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.

现在人们已经认识到，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细胞质量减少有关，不再代偿外周 胰岛素抵抗。因此，维持胰岛素分泌需求的最佳SS细胞群， 尤其是通过促进ss细胞的存活，是延缓2型糖尿病和1型糖尿病发病的关键。在……里面 在这方面，IRS-2已被证明在SS细胞的生长和存活中发挥关键作用。增加IRS-2 表达促进ss细胞的生长和存活，而IRS-2表达不足导致自发 SS-细胞凋亡。尽管在胰岛ss细胞中irs-2蛋白和mrna的半衰期很短，但有效的 以及对IRS-2表达的高度调控，主要是在转录水平上调节。在……下面 基础条件下，SS细胞IRS-2基因转录受FoxO转录因子通过胰岛素调控 IRS-2启动子中的反应元件(IRE)。当SS细胞中IRS-2/PI3K/PKB信号被激活时，FoxO 转录因子因此失活，IRS-2表达减少，这似乎是一种 时间负反馈机制，以防止IRS-2信号持续。然而，IRS-2 在ss-cell中可以通过替代手段独立控制其表达。葡萄糖，在生理上 相关范围，是ss-cell IRS-2基因转录的主要调控因子。这需要葡萄糖代谢，而且是 依赖于钙离子。它可能提供了一种机制，在细胞急剧变化期间保持ss细胞的健康 代谢需求，这一点很重要，因为其他因素，如胰岛素，只会增加SS细胞中IRS-2的表达 以依赖葡萄糖的方式。然而，这些早期的发现需要证实。这项提议意味着 从分子水平更好地了解胰腺SS细胞中IRS-2表达的调控。它是 旨在更好地描述基础条件下IRS-2基因转录的控制，重点是 识别PI3K/PKB信号下游的哪个特定FoxO转录因子会增加IRS-2 表情。此外，我们还将确定哪些特定的二级信号是由血糖升高引起的。 SS细胞的代谢与IRS-2表达增加有关(尤其是通过钙/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件(S)(GREs)，进而鉴定反式作用因子(S) 这与GRE的血糖调节方式特别相关。因此，我们可以更深入地了解 控制正常、肥胖和2型糖尿病原代SS细胞中IRS-2表达的分子机制将 从这些拟议的研究中浮现。 肥胖相关的2型糖尿病在美国是一个主要的健康问题，由胰腺SS细胞的丧失引起 能产生胰岛素的物质。需要新的治疗方法，旨在保护内源性 SS细胞群产生足够的胰岛素，可能无限期地延缓糖尿病的发生。IRS-2是一颗 基因是ss细胞存活的关键，预计对IRS-2表达控制的新见解将导致 一种在体内保持足够的SS细胞数量和足够的胰岛素产生的新方法，这反过来将 减轻，甚至预防，2型糖尿病的症状。