Mitogenic Signal Transduction in Pancreatic Beta-Cells

胰腺β细胞中的有丝分裂信号转导

• 批准号: 8280433
• 负责人: Christopher J Rhodes
• 金额: $ 33.25万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8280433
• 关键词: 1-Phosphatidylinositol 3-Kinase; 70-kDa Ribosomal Protein S6 Kinases; Abbreviations; Acute; Adenovirus Vector; Affinity; Apoptosis; Binding; Biological Assay; CREB1 gene; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium/calmodulin-dependent protein kinase; Carbohydrates; Cell Count; Cell Survival; Cells; Characteristics; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic AMP-Responsive DNA-Binding Protein; Cytoprotection; DNA; Data; Diabetes Mellitus; Disease; EMSA; Elements; Extracellular Signal Regulated Kinases; Feedback; Fluorescence; Funding; Gene Expression; Genes; Genetic Transcription; Glucose; Glycogen Synthase Kinase 3; Goals; Growth; Growth Factor; Half-Life; Hand; Health; Homologous Gene; Human; Indium; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Investigation; Lead; Link; Luciferases; MEKs; Maintenance; Mass Spectrum Analysis; Mediating; Messenger RNA; Metabolic; Mitogens; Molecular; Mus; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Oncogenic; PTEN gene; Pancreas; Pancreatic Diseases; Pathogenesis; Peripheral; Personal Satisfaction; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological; Play; Population; Production; Promoter Regions; Protein Kinase; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Renilla Luciferases; Reporter; Research; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Social Welfare; Son; Stimulus; Structure of beta Cell of islet; Symptoms; Text; Therapeutic; Thymidine Kinase; Trans-Activators; Transcriptional Regulation; Transducers; base; blood glucose regulation; cell growth; diabetic; glucose metabolism; growth factor receptor-bound protein 2; human FRAP1 protein; in vivo; infancy; insight; insulin receptor substrate-2 protein; interest; islet; mTOR protein; non-diabetic; novel; novel therapeutic intervention; novel therapeutics; prevent; promoter; response; tensin; therapeutic target; transcription factor; tumorigenesis

It has now been realized that type-2 diabetes is a disease of insulin insufficiency. Type-2 diabetes is associated with a decrease in functional pancreatic ss-cell mass that no longer compensates for the peripheral insulin resistance. As such, maintaining an optimal ss-cell population for the insulin secretory demand, especially by promoting ss-cell survival, is key for delaying the onset of type-2, as well as type-1, diabetes. In this regard, IRS-2 has been shown to play a pivotal role in ss-cell growth and survival. Increased IRS-2 expression promotes ss-cell growth and survival, whereas insufficient IRS-2 expression leads to spontaneous ss-cell apoptosis. Although IRS-2 protein and mRNA half-life is short in islet ss-cells, this is countered by efficient and highly regulated control of IRS-2 expression, predominately mediated at the transcriptional level. Under basal conditions, ss-cell IRS-2 gene transcription is controlled by a FoxO transcription factor via an insulin response element (IRE) in the IRS-2 promoter. When IRS-2/PI3K/PKB signaling is activated in ss-cells, FoxO transcription factors are consequently inactivated and IRS-2 expression is reduced, in what appears to be a temporal negative feedback mechanism to prevent IRS-2 signaling from being sustained. However, IRS-2 expression can be independently controlled in ss-cells by alternative means. Glucose, in the physiologically relevant range, is a major regulator of ss-cell IRS-2 gene transcription. This requires glucose metabolism and is Ca2+-dependent. It likely provides a mechanism to preserve ss-cell well-being during acute changes in metabolic demand, and is important since other factors, like incretins, only increae IRS-2 expression in ss-cells in a glucose-dependent fashion. However, these early findings need substantiating. This proposal means to gain a better insight into the control of IRS-2 expression in pancreatic ss-cells at the molecular level. It is intended to better characterize control of IRS-2 gene transcription under basal conditions with an emphasis on identifying which particular FoxO transcription factor downstream of PI3K/PKB signaling increases IRS-2 expression. In addition, we will pinpoint which particular secondary signals emanating from increased glucose metabolism in ss-cells link to increased IRS-2 expression (especially via Ca2+/CaMK). It is intended to define a glucose-regulatory cis-element(s) (GREs) in the IRS-2 gene promoter and then identify a trans-acting factor(s) that specifically associates with the GRE glucose-regulatory manner. Thus, a much deeper insight into the molecular mechanism that controls IRS-2 expression in normal, obese and type-2 diabetic primary ss-cells will emerge from these proposed studies. Obesity-linked type-2 diabetes is a major health problem in the US and caused by loss of pancreatic ss-cells that produce insulin. Novel therapeutic approaches are needed which are aimed at protecting the endogenous ss-cell population to produce enough insulin to delay, perhaps indefinitely, the onset of diabetes. IRS-2 is a gene key to ss-cell survival, and it is anticipated that new insight into the control of IRS-2 expression will lead to a novel means of maintaining adequate ss-cell numbers and sufficient insulin production in vivo, that in turn will alleviate, or perhaps even prevent, symptoms of type-2 diabetes.

现在已经意识到2型糖尿病是一种胰岛素不足的疾病。 2型糖尿病是 与功能性胰腺SS细胞质量的减少相关，不再补偿外围 胰岛素抵抗。因此，为胰岛素分泌需求维持最佳的SS细胞人群， 特别是通过促进SS细胞存活，是延迟2型和1型糖尿病的关键。在 在这方面，IRS-2已显示在SS细胞生长和生存中起关键作用。 IRS-2增加 表达促进SS细胞的生长和存活，而IRS-2表达不足会导致自发 SS细胞凋亡。尽管IRS-2蛋白和mRNA半衰期在胰岛ss细胞中较短，但这是通过有效的 以及对IRS-2表达的高度调节的控制，主要介导在转录水平上。在下面 基础条件，SS细胞IRS-2基因转录由FOXO转录因子通过胰岛素控制 IRS-2启动子中的响应元件（IRE）。当SS细胞激活IRS-2/PI3K/PKB信号传导时 因此，转录因子被灭活并降低了IRS-2的表达，这似乎是 时间负反馈机制，以防止IRS-2信号传导持续。但是，IRS-2 可以通过替代方式在SS细胞中独立控制表达。葡萄糖，在生理上 相关范围是SS细胞IRS-2基因转录的主要调节剂。这需要葡萄糖代谢，是 Ca2+依赖性。它可能提供了一种在急性变化期间保留SS细胞健康的机制 代谢需求，并且很重要，因为其他因素（例如肠肠蛋白酶）仅在SS细胞中递增IRS-2表达 以葡萄糖依赖的方式。但是，这些早期发现需要证实。该提议意味着 可以更好地了解分子水平胰腺SS细胞中IRS-2表达的控制。这是 旨在更好地表征对IRS-2基因转录在基础条件下的控制，重点是 确定PI3K/PKB信号下游的哪种特定FOXO转录因子增加IRS-2 表达。此外，我们将指出从增加葡萄糖发出的哪些特定次级信号 SS细胞中的代谢链接到IRS-2表达增加（尤其是通过Ca2+/camk）。它旨在定义一个 IRS-2基因启动子中的葡萄糖调节顺式元素（S）（S）（GRES），然后确定跨作用因子（S） 该专门与GRE葡萄糖调节方式相关联。因此，对 控制正常，肥胖和2型糖尿病初级SS细胞中IRS-2表达的分子机制将 从这些提出的研究中得出。 肥胖与2型糖尿病是美国的主要健康问题，是由于胰腺SS细胞的损失而引起的 产生胰岛素。需要新的治疗方法，旨在保护内源性 SS细胞种群可产生足够的胰岛素来延迟糖尿病的发作。 IRS-2是一个 SS细胞生存的基因键，预计对IRS-2表达控制的新见解将导致 一种在体内维持足够的SS细胞数量和足够胰岛素产生的新型手段 减轻甚至可以预防2型糖尿病的症状。