Cytosolic O-Glycosylation and Insulin Signaling

胞质 O-糖基化和胰岛素信号传导

• 批准号: 7468566
• 负责人: GERALD Warren HART
• 金额: $ 5.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7468566
• 关键词: Acetylation; Acetylglucosamine; Adipocytes; Adipose tissue; Affect; Amino Acids; Apoptosis; Binding; Cardiomyopathies; Cell Survival; Cells; Cellular Stress; Complex; Diabetes Mellitus; Disruption; End Point; Enzymes; Etiology; Eukaryota; Eukaryotic Cell; Figs - dietary; Foundations; Genetic Transcription; Glucose; Glycogen; Glycoproteins; HIV; Hela Cells; Hepatocyte; Hexosamines; Hyperglycemia; Hypoglycemia; In Vitro; Insulin; Insulin Resistance; Kinetics; Laboratories; Life; Link; Liver; Localized; Location; Maps; Mining; Modification; Molecular; Multienzyme Complexes; Muscle; Mutate; Myocardium; N-acetylglucopyranosylamine; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Extract; Null Lymphocytes; Nutrient; O-GlcNAc transferase; Organism; Pathway interactions; Peptides; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylated Peptide; Phosphorylation; Phosphotransferases; Play; Post-Translational Protein Processing; Protein phosphatase; Proteins; Proteomics; Regulation; Research Personnel; Resistance; Role; Sepharose; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Stress; Substrate Specificity; Therapeutic; Toxic effect; Transcriptional Regulation; Transferase; Transgenic Mice; Ubiquitination; Uridine Diphosphate; Yin-Yang; base; diabetic; glucose production; glucose uptake; glycosylation; inhibitor/antagonist; inorganic phosphate; insulin signaling; intracellular protein transport; member; microcystin; novel; peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase; prevent; programs; promoter; protein phosphatase inhibitor-1; protein transport; sensor; stable isotope; tautomycin; therapeutic target; transcription factor

Dynamic modification of nuclear and cytosolic proteins by O-linked N-Acetylglucosamine (O- GlcNAc) is as abundant as protein phosphorylation in all multi-cellular eukaryotes. Two- to five- percent of glucose is metabolized to the end product of the hexosamine biosynthetic pathway (HBP), leading to ~millimolar UDP-GlcNAc in cells. UDP-GlcNAc is the immediate donor for O- GlcNAcylation. O-GlcNAcylation often has an antagonistic, reciprocal ("Yin-Yang") relationship with Ser/Thr phosphorylation. Many laboratories have documented a key role for HBP, and more particularly, O-GlcNAcylation as a mechanism underlying glucose toxicity and insulin resistance, the hallmark of type II diabetes. We propose to continue our studies of the roles of O- GlcNAcylation in insulin signaling and resistance by elucidating the mechanisms by which elevated O-GlcNAc blocks insulin signaling in adipocytes and hepatocytes. We will reveal the site- specific interplay between phosphorylation, and O-GlcNAc's, and elucidate specific roles of each post-translational modification in signaling and transcriptional regulation key to insulin action. Specific Aims: 1) To continue to examine the Structural/Functional Significance of Protein Phosphatase 1 (PP1c) Interactions with O-GlcNAc Transferase (OGT). 2) To continue to elucidate the specific dynamic relationships between O-GlcNAcylation and O-Phosphorylation in the insulin signaling cascade, in order to explain O-GlcNAc's specific roles in hyperglycemic-induced insulin resistance. 3) To continue to examine the roles of O-GlcNAc in the functions/localization/stability and promoter activity of the insulin regulated FOXO1 transcription factor that plays a key role in regulating glucose production by the liver. These studies are revealing an unexpected paradigm for the regulation of signaling pathways by nutrients and by cellular stress. The ability of increased O-GlcNAcylation to block insulin signaling and the modification's sensitivity to stress and nutrients serves to unify current hypotheses of diabetes etiology at the molecular level. These studies will result in novel avenues for therapeutics.

通过O连接的N-乙酰葡萄糖胺（O-）对核和胞质蛋白的动态修饰（O-） 在所有多细胞真核生物中，GlcNAC）与蛋白质磷酸化一样丰富。两到五 将葡萄糖的百分比代谢为己糖胺生物合成途径的最终产物 （HBP），导致细胞中〜ill摩尔UDP-GLCNAC。 UDP-GLCNAC是O-的直接捐助者 Glcnacylation。 o-glcnacylation通常与与敌对的，相互的（“ yin-yang”）的关系 Ser/Thr磷酸化。许多实验室已经记录了HBP的关键作用，更多的 特别是，O-Glcnacylation作为葡萄糖毒性和胰岛素抵抗的机制， II型糖尿病的标志。我们建议继续研究O-的作用 通过阐明胰岛素信号传导和抗性的Glcnacylation通过阐明其机制 脂肪细胞和肝细胞中的O-GLCNAC升高可阻止胰岛素信号传导。我们将揭示该地点 - 磷酸化和O-GLCNAC之间的特定相互作用，并阐明每个角色的特定角色 胰岛素作用的信号传导和转录调节密钥中的翻译后修饰。 具体目的：1）继续检查蛋白质的结构/功能意义 磷酸酶1（PP1C）与O-GLCNAC转移酶（OGT）的相互作用。 2）继续 阐明O-Glcnacylation和O-磷酸化之间的特定动态关系 胰岛素信号级联，以解释O-GlCNAC在高血糖诱导的 胰岛素抵抗。 3）继续检查O-GlcNAC在 胰岛素调节的FOXO1转录的功能/定位/稳定性和启动子活性 在调节肝脏的葡萄糖产生中起关键作用的因素。 这些研究表明，通过 营养和细胞应激。 O-Glcnacylation增加胰岛素信号传导的能力 修改对压力和营养的敏感性用于统一当前的假设 分子水平的糖尿病病因。这些研究将导致治疗学的新途径。