HNF-4 AND APOLIPOPROTEIN B GENE EXPRESSION

HNF-4 和载脂蛋白 B 基因表达

• 批准号: 2774272
• 负责人: MARGARIT H HADZOPOULOU-CLADARAS
• 金额: $ 25.63万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2774272
• 关键词: apolipoproteins; complementary DNA; gene induction /repression; genetic promoter element; hormone receptor; liver; molecular cloning; nucleic acid sequence; protein structure function; tissue /cell culture; transcription factor

DESCRIPTION (Adapted from the Applicant's Abstract): This proposal addresses the understanding of basic mechanisms controlling liver-specific regulation of transcription that play a pivotal role in development and differentiation. The model used is the gene for apolipoprotein B (apo B100), the major protein constituent of low density lipoprotein (LDL), one of the most atherogenic components in the plasma. Knowledge of the molecular mechanisms that regulate apoB gene expression is clinically important because if the levels of apoB-100 are substantially reduced, the levels of LDL will also be lowered, reducing significantly the risks for coronary heart disease. Previous studies have identified the regulatory elements which are essential for expression of the apoB gene in liver. Of particular importance are the elements III and IV, which interact with the transcription factors HNF-4 and C/EBP, respectively. These elements play a central role in the apoB gene transcription, since substitution mutations that abolish binding of either HNF-4 or C/EBP to their cognate elements, dramatically decrease apoB gene transcription. HNF-4 and C/EBP activate apoB gene expression synergistically , however the molecular mechanism of this synergistic activation is not known. The specific aims of this proposal are: 1) to identify the domains of HNF-4 that are involved in the transcriptional activation of the apoB gene, 2) to elucidate the molecular mechanisms that are involved in the synergistic activation of the apoB promoter by HNF-4 and C/EBP. The proposed experiments will provide significant new information regarding the structure and function of HNF-4, the molecular mechanisms of transcriptional activation by nuclear hormone receptors and the molecular nature of apoB gene expression.

描述（改编自申请人的摘要）：本提案 解决了控制肝脏特异性的基本机制的理解 转录调控在发育和发育过程中发挥着关键作用 差异化。 使用的模型是载脂蛋白 B (apo B100），低密度脂蛋白（LDL）的主要蛋白质成分，一种 血浆中最容易导致动脉粥样硬化的成分。 的知识 临床上调节apoB基因表达的分子机制 重要的是，如果 apoB-100 的水平大幅降低， 低密度脂蛋白水平也将降低，从而显着降低患以下疾病的风险 冠心病。 之前的研究已经确定了监管 肝脏中 apoB 基因表达所必需的元素。 的 特别重要的是元素 III 和 IV，它们与 分别是转录因子 HNF-4 和 C/EBP。 这些元素起到了 由于替代突变，apoB 基因转录中发挥着核心作用 废除 HNF-4 或 C/EBP 与其同源元素的结合， 显着降低 apoB 基因转录。 HNF-4 和 C/EBP 激活 apoB基因协同表达，但其分子机制 这种协同激活尚不清楚。 本次活动的具体目标 建议是： 1) 确定参与 HNF-4 的域 apoB 基因的转录激活，2) 阐明分子 参与 apoB 协同激活的机制 由 HNF-4 和 C/EBP 启动子。 拟议的实验将提供 关于 HNF-4 结构和功能的重要新信息， 核激素转录激活的分子机制 受体和 apoB 基因表达的分子性质。