Role of Forkhead Proteins in Insulin Action

叉头蛋白在胰岛素作用中的作用

• 批准号: 7563957
• 负责人: DOMENICO ACCILI
• 金额: $ 40.47万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7563957
• 关键词: 1-Phosphatidylinositol 3-Kinase; Abbreviations; Acetylation; Acetyltransferase; Acute Promyelocytic Leukemia; Address; Adipocytes; Animals; Binding Proteins; Biological; Biological Assay; Biology; Boxing; Catalytic Domain; Cell Differentiation process; Cells; Chimeric Proteins; Cloning; Cultured Cells; DNA Binding; Data; Diabetes Mellitus; Disease; Drug Delivery Systems; EP300 gene; Enzymes; Equilibrium; Exclusion; Family; Funding; Gene Expression; Gene Expression Regulation; Gene Targeting; Genetic; Genetic Transcription; Gluconeogenesis; Goals; Grant; Hand; Hepatic; Histone Deacetylase; Human; Insulin; Insulin Receptor; Kinetics; Knock-in Mouse; Laboratories; Link; Liver; Lysine; Maps; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolism; Methods; Mus; Nuclear; Oxidative Stress; Pancreas; Pathway interactions; Phosphorylation; Physiological; Post-Translational Protein Processing; Protein-Serine-Threonine Kinases; Proteins; Proto-Oncogenes; Pyruvate; Pyruvates; Regulation; Research Personnel; Role; Signal Transduction; Site; Testing; Therapeutic; Transcription Coactivator; Transgenic Mice; Transgenic Organisms; Work; base; cell type; cellular imaging; forkhead protein; gain of function; glucose production; glucose-6-phosphatase; glycogenolysis; hepatic gluconeogenesis; in vivo; inorganic phosphate; insulin signaling; mutant; notch protein; novel; programs; promoter; protein degradation; protein protein interaction; research study; transcription factor

The mechanism of insulin action on gene expression is a key question in biology, with important ramifications for the treatment of diabetes and metabolic disorders. Studies supported by this grant have established a role for the O sub-family of Forkhead transcription factors in insulin regulation of gene expression. During the past funding cycle, we have demonstrated that FoxOl is the principal insulin- dependent transcription factor in the regulation of hepatic gluconeogenesis and pancreatic (3 cell mass. We have shown that: /, phosphorylation is the main mechanism by which insulin inhibits FoxOl by promoting its nuclear exclusion; ii, FoxOl expression can single-handedlyconfer insulin regulation on the expression of Glucose-6-phosphatase, the rate-limiting enzyme in glycogenolysis; Hi,FoxOl interacts with Pgcla to stimulate gluconeogenesis; iv, FoxOl links insulin signaling to Pdxl regulation of |3cell mass. We now present preliminarydata extending the gamut of FoxO functions to regulation of cell differentiation and protection against oxidative stress, while also expanding the repertoire of FoxO target genes. We demonstrate that these functions are based on two novel modes of FoxO action: acetylation-dependent 'targeting to nuclear Pml bodies, and protein/protein interactions with the Notch effector Csl. The latter observation indicates that FoxOl functions as a coactivator, and not only as a transcription factor. It also bridges together two important signalingpathways, the PI 3-kinase and the Hesl pathways. In the next five years, we will endeavor to integrate this new information in the mechanism of FoxOl action and its role in metabolic disorders. We propose to study: in Aiml, how phosphorylation- and acetylation-mediated mechanisms are integrated in vivo to determine the kineticsof FoxOl sub-cellularlocalization in physiologic conditions and disease states; in Aim 2, how acetylation-dependent sub-nucleartargeting of FoxOl regulates metabolism in liver, pancreatic (3 cells and adipocytes; and in Aim 3, how the balance between the coactivator and transcription functions of Foxol is determined. The studies will be carried out with genetic loss- and gain-of-function experiments in transgenic mice and cultured cells, using methods that have been fully implemented in the Pi's laboratory. The ultimate goal of this work is to find a therapeutic approach to modifying FoxOl function. Indeed, while FoxOl is an extremely attractive biological target to treat diabetes and metabolic diseases, it is largely intractable as a drug target. Therefore, it is hoped that by identifying mechanisms of action and interacting partners, new ways to modulate its function can be found.

胰岛素作用对基因表达的机制是生物学的关键问题，重要的是 治疗糖尿病和代谢疾病的后果。这笔赠款支持的研究 确定了叉头转录因子的O子家庭在基因调节中的作用 表达。在过去的资金周期中，我们证明了Foxol是主要的胰岛素 - 肝糖异生和胰腺调节中的依赖转录因子（3个细胞质量。 已经表明： /，磷酸化是胰岛素通过促进FOXOL抑制Foxol的主要机制 核排除； II，Foxol表达可以单手倾斜胰岛素调节 葡萄糖-6-磷酸酶，糖原分解中的速率限制酶；嗨，Foxol与PGCLA互动 刺激糖异生； IV，Foxol将胰岛素信号与| 3细胞质量的PDXL调节联系起来。我们现在 目前的初步数据将FOXO功能的范围扩展到调节细胞分化和 防止氧化应激，同时还扩大了FOXO靶基因的曲目。我们 证明这些功能基于Foxo作用的两种新型模式：乙酰化依赖性 靶向核PML体，以及与Notch效应子CSL的蛋白质/蛋白质相互作用。后者 观察表明，Foxol充当共激活因子，而不仅是转录因子。也是如此 桥接两个重要的信号路径，PI 3-激酶和HESL途径。在接下来的五个 多年来，我们将努力将这些新信息纳入Foxol Action的机制及其在其中的作用 代谢障碍。我们建议研究：在AIML中，磷酸化和乙酰化介导的如何 将机制集成在体内，以确定生理学中Foxol亚细胞化的动力学 疾病和疾病状态；在AIM 2中，Foxol的乙酰化依赖性亚核定量如何调节 肝脏，胰腺的代谢（3个细胞和脂肪细胞；在AIM 3中，如何平衡 确定Foxol的共激活因子和转录函数。研究将使用遗传进行 使用已有的方法 在PI的实验室中完全实施。这项工作的最终目标是找到一种治疗方法 修改Foxol功能。确实，虽然Foxol是治疗糖尿病的极具吸引力的生物学靶标 和代谢性疾病，它在很大程度上是棘手的作为药物靶标。因此，希望通过识别 可以找到动作和互动伙伴的机制，可以找到调节其功能的新方法。