MECHANISM OF ACTION AND FUNCTION OF NUCLEAR RECEPTORS

工作概述：核受体超家族构成了一类 调节基因表达的配体依赖性转录因子 在许多生物过程中，包括发育、细胞 增殖和分化。这个家族包括类固醇 激素和类维生素A受体以及孤儿受体， 不明 这些受体的活性也与疾病有关 由于某些受体信号通路的改变已经被 与各种疾病过程有关。 我们的实验室已经鉴定出， 克隆了三种新的受体，分别命名为TAK1、RTR和ROR γ。这些 受体包含该受体的其他成员的特征结构， 家族，并含有由两个“锌指”组成的DNA结合结构域 和推定的配体结合结构域。这些受体中的每一个都表现出 组织和细胞类型特异性表达的特定模式表明 这些受体在特定的生物学过程中起着调节作用， 流程. RTR的表达高度局限于睾丸， 与精子发生的特定阶段有关。RTR也很高 在胚胎癌和胚胎干细胞中表达， 在早期胚胎发育中的作用。RTR作为同二聚体最佳结合至 反应元件（DR0），包含核心基序的直接重复 AGGTCA。 鱼精蛋白2基因表达于细胞的同一时期， 精子发生RTR，在其启动子侧翼区含有DR0 和RTR的推定靶基因。RORg作为单体结合到单个 核心基序之前是富含AT的序列。 ROR γ受体mRNA是 在脂肪细胞分化过程中诱导，并且在T细胞中也高度表达。 淋巴细胞 RORg的基因组结构进行了表征和显示 由11个外显子组成。

Summary of Work: 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 certain receptor signaling path- ways have been linked to various disease processes. Our laboratory has identified and cloned three novel receptors named TAK1, RTR and ROR gamma. These receptors contain the characteristic structure of other members of this family and contain a DNA-binding domain consisting of two "zinc-fingers" and a putative ligand-binding domain. Each of these receptors exhibit a specific pattern of tissue- and cell type-specific expression suggesting that these receptors play a regulatory role in specific biological processes. RTR expression is highly restricted to the testis and associated with a specific stage of spermatogen- esis. RTR is also highly expressed in embryonal carcinoma and embryonic stem cells suggesting a role in early embryogenesis. RTR bind most optimally as a homodimer to response elements (DR0) containing a direct repeat of the core motif AGGTCA. The protamine 2 gene which is expressed at the same stage of spermatogenesis as RTR, contains a DR0 in its promoter flanking region and a putative target gene for RTR. RORg binds as a monomer to a single core motif preceded by an AT-rich sequence. ROR gamma receptor mRNA is induced during adipocyte differentiation and also highly expressed in T- lymphocytes. The genomic structure of RORg was characterized and shown to consist of 11 exons.