FUNCTION AND ACTION OF NUCLEAR RECEPTOR RORGAMMA

核受体 RORGAMMA 的功能和作用

• 批准号: 6289935
• 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/6289935
• 关键词: DNA binding protein; adipocytes; biological signal transduction; cell differentiation; embryonic stem cell; genetic promoter element; human tissue; messenger RNA; molecular cloning; protamines; protein structure; protein structure function; receptor binding; receptor expression; retinoid binding proteins; retinoids; spermatogenesis; steroid hormone receptor; testis; transcription factor; vitamin receptor

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. This family includes the steroid hormone and retinoid receptors and orphan receptors for which the ligand is unknown. The activity of these receptors is also relevant to disease since alterations in receptor signaling pathways have been linked to various disease processes. The objective of this study is to identify the biological functions of nuclear orphan receptor RORgamma identified in our laboratory. This includes the identification of its target genes and study of the mechanisms by which RORgamma regulates gene expression. In addition, we like to determine its role in disease and the therapeutic potential of this signaling pathway. RORgamma is able to induce transcriptional activation through its response element in many cell types. ROR gamma interacts with several co-activators including CBP, SRC-1 and RIP-140 as well as co-repressors, such as N- COR. It is likely that these interactions involve two different conformations of RORgamma, a transcriptionally active and inactive one. The regulation of the transition between these two states is being investigated. To study interactions between RORgamma and other nuclear proteins further yeast two-hybrid analysis was performed using RORgamma as bait. This analysis identified a novel gene referred to as GS encoding a nuclear protein containing several zinc-finger domains. Further characterization of this gene is in progress. Although RORgamma is expressed in several tissues, it is most highly expressed in the thymus suggesting specific roles in thymocyte and immune function. RORgamma is able to inhibit the expression of a number of immuno- regulatory genes, including Fas-ligand, interleukin-2 and 5- lipoxygenase. These genes have in common that they are regulated by the Egr family of transcription factors. We have demonstrated that RORgamma inhibits the expression of these genes by blocking the transcriptional activation by the Egr family members. This inhibition appears to involve a direct interaction between RORgamma and Egr. What domains are required for this interaction is being analyzed. To further characterize the function of this receptor a knock-out vector has been constructed and is being used in generating RORgamma-null mice. - nuclear receptor, gene regulation, transcription, adipocytes, thymus, gene knock-out, lymphoma, Fas ligand, kidney

核受体超家族是一类配体依赖性转录因子，在许多生物学过程中调节基因表达，包括发育、细胞增殖和分化。该家族包括类固醇激素和类维生素A受体以及配体未知的孤儿受体。这些受体的活性也与疾病有关，因为受体信号传导途径的改变与各种疾病过程有关。本研究的目的是确定我们实验室鉴定的核孤儿受体ROR γ的生物学功能。这包括其靶基因的鉴定和ROR γ调节基因表达的机制的研究。此外，我们想确定它在疾病中的作用和这种信号通路的治疗潜力。ROR γ能够在许多细胞类型中通过其应答元件诱导转录激活。ROR γ与包括CBP、SRC-1和RIP-140在内的几种共激活剂以及共阻遏物如N-COR相互作用。这些相互作用可能涉及ROR γ的两种不同构象，转录活性和非活性构象。目前正在研究这两种状态之间的转换规律。为了研究ROR γ和其他核蛋白之间的相互作用，使用ROR γ作为诱饵进行进一步的酵母双杂交分析。这一分析确定了一个新的基因称为GS编码的核蛋白含有几个锌指结构域。对该基因的进一步鉴定正在进行中。尽管ROR γ在几种组织中表达，但其在胸腺中表达最高，表明其在胸腺细胞和免疫功能中的特定作用。ROR γ能够抑制许多免疫调节基因的表达，包括Fas-配体、白细胞介素-2和5-脂氧合酶。这些基因的共同点是它们都受Egr家族转录因子的调控。我们已经证明ROR γ通过阻断Egr家族成员的转录激活来抑制这些基因的表达。这种抑制似乎涉及ROR γ和Egr之间的直接相互作用。正在分析这种互动需要哪些领域。为了进一步表征该受体的功能，构建了敲除载体，并用于产生ROR γ-缺失小鼠。- 核受体，基因调控，转录，脂肪细胞，胸腺，基因敲除，淋巴瘤，Fas配体，肾