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

Verhoog, Nicolette ; Allie-Reid, Fatima ; Vanden Berghe, Wim ; Smith, Carine ; Haegeman, Guy ; Hapgood, Janet ; Louw, Ann (2014-10)

Publication of this article was funded by the Stellenbosch University Open Access Fund.

Please cite as follows:

Verhoog N, et al. 2014. Inhibition of corticosteroid-binding globulin gene expression by glucocorticoids involves C/EBPβ. PLoS ONE 9(10), doi:10.1371/journal.pone.0110702.

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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.

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