REGULATION OF LIVER SPECIFIC GENE EXPRESSION

描述：（改编自研究者摘要）。 肝脏是 负责产生血浆和其他蛋白质的主要器官 用于基础代谢和化合物的解毒。 而 过去十年的研究表明，这些肝脏蛋白质 主要是由于肝脏特异性基因表达介导的， 肝脏富集的转录因子，目前尚不清楚如何 实现了肝脏特异性转录。 例如，许多问题 肝细胞核因子4（hepatocyte nuclear factor 4，HNF-4）的作用机制尚不清楚， 其中一个最重要的转录因子，用于确定肝脏 超过40个靶基因的表型和调节因子，包括那些参与 葡萄糖、脂肪酸和胆固醇代谢，血液凝固，以及 化学解毒 因此，本提案的目标是 通过研究三个基因，阐明肝脏特异性基因表达的机制， HNF-4的重要方面：（1）申请人最近表明，由于 其强且独特的同二聚化活性和独特的核 定位，HNF-4定义了一个新的亚群在核受体 超家族 他们建议研究特定的氨基酸， 确定同源与异源二聚化以及蛋白质的作用 受体功能的二聚化。 这将通过合理的 基于已知的定点诱变研究 其他受体的基因突变， HNF-4是最近发现的成熟型糖尿病患者， （二）申请人将研究 转录激活HNF-4通过分析相互作用 HNF-4，辅激活子，辅抑制子和基础转录机制 通过体内和体外试验;和（3）申请人将建立一个 研究HNF-4和 另一个肝脏富集的转录因子，C/EBP α，在 载脂蛋白B基因启动子。 两种肝脏强化之间的协同作用 转录因子可以解释肝脏特异性基因表达 和其他基因。 由于HNF-4直接或间接与 几种人类疾病，包括动脉粥样硬化，肝炎，血友病， 肝癌发生，以及最近的糖尿病，详细的机制 对HNF-4功能了解不仅有助于阐明肝脏特异性基因 表达和核受体的作用，但也提供了基础， 治疗试剂的可能的未来发展， 疾病。

DESCRIPTION: (Adapted from the investigator's abstract). The liver is the primary organ responsible for producing plasma and other proteins essential for basic metabolism and detoxification of chemical compounds. Whereas research during the past decade has shown that these liver proteins are produced largely as a result of liver-specific gene expression mediated by liver-enriched transcription factors, it is not known exactly how liver-specific transcription is achieved. For example, many questions remain about the mechanism of action of hepatocyte nuclear factor 4 (HNF-4), one of the most important transcription factors for determining the hepatic phenotype and regulator of over 40 target genes, including those involved in glucose, fatty acid, and cholesterol metabolism, blood coagulation, and chemical detoxification. The goal of this proposal, therefore, is to elucidate the mechanism of liver-specific gene expression by studying three important aspects of HNF-4: (1) The applicants recently showed that due to its strong and exclusive homodimerization activity and exclusive nuclear localization, HNF-4 defines a new subgroup in the nuclear receptor superfamily. They propose to investigate the specific amino acids that determine homo- vs. heterodimerization as well as the role of protein dimerization in receptor function. This will be achieved by rationally based site-directed mutagenesis studies derived from what is already known about other receptors as well as from a naturally occurring mutation in HNF-4 that was recently found in patients with maturity-onset diabetes of the young (MODY1); (2) The applicants will examine the mechanism of transcriptional activation by HNF-4 by analyzing the interaction between HNF-4, co-activators, co-repressors, and the basal transcription machinery by in vivo and in vitro assays; and (3) The applicants will establish an in vitro system to investigate the transcriptional synergy between HNF-4 and another liver-enriched transcription factor, C/EBP alpha, on the apolipoprotein B gene promoter. Synergy between tow liver-enriched transcription factors could explain liver-specific gene expression for this and other genes. Since HNF-4 has been directly or indirectly linked to several human diseases, including atherosclerosis, hepatitis, hemophilia, hepatocarcinogenesis, and, most recently, diabetes, detailed mechanistic knowledge of HNF-4 function will not only shed light on liver-specific gene expression and the action of nuclear receptors but also provide a basis for the possible future development of therapeutic reagents for a wide variety of diseases.