Identification of transcription enhancing fator for PTH receptor and analysis it's mechanism at jaw bone resorption site by oral cancer

口腔癌颌骨吸收部位PTH受体转录增强因子的鉴定及作用机制分析

• 批准号: 15592130
• 负责人: KAWANE Tesuya
• 金额: $ 2.18万
• 依托单位: Ohu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15592130/
• 关键词: PTH; PTHrP receptor; osteoblast; PTHrP; transcriptional factor; gel mobility shift assay; promoter; oral cancer

Parathyroid hormone (PTH) and PTH related protein (PTHrP) exert their effects on bone metabolism by binding to the G protein-coupled PTH/PTHrP receptor (PTH1R) expressed on osteoblasts. They increase expression of the osteoclast activating factor (RANKL) and enhance bone resorption.The rat, mouse and human PTH1R genes contain four 5' noncoding exons (Ul, U2, U3 and U4) and three promoter regions. A TATA-like promoter upstream of exon Ul is referred to as the P1 promoter and a GCrich promoter upstream of exon U3 and U4 is called the P2 and P3 promoters respectively. In rats, the downstream promoter (P2) was active in a variety of tissues including bone and kidney, while the upstream promoter (P1) was tissue-specific, showing activity in the kidney and the ovary.In the present study, we attempted to analyze the mechanism of transcription related factor(s) on the promoter P2 of the PTH1R in the rat osteoblasts and their mechanism at jaw bone resorption site by oral cancer.1.The core promo … More ter region (-128/+103) of the U3 promoter (P2) was composed of three important parts.(1)The +1/+12 region in the PTHSR (+11+25) fanctioned as an initiator (Inr) element. (2) The -128/-1 region fanctioned as an activator binding domain affected by MAZ and/or Sp1. (3) The +51/+103 region fanctioned as a downstream promoter element.2.The Inr element in the U3 promoter was recognized by specific protein(s). The PTH or IGF-I treatment decreased stability of that complex and attenuated the transcription activity ofPTH1R.3.Affinity purification revealed that the candidate protein(s) could bind to the PTHSR region were 112 and/or 129 kDa protein(s).4.In almost all of soft oral cancer tissues, the PTHrP expression markedly increased compared with the normal part. In the jaws adjacent to cancer tissues with high expression of PTI-IrP, one of the candidate protein expression did not decrease, but the PTH1 R expression downregulated. The bone metabolism marker such as RANKL and Cathepsin K were increased and OPG slightly decreased in this situation. Less

甲状旁腺激素(PTH)和甲状旁腺激素相关蛋白(PTHrP)通过与成骨细胞表达的G蛋白偶联PTH/PTHrP受体(PTH1R)结合而发挥骨代谢作用。它们增加破骨细胞激活因子(RANKL)的表达，促进骨吸收。大鼠、小鼠和人的PTH1R基因包含四个5‘非编码外显子(U1、U2、U3和U4)和三个启动子区域。外显子U1上游的类TATA启动子称为P1启动子，外显子U3和U4上游富含GC的启动子分别称为P2和P3启动子。在大鼠中，下游启动子(P2)在骨和肾等多种组织中都有活性，而上游启动子(P1)是组织特异性的，在肾脏和卵巢中表现出活性。本研究试图分析转录相关因子(S)对大鼠成骨细胞PTH1R启动子P2的作用机制及其在口腔癌颌骨吸收部位的作用机制。1.核心启动子…U3启动子(P2)的+1/+12区(+11+25)具有启动子(INR)元件的功能。(2)-128/-1区是MAZ和/或Sp1作用下的激活子结合域。(3)+51/+103区域为下游启动子元件。2.U3启动子中的INR元件被特异性蛋白识别(S)。PTH或IGF-I处理降低了该复合体的稳定性，减弱了PTH1R的转录活性。3.亲和纯化表明，候选蛋白(S)可与PTHSR区112和/或129 kDa的蛋白(S)结合。4.在几乎所有口腔癌组织中，PTHrP的表达明显高于正常组织。在PTI-IRP高表达的癌旁颌骨组织中，其中一个候选蛋白的表达没有下降，但PTH1R的表达下调。骨代谢指标RANKL、组织蛋白酶K升高，OPG略有下降。较少

项目成果

Identification of the promoter region of the parathyroid hormone receptor gene responsible for transcriptional suppression by insulin-like growth factor-I

• DOI: 10.1016/j.abb.2005.05.012
• 发表时间: 2005-07-01
• 期刊: ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
• 影响因子: 3.9
• 作者: Kawane, T;Mimura, J;Horiuchi, N
• 通讯作者: Horiuchi, N

Effect of leptin on renal 1α-hydroxylase expression in mice.

瘦素对小鼠肾1α-羟化酶表达的影响。

• 发表时间: 2004
• 期刊: Proceedings of 12th International Congress of Endocrinology.
• 作者: Hamaguchi;H.;Fujimoto;K.;Kawamoto;T.;Noshiro;M.;Maemura;K.;Takeda;N.;Nagai;R.;Furukawa;M.;Honma;S.;Honma;K.;Kurihara;H.;Kato;Y;Noboru Horiuchi
• 通讯作者: Noboru Horiuchi

Leptin corrects increased gene expression of renal 25-hydroxyvitamin D3-1α-hydroxylase and -24-hydroxylase in leptin-deficient, ob/ob mice

• DOI: 10.1210/en.2003-1010
• 发表时间: 2004-03-01
• 期刊: ENDOCRINOLOGY
• 影响因子: 4.8
• 作者: Matsunuma, A;Kawane, T;Horiuchi, N
• 通讯作者: Horiuchi, N

Effect of leptin on renal 1 1α-hydroxylase expression in mice.

瘦素对小鼠肾 1 1α-羟化酶表达的影响。

• 发表时间: 2004
• 期刊: Proceedings of 12th International Congress of Endocrinology
• 作者: Joh;S;Tetsuya Kawane;Tetsuya Kawane;Tetsuya Kawane;Noboru Horiuchi;Ayako Matsunuma;Tetsuya Kawane;Noboru Horiuchi
• 通讯作者: Noboru Horiuchi

Leptin corrects increased gene expression of 25-hydroxyvitamin D_3-1α-hydroxylase and-24-hydroxylase in leptin-deficient, ob/ob mice.

瘦素可纠正瘦素缺乏的 ob/ob 小鼠中 25-羟基维生素 D_3-1α-羟化酶和 24-羟化酶基因表达的增加。

• 发表时间: 2004
• 期刊: Endocrinology 145・3
• 作者: 阿部 匡聡;Ayako Matsunuma
• 通讯作者: Ayako Matsunuma