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首页> 外文期刊>Molecular and Cellular Biology >Retinoid X receptors stimulate and 9-cis retinoic acid inhibits 1,25-dihydroxyvitamin D3-activated expression of the rat osteocalcin gene.
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Retinoid X receptors stimulate and 9-cis retinoic acid inhibits 1,25-dihydroxyvitamin D3-activated expression of the rat osteocalcin gene.

机译：维甲酸X受体刺激和9-顺式视黄酸抑制1,25-二羟基维生素D3激活的大鼠骨钙素基因的表达。

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The vitamin D receptor (VDR) binds the vitamin D-responsive element (VDRE) as a heterodimer with an unidentified receptor auxiliary factor (RAF) present in mammalian cell nuclear extracts. VDR also interacts with the retinoid X receptors (RXRs), implying that RAF may be related to the RXRs. Here we demonstrate that highly purified HeLa cell RAF contained RXR beta immunoreactivity and that both activities copurified and precisely coeluted in high-resolution hydroxylapatite chromatography. Furthermore, an RXR beta-specific antibody disrupted VDR-RAF-VDRE complexes in mobility shift assays. These data strongly indicate that HeLa RAF is highly related to or is identical to RXR beta. Consequently, the effect of the 9-cis retinoic acid ligand for RXRs was examined in 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]-activated gene expression systems. Increasing concentrations of 9-cis retinoic acid (1 nM to 1 microM) markedly reduced 1,25(OH)2D3-dependent accumulation of osteocalcin mRNA in osteoblast-like ROS 17/2.8 cells. All-trans retinoic acid also interfered with vitamin D responsiveness, but it was consistently less potent than the 9-cis isomer. Transient transfection studies revealed that attenuation by 9-cis retinoic acid was at the transcriptional level and was mediated through interactions at the osteocalcin VDRE. Furthermore, overexpression of both RXR beta and RXR alpha augmented 1,25(OH)2D3 responsiveness in transient expression studies. Direct analysis of VDRE binding in mobility shift assays demonstrated that heteromeric interactions between VDR and RXR were enhanced by 1,25(OH)2D3 and were not affected appreciably by 9-cis retinoic acid, except that inhibition was observed at high retinoid concentrations. These data suggest a regulatory mechanism for osteocalcin gene expression that involves 1,25(OH)2D3-induced heterodimerization of VDR and unliganded RXR. 9-cis retinoic acid may attenuate 1,25(OH)2D3 responsiveness by diverting RXRs away from VDR-mediated transcription and towards other RXR-dependent transcriptional pathways.
机译：维生素D受体（VDR）与维生素D反应元件（VDRE）作为异二聚体与哺乳动物细胞核提取物中存在的未知受体辅助因子（RAF）结合。 VDR还与类维生素X受体（RXR）相互作用，这暗示RAF可能与RXR相关。在这里，我们证明了高度纯化的HeLa细胞RAF包含RXRβ免疫反应性，并且在高分辨率羟磷灰石色谱中这两种活性均被共纯化并精确共洗脱。此外，在迁移率变动分析中，RXRβ特异性抗体破坏了VDR-RAF-VDRE复合物。这些数据强烈表明HeLa RAF与RXR beta高度相关或相同。因此，在1,25-二羟基维生素D3 [1,25（OH）2D3]激活的基因表达系统中检查了9-顺式视黄酸配体对RXR的作用。 9-顺式视黄酸浓度的增加（从1 nM到1 microM）显着减少了成骨样ROS 17 / 2.8细胞中骨钙素mRNA的1,25（OH）2D3依赖性积累。全反式维甲酸也干扰维生素D的反应性，但其效力一直不如9顺式异构体强。瞬时转染研究表明，9-顺式视黄酸的衰减在转录水平上，并且是通过骨钙素VDRE的相互作用介导的。此外，在瞬时表达研究中，RXR beta和RXR alpha的过表达增强了1,25（OH）2D3的响应性。对VDRE结合进行迁移迁移分析的直接分析表明，VDR和RXR之间的异聚相互作用被1,25（OH）2D3增强，并且不受9-顺式视黄酸的影响，除非在高类维生素A浓度下观察到了抑制作用。这些数据表明骨钙素基因表达的调控机制涉及1,25（OH）2D3诱导的VDR和未配体RXR异源二聚化。 9-顺式视黄酸可以通过使RXR从VDR介导的转录转移到其他RXR依赖的转录途径来减弱1,25（OH）2D3的响应性。

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