Molecular nature of the vitamin D receptor and its role in regulation of gene expression.
Molecular nature of the vitamin D receptor and its role in regulation of gene expression.
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DOI：
10.1023/a:1010062929140
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发表时间：
2001-04-01
影响因子：
8.2
通讯作者：
Haussler, M R
中科院分区：
文献类型：
--
作者：
Jurutka, P W;Whitfield, G K;Haussler, M R
过去十年的临床和分子遗传学数据已经提供了明确的证据，证明核维生素D受体（VDR）在介导维生素D的作用中起着必不可少的作用。如图1所示，在其作为维生素D的激素代谢物在肾脏产生后，1,25 -二羟基维生素D3 （1,25 (OH) 2D3）作为VDR的配体发挥作用。与激素受体复合物诱导钙和磷的影响，导致正常骨矿化和重塑[1]。家族性靶组织对1,25 (OH) 2D3不敏感，被称为遗传性低钙维生素d抗性佝偻病（HVDRR），是一种常染色体隐性遗传病，表型为下肢严重弯曲，身材矮小，常伴有脱发。这种综合征的原因通常是编码人类(h) VDR[1]的基因缺陷，尽管也有可能出现[3]的例外。HVDRR患者（不包括脱发）的表型与经典的营养性佝偻病和肾性佝偻病相似，这一事实表明，1,25 (OH) 2d3配体的VDR不仅执行维生素D的骨矿物质稳态作用，而且表明VDR也参与皮肤正常的毛发生长周期（图1，左上）。除了钙/磷酸盐易位组织，如肠、肾和骨，在非传统靶点，包括免疫、神经和内分泌系统的细胞中，有无数明显的维生素D生物活性（图1，左下）。值得注意的例子包括1,25 (OH) 2D3维持胰岛素分泌
Clinical and molecular genetic data from the last decade have provided unequivocal evidence for the obligatory role of the nuclear vitamin D receptor (VDR) in mediating the actions of vitamin D. As illustrated in Fig. 1, following its renal production as the hormonal metabolite of vitamin D, 1, 25-dihydroxyvitamin D3 (1, 25 (OH) 2D3) functions as the ligand for VDR, with the hormone-receptor complex inducing calcemic and phosphatemic effects that result in normal bone mineralization and remodeling [1]. Familial target tissue insensitivity to 1, 25 (OH) 2D3, known as hereditary hypocalcemic vitamin D-resistant rickets (HVDRR), is an autosomal recessive disorder with a phenotype of severe bowing of the lower extremities, short stature and often alopecia [2]. The cause of this syndrome is usually a defect in the gene encoding human (h) VDR [1], although potential exceptions have been described [3]. The fact that the phenotype of HVDRR patients, excluding alopecia, mimics classic nutritional as well as renal rickets, indicates that 1, 25 (OH) 2D3-liganded VDR not only executes the bone mineral homeostatic actions of vitamin D, but suggests that VDR also participates in the normal hair growth cycle in skin (Fig. 1, upper left).Beyond calcium/phosphate translocating tissues, like intestine, kidney, and bone, there are a myriad of apparent vitamin D bioactivities in nontraditional targets, including cells of the immune, neural, and endocrine systems (Fig. 1, lower left). Notable examples include maintenance of insulin secretion by 1, 25 (OH) 2D3, the