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维生素D受体与视黄酸X受体形成异二聚体时可表现出DNA结合和反式激活功能,但与甲状腺激素受体则不然。

Vitamin D receptor displays DNA binding and transactivation as a heterodimer with the retinoid X receptor, but not with the thyroid hormone receptor.

作者信息

Thompson P D, Hsieh J C, Whitfield G K, Haussler C A, Jurutka P W, Galligan M A, Tillman J B, Spindler S R, Haussler M R

机构信息

Department of Biochemistry, College of Medicine, The University of Arizona, Tucson, Arizona 85724, USA.

出版信息

J Cell Biochem. 1999 Dec 1;75(3):462-80.

Abstract

The vitamin D receptor (VDR) is a transcription factor believed to function as a heterodimer with the retinoid X receptor (RXR). However, it was reported [Schräder et al., 1994] that, on putative vitamin D response elements (VDREs) within the rat 9k and mouse 28k calcium binding protein genes (rCaBP 9k and mCaBP 28k), VDR and thyroid hormone receptor (TR) form heterodimers that transactivate in response to both 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) and triiodothyronine (T(3)). We, therefore, examined associations of these receptors on the putative rCaBP 9k and mCaBP 28k VDREs, as well as on established VDREs from the rat osteocalcin (rOC) and mouse osteopontin (mOP) genes, plus the thyroid hormone response element (TRE) from the rat myosin heavy chain (rMHC) gene. In gel mobility shift assays, we found no evidence for VDR-TR heterodimer interaction with any tested element. Further, employing these hormone response elements linked to reporter genes in transfected cells, VDR and TR mediated responses to their cognate ligands only from the rOC/mOP and rMHC elements, respectively, while the CaBP elements were unresponsive to any combination of ligand(s). Utilizing the rOC and mOP VDREs, two distinct repressive actions of TR on VDR-mediated signaling were demonstrated: a T(3)-independent action, presumably via direct TR-RXR competition for DNA binding, and a T(3)-dependent repression, likely by diversion of limiting RXR from VDR-RXR toward the formation of TR-RXR heterodimers. The relative importance of these two mechanisms differed in a response element-specific manner. These results may provide a partial explanation for the observed association between hyperthyroidism and bone demineralization/osteoporosis.

摘要

维生素D受体(VDR)是一种转录因子,被认为与视黄酸X受体(RXR)形成异源二聚体发挥作用。然而,有报道称[施拉德等人,1994年],在大鼠9k和小鼠28k钙结合蛋白基因(rCaBP 9k和mCaBP 28k)内的假定维生素D反应元件(VDRE)上,VDR和甲状腺激素受体(TR)形成异源二聚体,可响应1,25 - 二羟基维生素D(3)(1,25(OH)(2)D(3))和三碘甲状腺原氨酸(T(3))进行反式激活。因此,我们研究了这些受体在假定的rCaBP 9k和mCaBP 28k VDRE上的关联,以及在大鼠骨钙素(rOC)和小鼠骨桥蛋白(mOP)基因已确定的VDRE上的关联,再加上大鼠肌球蛋白重链(rMHC)基因的甲状腺激素反应元件(TRE)。在凝胶迁移率变动分析中,我们没有发现VDR - TR异源二聚体与任何测试元件相互作用的证据。此外,在转染细胞中使用与报告基因相连的这些激素反应元件时,VDR和TR仅分别对来自rOC/mOP和rMHC元件的同源配体产生反应,而CaBP元件对任何配体组合均无反应。利用rOC和mOP VDRE,证明了TR对VDR介导的信号传导有两种不同的抑制作用:一种是不依赖T(3)的作用,可能是通过直接的TR - RXR竞争DNA结合;另一种是依赖T(3)的抑制作用,可能是通过将有限的RXR从VDR - RXR转向形成TR - RXR异源二聚体。这两种机制的相对重要性因反应元件而异。这些结果可能为观察到的数据甲状腺功能亢进与骨脱矿/骨质疏松之间的关联提供部分解释。

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