MECHANISM OF ACTION AND FUNCTION OF NUCLEAR RECEPTORS

核受体超家族构成了一类配体依赖的受体 在许多情况下调节基因表达的转录因子 生物过程，包括发育、细胞增殖和 差异化。这个家族包括类固醇激素和维甲酸。 配体未知的受体和孤儿受体。这个 这些受体的活性也与疾病有关，因为 在某些受体中，信号通路被连接到不同的 疾病过程。我们实验室已经鉴定并克隆了三部小说 受体命名为TAK1、RTR和ROR伽马。这些受体含有 此家族其他成员的特征结构，并包含 DNA结合域由两个“锌指”和一个假定的 配体结合区。这些受体中的每一个都表现出一种特定的 组织和细胞类型特异的表达模式表明 这些受体在特定的生物过程中起着调节作用。 观察表明，这一点进一步表明， 睾丸中的RTR和TAK1与特定阶段的 精子发生。此外，RTR的表达在 ROR-γ受体对胚胎癌细胞分化的影响 M RNA在脂肪细胞分化过程中被诱导。TAK1、RTR和RoR 每个伽马都与包含核心基序AGGTCA的反应元件结合。 ROR伽马作为单体与单个核心基序结合，前面有AT- 丰富的序列而RTR和TAK1作为同源二聚体结合到直接重复序列， DRO和DR1-DR5。对回应的描述 元素有助于确定这些基因的可能靶基因 孤儿受体。同时表达的鱼精蛋白2基因 作为RTR的精子发生阶段，在其启动子中含有DR0 侧翼区，已被确定为RTR的靶基因。串扰 在不同受体信号通路之间起着重要作用 基因表达的控制。我们已经证明了TAK1可以 拮抗甲状腺激素受体介导的反式激活 (T3R)和维甲酸受体(RARs和RXRs)。这种对立是应该的 TAK1同源二聚体与RAR-RXR异源二聚体的竞争 RXR同源二聚体与其各自的反应元件结合。

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 pathways 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. This is further indicated by observations showing that the expression of RTR and TAK1 in the testis is associated with a specific stage of spermatogenesis. Moreover, RTR expression is down-regulated during differentiation of embryonal carcinoma cells while ROR gamma receptor mRNA is induced during adipocyte differentiation. TAK1, RTR and ROR gamma bind each to response elements containing the core motif AGGTCA. ROR gamma binds as a monomer to a single core motif preceded by an AT- rich sequence whereas RTR and TAK1 bind as homodimers to direct repeats, DRO and DR1-DR5, respectively. The characterization of the response element has been helpful in identifying putative target genes for these orphan receptors. The protamine 2 gene which is expressed at the same stage of spermatogenesis as RTR and contains a DR0 in its promoter flanking region, has been identified as a target gene for RTR. Cross-talk between different receptor signaling pathways plays an important role in the control of gene expression. We have demonstrated that TAK1 can antagonize the transactivation mediated by the thyroid hormone receptor (T3R) and the retinoid receptors (RARs and RXRs). This antagonism is due to the competition of the TAK1 homodimers with RAR-RXR heterodimers and RXR homodimers for the binding to their respective response elements.