Regulation of de novo purine synthesis by the MAPK/ERK pathway
MAPK/ERK 途径对嘌呤从头合成的调节
基本信息
- 批准号:10321274
- 负责人:
- 金额:$ 33.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdipocytesAlzheimer&aposs DiseaseBiochemicalBiogenesisBiological AssayBiological MarkersBiologyBiomassBone MarrowCD3 AntigensCD8B1 geneCancer cell lineCatabolic ProcessCell Cycle ProgressionCell Differentiation processCell ProliferationCell membraneCell physiologyCellsCellular Metabolic ProcessChemicalsComplexDNA biosynthesisDataDiabetes MellitusDiseaseEnvironmentEnzymesEpithelialEventFRAP1 geneGenetic TranscriptionGlutamineGoalsGrowthGrowth FactorGuanosine TriphosphateHela CellsHomeostasisHuman Cell LineIn VitroIsotopesKnock-outMAP Kinase GeneMEK inhibitionMEKsMalignant NeoplasmsMammalian CellMeasuresMediatingMetabolicMetabolic ControlMetabolic DiseasesMetabolic PathwayMetabolismMitogensMolecularNerve DegenerationNon-Insulin-Dependent Diabetes MellitusNormal CellNucleic AcidsNucleotidesNutrientObesityOncogenicOrganismPathologicPathologyPathway interactionsPhosphorylationPhosphotransferasesPhysiologicalPlayPositioning AttributePost-Translational Protein ProcessingProcessProductionProliferatingProtein-Serine-Threonine KinasesProteinsProteomicsPurinesPyrimidinePyrimidinesRNA chemical synthesisRas/RafRecurrenceRegulationRibosomesRoleScienceSignal PathwaySignal TransductionSpleenSystemT-LymphocyteTherapeutic InterventionTimeTissuesTracerWestern Blottingbasec-myc Genescancer typecell growthcytokinefightinghuman diseaseinhibitorinsightinterestisotope incorporationliquid chromatography mass spectrometrymacromoleculemetabolomicsmutantnovel therapeutic interventionnucleotide metabolismpersonalized therapeuticphosphoproteomicspurine metabolismraf Kinasesreconstitutionresistance mechanismresponsetherapeutic targettranscription factor
项目摘要
PROJECT SUMMARY
Cells and organisms must coordinate their metabolic activity with changes in their nutrient environment. This
coordination is achieved via the signaling networks that integrate local and systemic nutrient inputs and relay
nutrient status to the control of cellular anabolic and catabolic processes. This task can be carried out by the
RAS-RAF-MEK-ERK cascade, a signaling system that is commonly activated by various growth factors and
oncogenic events. In response to a mitogen factor such as the epithelial growth factor (EGF), ERK is activated
and promotes cell proliferation and differentiation by regulating activity of transcription factors involved in cell
cycle progression and proliferation. However, much less is understood about how ERK signaling directly controls
metabolic processes. Targeting the kinases RAF, MEK or ERK is currently a strategy employed to treat several
diseases including cancer, type 2 diabetes, metabolic disorders and neurodegeneration, however mechanisms
of resistance often occur. Therefore, elucidating the downstream targets of ERK and more specifically the
molecular mechanisms by which ERK signaling drives metabolism is of great interest in order to identify new
therapeutic strategies against ERK driven disease. Recently we discovered that the mechanistic target of
rapamycin complex 1 (mTORC1) stimulates synthesis of purines and pyrimidines de novo through different
molecular mechanisms. Nucleotides play a central role in metabolism at a fundamental and cellular level. Purine
and pyrimidine bases can be synthesized de novo or recycled through the salvage pathways. Nucleotides carry
packets of chemical energy (e.g. ATP, GTP) throughout the cell to the many cellular functions that demand
energy, which include: synthesizing nucleic acids, proteins and cell membranes. Under this proposal, we propose
to study the influence of ERK signaling on nucleotide synthesis. We have identified that ERK signaling stimulates
de novo purine synthesis in various settings through posttranslational modification of the enzyme PFAS
(phosphoformylglycinamidine synthase) which belongs to the de novo purine synthesis pathway. We propose to
dissect the molecular mechanisms underlying this regulation (Specific Aim1). We will determine the role of the
ERK-PFAS axis in the control of cell growth (Specific Aim 2). Furthermore, we will determine the implication of
this regulation in ERK-mediated biology and disease (Specific Aim3). Thus, the overall goal of this proposal is to
decipher the molecular mechanisms by which ERK controls de novo nucleotide synthesis in normal and
pathological settings. We anticipate that the proposed studies will yield new insights into how nucleotide
synthesis is regulated by ERK and will uncover therapeutic targets to perturb ERK-mediated disease.
项目摘要
细胞和生物体必须协调其代谢活动与营养环境的变化。
协调是通过整合本地和系统养分输入和中继的信号网络来实现的
营养状况来控制细胞合成代谢和分解代谢过程。这项任务可以由
RAS-RAF-ERK-ERK级联,一种通常被各种生长因子激活的信号系统,
响应于促分裂因子如上皮生长因子(EGF),ERK被激活,
并通过调节参与细胞增殖和分化的转录因子的活性来促进细胞增殖和分化。
然而,关于ERK信号如何直接控制细胞周期的进展和增殖,
靶向激酶RAF、MEK或ERK是目前用于治疗几种代谢过程的策略。
包括癌症、2型糖尿病、代谢紊乱和神经变性在内的疾病,
因此,阐明ERK的下游靶点,更具体地说,
ERK信号传导驱动代谢的分子机制是非常感兴趣的,以便鉴定新的
针对ERK驱动的疾病的治疗策略。最近我们发现,
雷帕霉素复合物1(mTORC 1)通过不同的途径刺激嘌呤和嘧啶的从头合成,
分子机制。核苷酸在基础和细胞水平的代谢中发挥核心作用。嘌呤
和嘧啶碱基可以从头合成或通过补救途径再循环。
化学能包(如ATP,GTP)在整个细胞的许多细胞功能,需要
能源,包括:合成核酸,蛋白质和细胞膜。根据这一建议,我们建议,
研究ERK信号对核苷酸合成的影响。我们已经确定ERK信号刺激核苷酸合成,
通过PFAS酶的翻译后修饰在各种环境中从头合成嘌呤
(磷酸甲酰基甘氨脒合酶),属于从头嘌呤合成途径。我们建议
剖析这种调节的分子机制(特异性Aim 1)。我们将确定
ERK-PFAS轴在细胞生长控制中的作用(具体目标2)。
因此,本提案的总体目标是:
破译细胞外信号调节蛋白激酶控制正常和新生核苷酸合成的分子机制
病理环境。我们预计拟议的研究将对核苷酸如何产生新的见解
合成受ERK调节,并将发现干扰ERK介导疾病的治疗靶点。
项目成果
期刊论文数量(0)
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{{ truncateString('Issam BEN-SAHRA', 18)}}的其他基金
Control of RNA methylation by growth signals through the mTORC1 pathway
通过 mTORC1 途径通过生长信号控制 RNA 甲基化
- 批准号:
10469579 - 财政年份:2021
- 资助金额:
$ 33.18万 - 项目类别:
Control of RNA methylation by growth signals through the mTORC1 pathway
通过 mTORC1 途径通过生长信号控制 RNA 甲基化
- 批准号:
10277131 - 财政年份:2021
- 资助金额:
$ 33.18万 - 项目类别:
Control of RNA methylation by growth signals through the mTORC1 pathway
通过 mTORC1 途径通过生长信号控制 RNA 甲基化
- 批准号:
10630233 - 财政年份:2021
- 资助金额:
$ 33.18万 - 项目类别:
Regulation of de novo purine synthesis by the MAPK/ERK pathway
MAPK/ERK 途径对嘌呤从头合成的调节
- 批准号:
10539252 - 财政年份:2020
- 资助金额:
$ 33.18万 - 项目类别:
Regulation of de novo purine synthesis by the MAPK/ERK pathway
MAPK/ERK 途径对嘌呤从头合成的调节
- 批准号:
10078280 - 财政年份:2020
- 资助金额:
$ 33.18万 - 项目类别:
Linking Oncogenic Signaling to Tumor Metabolism
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- 资助金额:
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Linking oncogenic signaling to tumor metabolism
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8868257 - 财政年份:2015
- 资助金额:
$ 33.18万 - 项目类别:
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