Action of the nuclear orphan receptor RTR

核孤儿受体RTR的作用

• 批准号: 6227937
• 负责人: Anton M Jetten
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6227937
• 关键词: biological signal transduction; cell differentiation; embryonic stem cell; gene expression; gene induction /repression; genetic regulation; genetic transcription; molecular cloning; pathologic process; receptor; receptor expression; testis; transcription factor; trophoblast

The nuclear receptor superfamily constitutes a class of ligand- dependent transcriptional factors that regulate gene expression during many biological processes, including development, cellular proliferation and differentiation. The activity of these receptors is relevant to disease since alterations in receptor signaling pathways have been linked to various disease processes. Our laboratory has identified and cloned a novel nuclear orphan receptor named RTR. The objective of this study is to identify the biological functions of RTR. This includes identification of its target genes and to understand the mechanism by which RTR regulates gene expression. In addition, we like to determine its potential role in disease and the therapeutic potential of this signaling pathway. The expression pattern of this receptor during development and in the adult is limited. RTR is expressed in embryonic stem cells during neuronal cell differentiation, in trophoblast cells and in the testis. In embryonal carcinoma cells RTR is down-regulated when when cells are induced to differentiate. RTR acts as a repressor of transcription. For example, it can inhibit the transactivation by the nuclear receptor ERR1. We have demonstrated that the co-repressor N-COR can interact with RTR and likely mediates the repressor function of RTR. However, no interaction was observed between RTR and the co-repressor SMRT. Recently we cloned a novel gene referred to as RAP80 that is able to interact with RTR and may play a role in the repressor function of RTR. RAP80 is an 80 kD nuclear protein containing two zinc finger domains at its carboxy terminus. RAP80 is present in the nucleus in a speckled manner. It is expressed in many different cell types. Although N-COR and RAP80 are able to compete for binding to RTR, different regions of RTR are involved in the interaction. What domain of RAP80 is required for RTR interaction is being determined. - nuclear receptor, co-repressor, gene regulation, transcription, repression, orphan receptor,trophoblast, testis

核受体超家族构成了一类配体依赖的转录因子，在发育、细胞增殖和分化等许多生物学过程中调节基因的表达。这些受体的活性与疾病有关，因为受体信号通路的变化与各种疾病过程有关。本实验室已鉴定并克隆了一个新的核孤儿受体，命名为RTR。本研究的目的是鉴定RTR的生物学功能。这包括鉴定其靶基因和了解RTR调节基因表达的机制。此外，我们希望确定它在疾病中的潜在作用以及这一信号通路的治疗潜力。这种受体在发育过程中和成体中的表达模式是有限的。RTR在神经细胞分化过程中的胚胎干细胞、滋养层细胞和睾丸中均有表达。在胚胎癌细胞中，当细胞被诱导分化时，RTR被下调。RTR是转录的抑制子。例如，它可以抑制核受体ERR1的反式激活。我们已经证明，共抑制因子N-COR可以与RTR相互作用，并可能介导RTR的抑制功能。然而，未观察到RTR与共抑制物SMRT之间的相互作用。最近，我们克隆了一个新的基因，称为RAP80，它能够与RTR相互作用，并可能在RTR的阻遏功能中发挥作用。RAP80是一个80kD的核蛋白，其羧基末端含有两个锌指结构域。RAP80以斑点状的形式存在于细胞核中。它在许多不同的细胞类型中表达。虽然N-COR和RAP80能够竞争结合RTR，但RTR的不同区域参与了相互作用。RTR交互需要RAP80的哪个域正在确定中。-核受体、共抑制物、基因调控、转录、抑制、孤儿受体、滋养层细胞、睾丸