Inhibition of corticosteroid-binding globulin gene expression by glucocorticoids involves C/EBPβ.
Inhibition of corticosteroid-binding globulin gene expression by glucocorticoids involves C/EBPβ.
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DOI：
10.1371/journal.pone.0110702
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Louw A
中科院分区：
文献类型：
--
作者：
Verhoog N;Allie-Reid F;Vanden Berghe W;Smith C;Haegeman G;Hapgood J;Louw A
皮质类固醇结合球蛋白（CBG）是一种主要在肝脏中产生的负性急性期蛋白，负责糖皮质激素（GC）的转运。它还调节GC的生物利用度，因为只有游离或未结合的类固醇具有生物活性。因此，CBG水平的波动可以直接影响GC的生物利用度。本研究探讨GC抑制CBG表达的分子机制。GC通过糖皮质激素受体（GR）调节基因表达，糖皮质激素受体直接与DNA结合或通过与其他DNA结合的转录因子结合而间接起作用。虽然Cbg启动子中不存在GC反应元件（GRE），但存在能够与GR连接的C/EBPβ的推定结合位点，以及参与GR信号传导的HNF 3 α。通过使用Cbg的特异性缺失和突变启动子报告构建体，C/EBPβ而不是HNF 3 α被鉴定为DEX介导的Cbg启动子活性抑制的重要介质。此外，敲低C/EBPβ蛋白表达可减少DEX诱导的CBG mRNA抑制，证实C/EBPβ参与GC介导的CBG抑制。DEX处理后的染色质免疫沉淀（ChIP）表明C/EBPβ和GR共同募集到Cbg启动子的增加，而C/EBPβ敲低阻止GR募集。总之，结果表明，CBG的DEX抑制涉及GR与C/EBPβ的束缚。
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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