Cross-talk between GCN2 and mTOR in integration of nutrient signaling
GCN2 和 mTOR 在营养信号整合中的串扰
基本信息
- 批准号:7847735
- 负责人:
- 金额:$ 19.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-01 至 2010-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffinityAmino AcidsAmino Acids ActivationAmino Acyl-tRNA SynthetasesAnimalsBackBindingBinding ProteinsCell LineCellsCellular StressComplement 3aComplexCulture MediaDataDependenceDiabetes MellitusDietDietary ProteinsDrug DesignDrug usageElementsEmbryoEukaryotic Initiation Factor-2ExcisionFeedbackFibroblastsFunctional disorderGenesGoalsGrowthGrowth FactorHealthHumanInsulinInsulin ReceptorLeadLiverMalignant NeoplasmsMammalian CellMetabolicMusNamesNutrientNutritional SupportObesityOrganismOrthologous GeneOvernutritionPathway interactionsPhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPlayProcessProtein BiosynthesisProtein DephosphorylationProteinsRegulationReportingResistanceRibosomal Protein S6 KinaseRoleSignal PathwaySignal TransductionSirolimusSmall Interfering RNAStressTissuesTransfectionTransfer RNATranslation InitiationTranslationsUp-RegulationUpper armYeastsactivating transcription factor 4biological adaptation to stressdeprivationdetection of nutrienthepatoma cellimprovedinhibitor/antagonistinsulin sensitivityinsulin signalingloss of function mutationmTOR proteinmeetingsmutantnovelphosphatase inhibitorresponsesensorstressor
项目摘要
The mTOR (mammalian target of rapamycin) and GCN2 [eukaryotic initiation factor 2 alpha (eIF2α)
kinase 4] pathways play critical roles in integrating the organism¿s response to insulin, growth factors,
energy status, and nutrient availability, and both pathways play key roles in the regulation of
translation initiation and thus major roles in regulation of protein synthesis and growth. These
pathways provide an interface between nutrient sensing and the regulation of major metabolic
responses and, thus, have widespread significance for organismal health, especially as related to
diabetes, obesity and cancer. Our long‐term goal is to define the signaling or cross‐talk mechanisms
between the ¿amino acid sensor¿ GCN2 and mTOR pathways and to further elucidate the influence of
amino acid supply on protein synthesis and insulin signaling. Cross‐talk between mTOR and GCN2
has been reported in yeast and appears to occur in mammalian cells although this has not been directly
investigated to any extent. Our preliminary data strongly supports the hypothesis that GCN2 activation
by amino acid deprivation (and presumably the activation of other eIF2α kinases by other types of cell
stress) will lead to suppression of mTOR signaling both in tissues of whole animals and in cells in
culture. Our specific aims are (1) to determine if GCN2, eIF2α phosphorylation, and/or an increase in
activating transcription factor 4 (ATF4) are (is) necessary and/or sufficient for the regulation of S6K and
4E‐BP phosphorylation state (i.e., dephosphorylation in response to amino acid deprivation, or
phosphorylation in response to amino acid addition) and the amount of total 4E‐BP in response to
amino acids (i.e., increase in total nonphosphorylated 4E‐BP in response to amino acid deprivation); (2)
to determine if the decreased phosphorylation of S6K1 and 4E‐BP1 that is observed in response to amino
acid deprivation is due to increased action of a phosphatase, to suppressed activity of a kinase, or to a
combination of the two, and to determine if a transcriptional target of the eIF2α/ATF4 integrated stress
response pathway is responsible for the regulation of S6K1 and 4E‐BP1 phosphorylation state in
response to amino acids; and (3) to determine if insulin signaling is impaired in GCN2(‐/‐)cells (or in
cells with inactive mutant forms of eIF2α or GADD34) or GCN2(‐/‐) mice due to sustained
phosphorylation of S6K, and to determine if GCN2 activation suppresses mTOR target (i.e., S6K and 4EBP)
phosphorylation and improves insulin sensitivity (via removal of the feedback inhibition of S6K on
insulin signaling) in intact mice. Studies will be carried out in murine embryonic fibroblasts and human
liver‐derived cell lines and in whole mice using a variety of approaches including use of cells or animals
with loss of function mutations, nutrient‐modified diets or culture medium, and specific inducers of
each signaling pathway.
mTOR(哺乳动物雷帕霉素靶点)和GCN2[真核起始因子2 α (eIF2α)]
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MARTHA H STIPANUK其他文献
MARTHA H STIPANUK的其他文献
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{{ truncateString('MARTHA H STIPANUK', 18)}}的其他基金
Nutritional Regulation of y-Glutamylcysteine Synthetase
γ-谷氨酰半胱氨酸合成酶的营养调节
- 批准号:
7251533 - 财政年份:2004
- 资助金额:
$ 19.25万 - 项目类别:
Nutritional Regulation of y-Glutamylcysteine Synthetase
γ-谷氨酰半胱氨酸合成酶的营养调节
- 批准号:
7082073 - 财政年份:2004
- 资助金额:
$ 19.25万 - 项目类别:
Nutritional Regulation of y-Glutamylcysteine Synthetase
γ-谷氨酰半胱氨酸合成酶的营养调节
- 批准号:
6919340 - 财政年份:2004
- 资助金额:
$ 19.25万 - 项目类别:
Nutritional Regulation of y-Glutamylcysteine Synthetase
γ-谷氨酰半胱氨酸合成酶的营养调节
- 批准号:
6823169 - 财政年份:2004
- 资助金额:
$ 19.25万 - 项目类别:
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