, G., Hapgood, J., & Louw, A. (2014). Inhibition of corticosteroid-binding globulin gene expression by glucocorticoids involves C/EBPβ. <i>PLoS One</i>, http://hdl.handle.net/11427/15133en_ZA
dc.identifier.chicagocitationVerhoog, Nicolette, Fatima Allie-Reid, Wim Vanden Berghe, Carine Smith, Guy Haegeman, Janet Hapgood, and Ann Louw "Inhibition of corticosteroid-binding globulin gene expression by glucocorticoids involves C/EBPβ." <i>PLoS One</i> (2014) http://hdl.handle.net/11427/15133en_ZA
dc.identifier.citationVerhoog, N., Allie-Reid, F., Vanden Berghe, W., Smith, C., Haegeman, G., Hapgood, J., & Louw, A. (2014). Inhibition of corticosteroid-binding globulin gene expression by glucocorticoids involves C/EBPβ. PLOS ONE, 9(10). doi:10.1371/journal.pone.0110702en_ZA
dc.identifier.ris TY - Journal Article AU - Verhoog, Nicolette AU - Allie-Reid, Fatima AU - Berghe, Wim Vanden AU - Smith, Carine AU - Haegeman, Guy AU - Hapgood, Janet AU - Louw, Ann AB - Corticosteroid-binding globulin (CBG), a negative acute phase protein produced primarily in the liver, is responsible for the transport of glucocorticoids (GCs). It also modulates the bioavailability of GCs, as only free or unbound steroids are biologically active. Fluctuations in CBG levels therefore can directly affect GC bioavailability. This study investigates the molecular mechanism whereby GCs inhibit the expression of CBG. GCs regulate gene expression via the glucocorticoid receptor (GR), which either directly binds to DNA or acts indirectly via tethering to other DNA-bound transcription factors. Although no GC-response elements (GRE) are present in the Cbg promoter, putative binding sites for C/EBPβ, able to tether to the GR, as well as HNF3α involved in GR signaling, are present. C/EBPβ, but not HNF3α, was identified as an important mediator of DEX-mediated inhibition of Cbg promoter activity by using specific deletion and mutant promoter reporter constructs of Cbg . Furthermore, knockdown of C/EBPβ protein expression reduced DEX-induced repression of CBG mRNA, confirming C/EBPβ’s involvement in GC-mediated CBG repression. Chromatin immunoprecipitation (ChIP) after DEX treatment indicated increased co-recruitment of C/EBPβ and GR to the Cbg promoter, while C/EBPβ knockdown prevented GR recruitment. Together, the results suggest that DEX repression of CBG involves tethering of the GR to C/EBPβ. DA - 2014 DB - OpenUCT DO - 10.1371/journal.pone.0110702 DP - University of Cape Town J1 - PLoS One LK - https://open.uct.ac.za PB - University of Cape Town PY - 2014 T1 - Inhibition of corticosteroid-binding globulin gene expression by glucocorticoids involves C/EBPβ TI - Inhibition of corticosteroid-binding globulin gene expression by glucocorticoids involves C/EBPβ UR - http://hdl.handle.net/11427/15133 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/15133
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pone.0110702
dc.identifier.vancouvercitationVerhoog N, Allie-Reid F, Berghe WV, Smith C, Haegeman G, Hapgood J, et al. Inhibition of corticosteroid-binding globulin gene expression by glucocorticoids involves C/EBPβ. PLoS One. 2014; http://hdl.handle.net/11427/15133.en_ZA
dc.language.isoengen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.publisher.departmentDepartment of Molecular and Cell Biologyen_ZA
dc.publisher.facultyFaculty of Scienceen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_ZA
dc.rights.holder© 2014 Verhoog et alen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourcePLoS Oneen_ZA
dc.source.urihttp://journals.plos.org/plosoneen_ZA
dc.subject.otherProtein expressionen_ZA
dc.subject.otheren_ZA
dc.subject.otherGene expressionen_ZA
dc.subject.otherMessenger RNAen_ZA
dc.subject.otherChromatinen_ZA
dc.subject.otherTranscription factorsen_ZA
dc.titleInhibition of corticosteroid-binding globulin gene expression by glucocorticoids involves C/EBPβen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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