NEW ASPECTS OF DNA RECOGNITION BY NUCLEAR RECEPTORS

核受体 DNA 识别的新方面

• 批准号: 2906236
• 负责人: Martin L. Privalsky
• 金额: $ 17.04万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-23 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2906236
• 关键词: DNA binding protein; RNA splicing; chromosome translocation; dimer; genetic regulatory element; high performance liquid chromatography; hormone receptor; nuclear membrane; nucleic acid sequence; phosphorylation; polymerase chain reaction; posttranslational modifications; protein sequence; protein structure; receptor binding; tissue /cell culture; transcription factor

Our ultimate goal is to better understand how different nuclear hormone receptors recognize different target DNA sequences. Nuclear hormone receptors are ligand-regulated transcription factors, and modulate the expression of specific target genes in response to small hydrophobic hormones, such as steroids, thyroid hormones, and retinoids. The DNA recognition properties of each receptor play the critical role of defining the particular repertoire of target genes which respond to a given hormone. However, our understanding in incomplete of how the nuclear receptors, which posses generally similar zinc-finger domains, manifest the specificity necessary to recognize inherently distinct sets of target genes. Recent work by ourselves and others has revealed that: (A) regions outside of the zinc-finger domain play critical and unanticipated roles in DNA sequence-specificity, (B) nuclear hormone receptors recognize DNA binding sites not only as protein dimers, but also by novel mechanisms involving monomers and high-order oligomeric complexes, and ~ post-translational protein modifications can alter DNA recognition. These observations confirm that important elements of DNA recognition by nuclear receptors have not been previously explored, and suggest plausible mechanisms by which the specificity of different receptors for different target genes is generated and defined. We will investigate: A. How do different nuclear receptors recognize distinct DNA half- sites? B. What are the different roles of protein monomers, dimers and oligomers in DNA recognition by different members of the nuclear hormone receptor family. C. Is the mode and specificity of DNA recognition by nuclear receptors altered by post-translational modification, alternative splicing, or chromosomal translocations? Nuclear hormone receptors play central roles in metazoan homeostasis, development, and differentiation. Aberrant human receptors have been implicated in many endocrine and neoplastic diseases. Our experiments will help resolve important aspects of nuclear hormone receptor signaling and physiology, and will also contribute toward a broader comprehension of how DNA recognition specificity is achieved by other transcription factors.

我们的最终目标是更好地了解不同的核能如何 激素受体识别不同的目标DNA序列。 核 激素受体是配体调节的转录因子，并且 调节特定靶基因的表达以响应小 疏水性激素，例如类固醇、甲状腺激素和 类维生素A。 每个受体的 DNA 识别特性发挥着 定义靶基因的特定库的关键作用 对特定的激素做出反应。 然而，我们的理解是 核受体如何不完整，通常具有 相似的锌指结构域，表现出必要的特异性 识别本质上不同的靶基因组。 最近的工作 我们自己和其他人已经揭示：（A） 锌指结构域在 DNA 中发挥着关键且意想不到的作用 序列特异性，(B) 核激素受体识别 DNA 结合位点不仅作为蛋白质二聚体，而且还通过新颖的 涉及单体和高阶寡聚复合物的机制， ~ 翻译后蛋白质修饰可以改变 DNA 认出。 这些观察结果证实了重要的要素 以前从未有过核受体对 DNA 的识别 探索并提出了特异性的合理机制 产生针对不同靶基因的不同受体 定义的。 我们将调查： A. 不同的核受体如何识别不同的 DNA 半 网站？ B. 蛋白质单体、二聚体和蛋白质的不同作用是什么？ DNA 寡聚体被不同的核成员识别 激素受体家族。 C. 核识别DNA的模式和特异性 通过翻译后修饰改变的受体，替代 剪接，还是染色体易位？ 核激素受体在后生动物体内平衡中发挥核心作用， 发展、差异化。 异常的人类受体 与许多内分泌和肿瘤疾病有关。 我们的 实验将有助于解决核激素的重要方面 受体信号传导和生理学，也将有助于 更广泛地理解 DNA 识别特异性是如何实现的 通过其他转录因子。