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Kinase-dependent Regulation of Metabolic Enzymes

代谢酶的激酶依赖性调节

基本信息

批准号：
9700784
负责人：
JEFFREY R PETERSON
金额：
$ 3.68万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9700784
关键词：
Actins Anabolism Antineoplastic Agents Antiparasitic Agents Architecture Bacteria Biochemical Biological Process Cell Proliferation Cells Coupled Cultured Cells Cytoskeletal Proteins Data Development Disease Drosophila genus Drug Targeting Drug usage Enzymes Event Feedback Filament Fluorescence Microscopy Funding Goals Grant Growth Growth Factor Guanine Nucleotides Human Immunosuppressive Agents In Vitro Individual Inosine Monophosphate Intervention Length Link Malignant Neoplasms Mammalian Cell Measures Mediating Metabolic Metabolism Molecular Molecular Structure Mutation Nucleotide Biosynthesis Nucleotides Nutrient Nutrient Depletion Oogenesis Organism Oxidoreductase Pathway interactions Patients Pharmacology Phosphorylation Phosphotransferases Physiological Polymers Prevalence Process Protein Dynamics Protein Tyrosine Kinase Proteins Purines Pyrimidine Recombinant Proteins Regulation Role Signal Pathway Signal Transduction Structure Supporting Cell Testing Therapeutic Therapeutic Intervention Tubulin Tyrosine Work Yeasts base cancer therapy cell growth genetic approach in vivo insight knock-down macromolecule mutant novel nucleotide metabolism polymerization reconstitution response small molecule inhibitor targeted treatment tumor progression

项目摘要

Project Summary Growth-promoting signals and changes in metabolism are important mechanisms in the development and progression of cancer and other proliferative disorders, but the mechanisms that mediate interactions between these key regulatory events are poorly understood. Recently, we discovered a surprising and novel mechanism for control of nucleotide synthesis by Ack, a growth-factor regulated tyrosine kinase. Ack controls the activity of the rate-limiting enzyme in CTP synthesis, CTP synthase (CTPS) by regulating the assembly and disassembly of an enzymatically active macromolecular structure composed of CTPS and the rate-limiting enzyme in guanine nucleotide biosynthesis, IMPDH. We call these structures FINS for filaments involved in nucleotide synthesis. Based on this preliminary data, our central hypothesis is that inadequate cellular nucleotide pools trigger Ack-dependent FINS assembly to stimulate balanced purine and pyrimidine biosynthesis. Here, we will test this hypothesis using mechanistic biochemical studies that will be subsequently validated in vivo in Drosophila, where we have shown a critical requirement for this pathway in oogenesis. The work will illuminate how two important fields, signaling and metabolism, intersect through the dynamic assembly of a macromolecular protein assembly. The current use of drugs that inhibit IMPDH and trigger FINS assembly in patients highlights the importance of this work and its potential for discovery of additional therapeutic avenues for immuosuppression as well as anti-neoplastic and anti-parasitic interventions.

项目概要生长促进信号和代谢变化是发育的重要机制以及癌症和其他增殖性疾病的进展，但介导相互作用的机制人们对这些关键监管事件之间的关系知之甚少。最近，我们发现了一个令人惊奇且新颖的 Ack（一种生长因子调节的酪氨酸激酶）控制核苷酸合成的机制。确认控制 CTP合成中的限速酶CTP合成酶(CTPS)的活性通过调节组装和由 CTPS 和限速组成的酶活性大分子结构的分解鸟嘌呤核苷酸生物合成酶，IMPDH。我们将这些涉及的细丝结构称为 FINS 核苷酸合成。根据这些初步数据，我们的中心假设是细胞不足核苷酸池触发 Ack 依赖性 FINS 组装，刺激平衡的嘌呤和嘧啶生物合成。在这里，我们将使用随后将进行的机械生化研究来检验这一假设在果蝇体内得到验证，我们已经证明了该途径在卵子发生中的关键要求。这工作将阐明信号传导和新陈代谢这两个重要领域如何通过动态交叉大分子蛋白质组装体的组装。目前使用抑制IMPDH和触发FINS的药物在患者体内的组装凸显了这项工作的重要性及其发现其他疾病的潜力免疫抑制以及抗肿瘤和抗寄生虫干预的治疗途径。