Search for fat-soluble ligand of nuclear orphan receptor.

寻找核孤儿受体的脂溶性配体。

• 批准号: 05660106
• 负责人: KATO Shigeaki
• 金额: $ 1.34万
• 依托单位: Tokyo University of Agriculture
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05660106/
• 关键词: nuclear receptor; fat-soluble ligand; gene expression; transcriptional control; vitamin D; vitamin A; orphan receptor; 脂溶性生理活性物質

Steroid/thyroid/vitamin A,D nuclear receptors form a gene superfamily, and they resemble each other in terms of structure and function. Besides of the nuclear receptors, whose ligands have been found, receptors with unknown ligands exist as "orphan receptor" . When the ligand for orphan receptor will be identified, a new signaling pathway becomes clear. Moreover, a cross-talk with the signaling pathways for fat-soluble ligands will be clarified.In the present study, the subtypes and isoforms for vitamin A receptors (RARs, RXRs) and vitamin D receptors (VDR) as well as orphan receptors have been searched with cDNAs encoding RAR,RXR and VDR from the cDNA libraries of various mammalian tissues. Consequently, we found a VDR isoform (VDR1) acting as a dominant negative receptor against the wild type of VDR (VDR0). Considering the presence of multiple active forms of vitamin D on biological actions, one of these compounds may act as a ligand for VDR1. In addition, the functional analysis of identified orphan receptors is under investigation.

类固醇/甲状腺/维生素A、D核受体构成一个基因超家族，它们在结构和功能上彼此相似。除了已发现配体的核受体外，配体未知的受体被称为“孤儿受体”。当孤儿受体的配体被确定时，一条新的信号通路就变得清晰起来。此外，与脂溶性配体信号通路的串扰将被澄清。本研究利用编码RAR、RXR和VDR的cDNA从多种哺乳动物组织文库中寻找维生素A受体（RARs、RXRs）和维生素D受体（VDR）以及孤儿受体的亚型和同工型。因此，我们发现VDR异构体（VDR1）作为VDR野生型（VDR0）的显性负受体。考虑到多种活性形式的维生素D在生物活动中的存在，其中一种化合物可能作为VDR1的配体。此外，鉴定的孤儿受体的功能分析正在进行中。

项目成果

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R.Kojima 等人：“视黄酸的体内异构化：快速异构体交换和基因表达。”

Y.Kamei: "Vitamin D receptor gene expression is up‐regulated by 1,25‐dihydroxyvitamin D3 in 3T3‐L1 preadipocytes" Biochem.Biophys,Res.Commun.193. 948-955 (1993)

Y.Kamei：“3T3-L1 前脂肪细胞中维生素 D 受体基因表达被 1,25-二羟基维生素 D3 上调”Biochem.Biophys，Res.Commun.193 (1993)。

R.Kojima,et al.: "In vivo isomerization of retinoic acid:rapid isomer exchange and gene expression." J.Biol.Chem.269. 32700-32707 (1994)

R.Kojima 等人：“视黄酸的体内异构化：快速异构体交换和基因表达”。

加藤茂明: "受容体の分子生物学" 日本臨床 日本臨床社, 17-23(7) (1994)

加藤茂明：“受体的分子生物学” Nippon Clinic Nippon Clinic，17-23(7) (1994)

H.Sasaki,et al.: "Transcriptional activity of a fluorinated vitamin D analog on VDR-RXR mediated gene expression." Biochemistry. 34. 370-377 (1995)

H.Sasaki 等人：“氟化维生素 D 类似物对 VDR-RXR 介导的基因表达的转录活性。”