NEW ASPECTS OF DNA RECOGNITION BY NUCLEAR RECEPTORS

我们的最终目标是更好地了解不同的核 激素受体识别不同的靶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，以响应小的 疏水性激素，如类固醇、甲状腺激素，和 类维生素A。 每种受体的DNA识别特性都发挥着 定义特定靶基因库的关键作用 对特定的激素有反应。 然而，我们的理解， 不完全的核受体， 类似的锌指结构域，表现出必要的特异性， 识别固有的不同的靶基因组。 最近的工作 我们自己和其他人已经表明：（A）区域以外的 锌指结构域在DNA中起着关键和意想不到的作用 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，而且还通过新的 涉及单体和高级低聚复合物的机制， 翻译后蛋白质修饰可以改变DNA 识别. 这些观察结果证实， 核受体的DNA识别以前没有被发现。 探索，并提出合理的机制，特异性 产生了针对不同靶基因的不同受体， 定义了 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 寡聚体在DNA识别的不同成员的核 激素受体家族 C.是细胞核识别DNA的方式和特异性 通过翻译后修饰改变的受体 剪接或染色体易位 核激素受体在后生动物体内平衡中起核心作用， 发展和分化。 异常的人类受体 与许多内分泌和肿瘤疾病有关。 我们 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 其他转录因子。

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.