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: 6896110
• 负责人: Martin L. Privalsky
• 金额: $ 25.07万
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6896110
• 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，控制着后生动物正常繁殖、分化和内稳态的许多关键方面；异常的核受体是多种人类内分泌和肿瘤疾病的致病因素。这项建议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，以及在这一过程中导致疾病的损伤。许多核受体表现出双峰转录特性，可以抑制或激活基因表达。我们和其他人已经确定了一个“辅阻遏子”家族，这些辅阻遏子在物理上与核受体相关，招募额外的蛋白质，并介导转录抑制。许多影响核受体功能的信号通过辅抑制子募集或功能的变化来表现其影响。我们建议继续研究核受体的作用是如何通过这些辅抑制子介导的。虽然这些研究的重点是抑制，但这些研究的各个方面也将涉及辅助激活因子的功能，以及核受体功能的其他效应因子和调节因子。我们的实验将解决五个广泛问题的具体方面：特定目标1.为什么不同的核受体亚型在与辅助抑制物和中介抑制物相互作用的能力上存在差异？特定目标2.靶DNA的性质如何影响压抑？具体目标3.不同激素配体的结合如何调节抑制？具体目标4.非配基信号转导通路如何调节抑制？具体目标5.辅酶抑制剂功能缺陷是如何导致疾病的？这些实验的结果将有助于更好地理解核激素受体功能背后的分子基础，无论是在正常的还是疾病的生物体中。更广泛地说，我们预计我们对辅阻遏物作用的研究将有助于阐明更普遍的真核转录抑制现象。