Target genes of RORα which controls postnatal development of cerebeller Purkinje cells

控制小脑浦肯野细胞出生后发育的 RORα 靶基因

• 批准号: 09680777
• 负责人: MATSUI Takashi
• 金额: $ 1.98万
• 依托单位: UNIVERSITY OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09680777/
• 关键词: RORα; nuclear receptor; transcription regulation; Purkinje cells; promoter; 小脳プルキン工細胞; 生後分化; 糖脂質; コアクチベータ-; プルキンエ細胞

We analyzed regulatory mechanisms of transcription of three genes, Pcp-2, prosaposin and 5-lipoxygenase genes, which are expressed in the Purkinje cells and contain a RORα-responsive elemenet (RORE). RORα-dependent transcription of the Pcp-2 gene which does not contain a glucocorticoid responsive element was shown to be repressed by glucocorticoid receptor (GR). Reciprocally, GR-dependent transcription of MMTV promoter was repressed by RORα. Regions essential for the transcriptional antagonism was mapped to the N-terminus of GR and the C-terminus of RORα, respectively. Since RORα and GR did not directly interact each other, it was suggested that a novel mediator common for RORα and GR confers the transcriptional antagonism between them.Prosaposin gene (pSAP) contains a RORE which is efficiently bound with RORα. Although RORα activated transcription of the tk gene promoter linked with the RORE of pSAP gene, it failed to activate transcription of pSAP gene both in P19 and HeLa cells. In contrast, although GRE linked to pSAP gene failed to activate its transcription in P19, it activated the transcription in HeLa cells. These results indicated that transcriptional activation by nuclear receptors is dependent both on type of promoter and cell-type. Since promoters of eukaryptic genes show a structural variety, basal transcriptional complex formed on the promoter might differ from one to another. Nuclear receptor bound with its cognate responsive element interact differently to the basal transcription complex.Transcription of 5-lipoxygenase (5-LO) gene has been demonstrated to be repressed by RORα. We recently observed that the transcriptional repression results from suppression of EGR1 function which actc as a transactivator of this gene.

我们分析了浦肯野细胞中表达的3个基因，ppp -2、prosaposin和5-脂氧合酶基因的转录调控机制，这些基因含有一个ror α-反应元件（RORE）。不含糖皮质激素应答元件的Pcp-2基因的r α依赖性转录被糖皮质激素受体（GR）抑制。反过来，gr依赖性的MMTV启动子转录被rora抑制。转录拮抗的关键区域分别定位于GR的n端和RORα的c端。由于RORα和GR之间没有直接相互作用，因此我们认为RORα和GR之间可能存在一种新的共同介质。Prosaposin基因（pSAP）含有一个与RORα有效结合的RORE。在P19细胞和HeLa细胞中，rora α虽然激活了pSAP基因RORE连接的tk基因启动子的转录，但未能激活pSAP基因的转录。相比之下，与pSAP基因相关的GRE在P19中未能激活其转录，但在HeLa细胞中激活了其转录。这些结果表明，核受体的转录激活依赖于启动子类型和细胞类型。由于真核基因的启动子具有结构多样性，因此在启动子上形成的基础转录复合体可能各不相同。核受体与其同源响应元件结合，对基础转录复合体的相互作用不同。5-脂氧合酶（5-LO）基因的转录已被证实受到rora的抑制。我们最近观察到，转录抑制是由于EGR1功能的抑制，EGR1作为该基因的反激活子。

项目成果

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S.Sashihara：“致癌基因和信号转导途径参与 Na^ 通道表达的调节”肿瘤发生中的批判性评论。

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F. Kayama 等。

松井隆司: "小脳形成とオーファン核内レセプターRORα"蛋白質・核酸・酵素. 42. 2039-2048 (1997)

Takashi Matsui：“小脑形成和孤儿核受体 RORα”蛋白质、核酸和酶。 42. 2039-2048 (1997)

T.Matsui: "Transcriptional regulation of a Purkinje cell-specific gene through a functional interaction between RORα and RAR." Genes to Cells. 2. 263-272 (1997)

T.Matsui：“通过 RORα 和 RAR 之间的功能相互作用对浦肯野细胞特异性基因进行转录调节。”2. 263-272 (1997)

T. Matsui: "Cerebeller development and orphan nuclear receptor RORα"Protein, Nucleic Acid and Enzyme. 42. 2039-2048 (1997)

T. Matsui：“小脑发育和核孤儿受体 RORα”蛋白质、核酸和酶。 42. 2039-2048 (1997)