HNF-4 AND APOLIPOPROTEIN B GENE EXPRESSION

描述(改编自申请人的摘要)：本提案 解决对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中发挥关键作用 差异化。使用的模型是载脂蛋白B(Apo)的基因 B100)，低密度脂蛋白的主要蛋白质成分，一 血浆中最易致动脉粥样硬化的成分。了解以下内容 调控载脂蛋白B基因表达的分子机制在临床上 这一点很重要，因为如果apoB-100水平大幅降低， 低密度脂蛋白水平也将降低，显著降低 冠心病。此前的研究已经确定了监管机构 载脂蛋白B基因在肝脏中表达所必需的元件。的 特别重要的是元素III和IV，它们与 转录因子HNF-4和C/EBP。这些元素起到了 在apoB基因转录中的中心作用，因为替代突变 取消HNF-4或C/EBP与其同源元素的结合， 显著降低apoB基因转录。HNF-4和C/EBP激活 载脂蛋白B基因的协同表达，但其分子机制 这种协同激活尚不清楚。这样做的具体目的是 建议：1)确定HNF-4的结构域，这些结构域参与 转录激活载脂蛋白B基因，2)阐明分子 载脂蛋白B协同激活的机制 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 受体和载脂蛋白B基因表达的分子本质。

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.