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.

我们分析了三个基因（Pcp-2、prosaposin 和 5-脂氧合酶基因）的转录调控机制，这些基因在浦肯野细胞中表达，并包含 Pcp-2 基因的 RORα 响应元件 (RORE)。不包含糖皮质激素反应元件，被糖皮质激素受体 (GR) 抑制，相反，GR 依赖性转录。 MMTV 启动子被 RORα 抑制。转录拮抗作用必需的区域分别映射到 GR 的 N 末端和 RORα 的 C 末端，因为 RORα 和 GR 不直接相互作用，因此表明存在一种新的介质。 RORα 和 GR 的共同点赋予它们之间的转录拮抗作用。 Prosaposin 基因 (pSAP) 含有一个 RORE，它与 RORα 有效结合，尽管 RORα 激活了 RORα 的转录。 tk基因启动子与pSAP基因的RORE连接，在P19和HeLa细胞中均未能激活pSAP基因的转录，相反，虽然与pSAP基因连接的GRE未能在P19中激活其转录，但在HeLa细胞中却激活了pSAP基因的转录。这些结果表明，核受体的转录激活取决于启动子的类型和细胞类型，因为真核基因的启动子表现出结构多样性，所以启动子上形成的基础转录复合物可能各不相同。与其同源反应元件结合的核受体与基础转录复合物的相互作用不同。5-脂氧合酶 (5-LO) 基因的转录已被证明受到 RORα 的抑制，我们最近观察到转录抑制是 EGR1 功能抑制的结果。 actc 作为该基因的反式激活子。

项目成果

S.Sashihara: "Oncogenes and Signal Transduction Pathways Involved in Regulation of Na^+ Channel Expression" Critical Reviews in Oncogenesis. 9. 19-24 (1998)

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。

F. Kayama et. al.: "Proinflammatory cytokines and interleukin-6 in the renal response to bacterial endotoxin."Cytokine. 9. 688-695 (1997)

F. Kayama 等。

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)

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)

M. Ogata et al: "Carrageenan primes leukocytes to enhance lipopolysaccharide-induced tumor necrosis factor alpha production."Infection and Immunity. 67. 3284-3289 (1999)

M. Ogata 等人：“卡拉胶启动白细胞以增强脂多糖诱导的肿瘤坏死因子 α 的产生。”感染和免疫。