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

(2014) PLOS ONE. 9(10).
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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.
Keywords
FREE HORMONE HYPOTHESIS, ALPHA-1-ACID GLYCOPROTEIN GENE, ACUTE-PHASE RESPONSE, CIS-REGULATORY ELEMENTS, PROXIMAL PROMOTER, TRANSCRIPTION FACTORS, MATHEMATICAL-MODEL, PLASMA-CORTISOL, SEPTIC SHOCK, RECEPTOR

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Chicago
Verhoog, Nicolette, Fatima Allie-Reid, Wim Vanden Berghe, Carine Smith, Guy Haegeman, Janet Hapgood, and Ann Louw. 2014. “Inhibition of Corticosteroid-binding Globulin Gene Expression by Glucocorticoids Involves C/EBPβ.” Plos One 9 (10).
APA
Verhoog, 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).
Vancouver
1.
Verhoog N, Allie-Reid F, Vanden Berghe W, Smith C, Haegeman G, Hapgood J, et al. Inhibition of corticosteroid-binding globulin gene expression by glucocorticoids involves C/EBPβ. PLOS ONE. 2014;9(10).
MLA
Verhoog, Nicolette, Fatima Allie-Reid, Wim Vanden Berghe, et al. “Inhibition of Corticosteroid-binding Globulin Gene Expression by Glucocorticoids Involves C/EBPβ.” PLOS ONE 9.10 (2014): n. pag. Print.
@article{5840148,
  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.},
  articleno    = {e110702},
  author       = {Verhoog, Nicolette and Allie-Reid, Fatima and Vanden Berghe, Wim and Smith, Carine and Haegeman, Guy and Hapgood, Janet and Louw, Ann},
  issn         = {1932-6203},
  journal      = {PLOS ONE},
  language     = {eng},
  number       = {10},
  pages        = {14},
  title        = {Inhibition of corticosteroid-binding globulin gene expression by glucocorticoids involves C/EBP\ensuremath{\beta}},
  url          = {http://dx.doi.org/10.1371/journal.pone.0110702},
  volume       = {9},
  year         = {2014},
}

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