Functional cooperation between CCAAT/enhancer-binding proteins and the vitamin D receptor in regulation of 25-hydroxyvitamin D324-hydroxylase
Functional cooperation between CCAAT/enhancer-binding proteins and the vitamin D receptor in regulation of 25-hydroxyvitamin D324-hydroxylase
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DOI：
10.1128/mcb.25.1.472-487.2005
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发表时间：
2005-01-01
影响因子：
5.3
通讯作者：
Christakos, S
中科院分区：
文献类型：
--
作者：
Dhawan, P;Peng, XR;Christakos, S
1，25-二羟基维生素D-3 [1，25（OH）（2）D-3]诱导25-羟基维生素D-3 24-羟化酶[24（OH）ase]的合成，这是一种参与其催化作用的酶，从而调节其自身的代谢。在这里，我们证明了CCAAT增强子结合蛋白β（C/EBP β）在肾脏和成骨细胞中由1，25（OH）（2）D-3诱导，并且是维生素D受体（VDR）介导的24（OH）ase转录的有效增强子。转染研究表明，1，25（OH）2D 3对24（OH）ase转录的诱导最多可被C/EBP β增强10倍。在显性阴性C/EBP或C/EBP beta（-/-）小鼠的成骨细胞中观察到1，25（OH）（2）D-3诱导的24（OH）ase转录的抑制。在大鼠24（OH）ase启动子的-395至-388（-395/-388）位鉴定出C/EBP位点。该位点的突变抑制C/EBP β结合，并显著减弱对C/EBP β的转录反应。我们还报道了CBP/p300与C/EBP β在调节VDR介导的24（OH）ase转录中的合作。我们发现，不仅1，25（OH）（2）D-3，而且甲状旁腺激素（PTH）也能诱导成骨细胞表达C/EBP β。PTH增强了成骨细胞对1，25（OH）（2）D-3反应的C/EBP β和24（OH）ase表达的诱导。人类VDR启动子（含有两个假定的C/EBP位点）的数据表明C/EBP β在蛋白激酶A介导的VDR转录诱导中的作用。从这项研究中，已经建立了一个基本的作用，第一次在1，25（OH）（2）D-3诱导的转录C/EBP家族的转录因子和VDR之间的协同效应和串扰。这些发现还表明C/EBP β在PTH和1，25（OH）（2）D-3之间的串扰中的新作用，该串扰涉及VDR转录的调节。
1,25-Dihydroxyvitamin D-3 [1,25(OH)(2)D-3] induces the synthesis of 25-hydroxyvitamin D-3 24-hydroxylase [24(OH)ase], an enzyme involved in its catabolism, thereby regulating its own metabolism. Here we demonstrate that CCAAT enhancer binding protein beta (C/EBPbeta) is induced by 1,25(OH)(2)D-3 in kidney and in osteoblastic cells and is a potent enhancer of vitamin D receptor (VDR)-mediated 24(OH)ase transcription. Transfection studies indicate that 1,25(OH)2D3 induction of 24(OH)ase transcription is enhanced a maximum of 10-fold by C/EBPbeta. Suppression of 1,25(OH)(2)D-3-induced 24(OH)ase transcription was observed with dominant negative C/EBP or osteoblastic cells from C/EBPbeta(-/-) mice. A C/EBP site was identified at positions -395 to -388 (-395/-388) in the rat 24(OH)ase promoter. Mutation of this site inhibited C/EBPbeta binding and markedly attenuated the transcriptional response to C/EBPbeta. We also report the cooperation of CBP/p300 with C/EBPbeta in regulating VDR-mediated 24(OH)ase transcription. We found that not only 1,25(OH)(2)D-3 but also parathyroid hormone (PTH) can induce C/EBPbeta expression in osteoblastic cells. PTH potentiated the induction of C/EBPbeta and 24(OH)ase expression in response to 1,25(OH)(2)D-3 in osteoblastic cells. Data with the human VDR promoter (which contains two putative C/EBP sites) indicate a role for C/EBPbeta in the protein kinase A-mediated induction of VDR transcription. From this study a fundamental role has been established for the first time for cooperative effects and cross talk between the C/EBP family of transcription factors and VDR in 1,25 (OH)(2)D-3-induced transcription. These findings also indicate a novel role for C/EBPbeta in the cross talk between PTH and 1,25(OH)(2)D-3 that involves the regulation of VDR transcription.