Role of cofactors in nuclear hormone receptor function.

辅因子在核激素受体功能中的作用。

• 批准号: 6545145
• 负责人: Martin L. Privalsky
• 金额: $ 28.41万
• 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: 1998-04-20 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6545145
• 关键词: binding sites; biological signal transduction; cell line; clinical research; endocrine disorder; gel mobility shift assay; gene expression; gene induction /repression; genetic regulation; hormone receptor; hormone sensitivity /resistance; human tissue; ligands; mutant; nuclear receptors; polymerase chain reaction; protein isoforms; protein structure function; site directed mutagenesis; transcription factor; triiodothyronine; western blottings; yeast two hybrid system

Nuclear receptors are hormone-regulated transcription factors that control many key aspects of normal metazoan reproduction, differentiation, and homeostasis; aberrant nuclear receptors are causal factors in a variety of human endocrine and neoplastic disorders. The ultimate goal of this proposal is to better understand how nuclear receptors participate in signal transduction in normal cells, and the lesions in this process that lead to disease. Many nuclear receptors exhibit bimodal transcriptional properties, and can either repress or activate gene expression. We and others have identified a family of "corepressors" that physically associate with nuclear receptors, recruit additional proteins, and mediate transcriptional repression. Many signals that impact on nuclear receptor function manifest their effects through changes in corepressor recruitment or function. We propose to continue our research into how the actions of nuclear receptors are mediated through these corepressors. Although focused on repression, aspects of these studies will also touch on the functions of coactivators, and on additional effectors and regulators of nuclear receptor function. Our experiments will address specific aspects of five broad questions: Specific Aim 1. Why do different nuclear receptor isoforms differ in the ability to interact with corepressor and mediate repression? Specific Aim 2. How does the nature of target DNA influence repression? Specific Aim 3. How does the binding of different hormone ligands regulate repression? Specific Aim 4. How do non-ligand signal transduction pathways regulate repression? Specific Aim 5. How do defects in corepressor function lead to disease? The results from these experiments will contribute to a better understanding of the molecular basis behind nuclear hormone receptor function in both the normal and diseased organism. More broadly., we anticipate that our studies of corepressor action will help clarify the more general phenomenon of eukaryotic transcriptional repression.

核受体是激素调节的转录因子，控制正常后生动物繁殖，分化和稳态的许多关键方面。异常的核受体是各种人内分泌和肿瘤性疾病中的因果因素。 该提案的最终目标是更好地了解核受体如何参与正常细胞的信号转导，以及导致疾病的过程中的病变。 许多核受体表现出双峰转录特性，并且可以抑制或激活基因表达。 我们和其他人已经确定了与核受体，募集其他蛋白质并介导转录抑制作用的“核压力”家族。 对核受体功能影响的许多信号通过核心压力募集或功能的变化表现出它们的影响。 我们建议继续研究核受体的作用如何通过这些核心序列介导。 尽管专注于抑制作用，但这些研究的各个方面也将涉及共激活因子的功能，以及核受体功能的其他效应子和调节剂。 我们的实验将解决五个广泛问题的特定方面：特定目标1。为什么不同的核受体同工型与核心压力和介导抑制作用的能力有所不同？特定目标2。目标DNA的性质如何影响抑制？特定目标3。不同激素配体的结合如何调节抑制？特定目标4。非配体信号转导途径如何调节抑制？具体目标5。核心功能的缺陷如何导致疾病？这些实验的结果将有助于更好地理解正常生物体和患病生物体中核激素受体功能背后的分子基础。更广泛地。我们预计，我们对核心压力作用的研究将有助于阐明真核转录抑制的更一般现象。