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：
10539252
负责人：
Issam BEN-SAHRA
金额：
$ 33.18万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
https://reporter.nih.gov/project-details/10539252
关键词：
Acute Adipocytes Alzheimer&apos s Disease Biochemical Biogenesis Biological Assay Biological Markers Biology Biomass Bone Marrow CD3 Antigens CD8B1 gene Cancer cell line Catabolic Process Cell Cycle Progression Cell Differentiation process Cell Proliferation Cell membrane Cell physiology Cells Cellular Metabolic Process Chemicals Complex DNA biosynthesis Data Diabetes Mellitus Disease Environment Enzymes Epithelium Event FRAP1 gene Genetic Transcription Glutamine Goals Growth Growth Factor Guanosine Triphosphate Hela Cells Homeostasis Human Cell Line In Vitro Isotopes Knock-out MAP Kinase Gene MEK inhibition MEKs Malignant Neoplasms Mammalian Cell Measures Mediating Metabolic Metabolic Control Metabolic Diseases Metabolic Pathway Metabolism Mitogens Molecular Nerve Degeneration Non-Insulin-Dependent Diabetes Mellitus Normal Cell Nucleic Acids Nucleotides Nutrient Obesity Oncogenic Organism PIK3CG gene Pathologic Pathology Pathway interactions Phosphorylation Phosphotransferases Physiological Play Positioning Attribute Post-Translational Protein Processing Process Production Proliferating Protein-Serine-Threonine Kinases Proteins Proteomics Purines Pyrimidine Pyrimidines RNA chemical synthesis Ras/Raf Recurrence Regulation Ribosomes Role Science Serine Signal Pathway Signal Transduction Spleen System T-Lymphocyte Therapeutic Intervention Tissues Tracer Western Blotting base c-myc Genes cell growth cytokine fighting human disease inhibitor insight interest isotope incorporation liquid chromatography mass spectrometry macromolecule metabolomics mutant novel therapeutic intervention nucleotide metabolism personalized therapeutic phosphoproteomics purine metabolism raf Kinases reconstitution resistance mechanism response therapeutic target transcription 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.

项目概要细胞和生物体必须协调其代谢活动与其营养环境的变化。通过整合局部和系统营养输入和中继的信号网络实现协调营养状态来控制细胞的合成代谢和分解代谢过程。 RAS-RAF-MEK-ERK 级联，一种通常由各种生长因子激活的信号系统，响应于有丝分裂因子，如上皮生长因子 (EGF)，ERK 被激活。并通过调节细胞相关转录因子的活性来促进细胞增殖和分化周期进展和增殖。然而，对于 ERK 信号如何直接控制的了解却少之又少。靶向 RAF、MEK 或 ERK 激酶是目前用于治疗多种代谢过程的策略。疾病包括癌症、2型糖尿病、代谢紊乱和神经退行性疾病，但机制因此，阐明 ERK 的下游靶点，更具体地说是阐明耐药性。为了识别新的 ERK 信号驱动代谢的分子机制，人们非常感兴趣最近我们发现了针对 ERK 驱动疾病的治疗策略。雷帕霉素复合物 1 (mTORC1) 通过不同的方式刺激嘌呤和嘧啶从头合成分子机制。核苷酸在基础和细胞水平的代谢中发挥着核心作用。嘧啶碱基可以从头合成或通过核苷酸携带的回收途径回收。化学能量包（例如 ATP、GTP）遍布整个细胞，满足许多细胞功能的需要能量，包括：合成核酸、蛋白质和细胞膜。根据本提案，我们提出。为了研究 ERK 信号传导对核苷酸合成的影响，我们发现 ERK 信号传导会刺激。通过酶 PFAS 的翻译后修饰在各种环境下从头合成嘌呤（磷酸甲酰甘氨脒合酶）属于从头嘌呤合成途径。剖析这一调节背后的分子机制（具体目标1）。 ERK-PFAS 轴控制细胞生长（具体目标 2）。此外，我们将确定 ERK 介导的生物学和疾病中的这种调节（具体目标3）因此，该提案的总体目标是破译 ERK 在正常和正常情况下控制核苷酸从头合成的分子机制我们预计所提出的研究将对核苷酸如何发挥作用产生新的见解。合成受 ERK 调节，并将发现干扰 ERK 介导疾病的治疗靶点。