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

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

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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:
Nutritional Regulation of Cystein Dioxygenase
半胱氨酸双加氧酶的营养调节
  • 批准号:
    7216208
  • 财政年份:
    2000
  • 资助金额:
    $ 19.25万
  • 项目类别:
Nutritional Regulation of Cysteine Dioxygenase
半胱氨酸双加氧酶的营养调节
  • 批准号:
    7799019
  • 财政年份:
    2000
  • 资助金额:
    $ 19.25万
  • 项目类别:
CYSTEINE DIOXYGENASE TRANSGENIC MOUSE MODEL
半胱氨酸双加氧酶转基因小鼠模型
  • 批准号:
    6198521
  • 财政年份:
    2000
  • 资助金额:
    $ 19.25万
  • 项目类别:
Nutritional Regulation of Cystein Dioxygenase
半胱氨酸双加氧酶的营养调节
  • 批准号:
    7114086
  • 财政年份:
    2000
  • 资助金额:
    $ 19.25万
  • 项目类别:
Nutritional Regulation of Cysteine Dioxygenase
半胱氨酸双加氧酶的营养调节
  • 批准号:
    8728444
  • 财政年份:
    2000
  • 资助金额:
    $ 19.25万
  • 项目类别:
Nutritional Regulation of Cysteine Dioxygenase
半胱氨酸双加氧酶的营养调节
  • 批准号:
    7856329
  • 财政年份:
    2000
  • 资助金额:
    $ 19.25万
  • 项目类别:

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