Deletion of deoxyribonucleic Acid binding domain of the vitamin d receptor abrogates genomic and nongenomic functions of vitamin d.

Erben RG; Soegiarto DW; Weber KZeitz ULieberherr MGniadecki RMoller GAdamski JBalling R

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Deletion of deoxyribonucleic Acid binding domain of the vitamin d receptor abrogates genomic and nongenomic functions of vitamin d.

机译：Deletion of deoxyribonucleic Acid binding domain of the vitamin d receptor abrogates genomic and nongenomic functions of vitamin d.

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The vitamin D hormone 1,25-dihydroxyvitamin D(3) 1,25-(OH)(2)D(3), the biologically active form of vitamin D, is essential for an intact mineral metabolism. Using gene targeting, we sought to generate vitamin D receptor (VDR) null mutant mice carrying the reporter gene lacZ driven by the endogenous VDR promoter. Here we show that our gene-targeted mutant mice express a VDR with an intact hormone binding domain, but lacking the first zinc finger necessary for DNA binding. Expression of the lacZ reporter gene was widely distributed during embryogenesis and postnatally. Strong lacZ expression was found in bones, cartilage, intestine, kidney, skin, brain, heart, and parathyroid glands. Homozygous mice are a phenocopy of mice totally lacking the VDR protein and showed growth retardation, rickets, secondary hyperparathyroidism, and alopecia. Feeding of a diet high in calcium, phosphorus, and lactose normalized blood calcium and serum PTH levels, but revealed a profound renal calcium leak in normocalcemic homozygous mutants. When mice were treated with pharmacological doses of vitamin D metabolites, responses in skin, bone, intestine, parathyroid glands, and kidney were absent in homozygous mice, indicating that the mutant receptor is nonfunctioning and that vitamin D signaling pathways other than those mediated through the classical nuclear receptor are of minor physiological importance. Furthermore, rapid, nongenomic responses to 1,25-(OH)(2)D(3) in osteoblasts were abrogated in homozygous mice, supporting the conclusion that the classical VDR mediates the nongenomic actions of 1,25-(OH)(2)D(3).

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《Molecular Endocrinology》 |2002年第7期|1524-1537|共14页
作者
Erben RG; Soegiarto DW; Weber KZeitz ULieberherr MGniadecki RMoller GAdamski JBalling R;
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作者单位

Institute of Animal Physiology, Ludwig Maximilians University (R.G.E., K.W., U.Z.), 80539 Munich, Germany.;

ortnet.ne.jp;

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原文格式 PDF
正文语种英语
中图分类内分泌腺疾病及代谢病;内分泌生理学;
关键词
Laboratory mice; binding; Vitamins; Vitamin D; 维生素类; 维生素D;

Deletion of deoxyribonucleic Acid binding domain of the vitamin d receptor abrogates genomic and nongenomic functions of vitamin d.

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