Mitogenic Signal Transduction in Pancreatic Beta-Cells
胰腺β细胞中的有丝分裂信号转导
基本信息
- 批准号:8492069
- 负责人:
- 金额:$ 32.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1998
- 资助国家:美国
- 起止时间:1998-09-30 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-Kinase70-kDa Ribosomal Protein S6 KinasesAbbreviationsAcuteAdenovirus VectorAffinityApoptosisBindingBiological AssayCREB1 geneCa(2+)-Calmodulin Dependent Protein KinaseCalcium/calmodulin-dependent protein kinaseCarbohydratesCell CountCell SurvivalCellsCharacteristicsCyclic AMPCyclic AMP-Dependent Protein KinasesCyclic AMP-Responsive DNA-Binding ProteinCytoprotectionDNADataDiabetes MellitusDiseaseEMSAElementsExtracellular Signal Regulated KinasesFeedbackFluorescenceFundingGene ExpressionGenesGenetic TranscriptionGlucoseGlycogen Synthase Kinase 3GoalsGrowthGrowth FactorHalf-LifeHandHealthHomologous GeneHumanIndiumInsulinInsulin ReceptorInsulin ResistanceInsulin-Dependent Diabetes MellitusInvestigationLeadLinkLuciferasesMEKsMaintenanceMass Spectrum AnalysisMediatingMessenger RNAMetabolicMitogensMolecularMusNatural regenerationNon-Insulin-Dependent Diabetes MellitusNonesterified Fatty AcidsObesityOncogenicPTEN genePancreasPancreatic DiseasesPathogenesisPeripheralPersonal SatisfactionPhosphatidylinositolsPhosphoric Monoester HydrolasesPhosphotransferasesPhysiologicalPlayPopulationProductionPromoter RegionsProtein KinaseProteinsProto-Oncogene Proteins c-aktRegulationRenilla LuciferasesReporterResearchResponse ElementsReverse Transcriptase Polymerase Chain ReactionRoleSignal PathwaySignal TransductionSignal Transduction PathwaySiteSocial WelfareSonStimulusStructure of beta Cell of isletSymptomsTextTherapeuticThymidine KinaseTrans-ActivatorsTranscriptional RegulationTransducersbaseblood glucose regulationcell growthdiabeticglucose metabolismgrowth factor receptor-bound protein 2human FRAP1 proteinin vivoinfancyinsightinsulin receptor substrate-2 proteininterestisletmTOR proteinnon-diabeticnovelnovel therapeutic interventionnovel therapeuticspreventpromoterresponsetensintherapeutic targettranscription factortumorigenesis
项目摘要
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
项目成果
期刊论文数量(13)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
IGF-I and GH post-receptor signaling mechanisms for pancreatic beta-cell replication.
- DOI:10.1677/jme.0.0240303
- 发表时间:2000-06
- 期刊:
- 影响因子:3.5
- 作者:CJ Rhodes
- 通讯作者:CJ Rhodes
Increased phagocyte-like NADPH oxidase and ROS generation in type 2 diabetic ZDF rat and human islets: role of Rac1-JNK1/2 signaling pathway in mitochondrial dysregulation in the diabetic islet.
- DOI:10.2337/db11-0809
- 发表时间:2011-11
- 期刊:
- 影响因子:7.7
- 作者:Syed I;Kyathanahalli CN;Jayaram B;Govind S;Rhodes CJ;Kowluru RA;Kowluru A
- 通讯作者:Kowluru A
Specific glucose-induced control of insulin receptor substrate-2 expression is mediated via Ca2+-dependent calcineurin/NFAT signaling in primary pancreatic islet β-cells.
- DOI:10.2337/db11-0341
- 发表时间:2011-11
- 期刊:
- 影响因子:7.7
- 作者:Demozay D;Tsunekawa S;Briaud I;Shah R;Rhodes CJ
- 通讯作者:Rhodes CJ
Glucose and fatty acids synergize to promote B-cell apoptosis through activation of glycogen synthase kinase 3β independent of JNK activation.
- DOI:10.1371/journal.pone.0018146
- 发表时间:2011-04-26
- 期刊:
- 影响因子:3.7
- 作者:Tanabe K;Liu Y;Hasan SD;Martinez SC;Cras-Méneur C;Welling CM;Bernal-Mizrachi E;Tanizawa Y;Rhodes CJ;Zmuda E;Hai T;Abumrad NA;Permutt MA
- 通讯作者:Permutt MA
Stimulation of pancreatic beta-cell proliferation by growth hormone is glucose-dependent: signal transduction via janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) with no crosstalk to insulin receptor substrate-mediated mit
生长激素对胰腺 β 细胞增殖的刺激是葡萄糖依赖性的:通过 janus 激酶 2 (JAK2)/信号转导器和转录激活剂 5 (STAT5) 进行信号转导,与胰岛素受体底物介导的 mit 没有串扰
- DOI:
- 发表时间:1999
- 期刊:
- 影响因子:0
- 作者:Cousin,SP;Hügl,SR;MyersJr,MG;White,MF;Reifel-Miller,A;Rhodes,CJ
- 通讯作者:Rhodes,CJ
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Christopher J Rhodes其他文献
Who knew? PPARs may act in the brain too
谁知道?
- DOI:
10.1038/s42255-022-00625-6 - 发表时间:
2022 - 期刊:
- 影响因子:20.8
- 作者:
R. Seeley;Christopher J Rhodes - 通讯作者:
Christopher J Rhodes
Christopher J Rhodes的其他文献
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{{ truncateString('Christopher J Rhodes', 18)}}的其他基金
An Interdisciplinary Molecular Metabolism Training Program
跨学科分子代谢培训计划
- 批准号:
8515773 - 财政年份:2010
- 资助金额:
$ 32.09万 - 项目类别:
An Interdisciplinary Molecular Metabolism Training Program
跨学科分子代谢培训计划
- 批准号:
7869732 - 财政年份:2010
- 资助金额:
$ 32.09万 - 项目类别:
An Interdisciplinary Molecular Metabolism Training Program
跨学科分子代谢培训计划
- 批准号:
8712473 - 财政年份:2010
- 资助金额:
$ 32.09万 - 项目类别:
An Interdisciplinary Molecular Metabolism Training Program
跨学科分子代谢培训计划
- 批准号:
8293342 - 财政年份:2010
- 资助金额:
$ 32.09万 - 项目类别:
An Interdisciplinary Molecular Metabolism Training Program
跨学科分子代谢培训计划
- 批准号:
8091288 - 财政年份:2010
- 资助金额:
$ 32.09万 - 项目类别: