Title
Inhibition of Corticosteroid-Binding Globulin Gene Expression by Glucocorticoids Involves C/EBP beta Inhibition of Corticosteroid-Binding Globulin Gene Expression by Glucocorticoids Involves C/EBP beta
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Publication type
article
Publication
Subject
Engineering sciences. Technology
Source (journal)
PLoS ONE
Volume/pages
9(2014) :10 , 14 p.
ISSN
1932-6203
1932-6203
Article Reference
e110702
Carrier
E-only publicatie
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
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/EBP beta, able to tether to the GR, as well as HNF3 alpha involved in GR signaling, are present. C/EBP beta, but not HNF3 alpha, 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/EBP beta protein expression reduced DEX-induced repression of CBG mRNA, confirming C/EBP beta's involvement in GC-mediated CBG repression. Chromatin immunoprecipitation (ChIP) after DEX treatment indicated increased co-recruitment of C/EBP beta and GR to the Cbg promoter, while C/EBP beta knockdown prevented GR recruitment. Together, the results suggest that DEX repression of CBG involves tethering of the GR to C/EBP beta.
E-info
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Full text (open access)
https://repository.uantwerpen.be/docman/irua/843315/121167.pdf
Handle