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
• 负责人: Issam BEN-SAHRA
• 金额: $ 32万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10277131
• 关键词: A549; Address; Aging; Anabolism; Apoptosis; Binding; Biochemical; Biological; Biology; Biomass; CRISPR/Cas technology; Cell Cycle Arrest; Cell Proliferation; Cell Survival; Cells; Clinic; Clinical; Complex; Consumption; DNA Methylation; DNA Modification Methylases; Data; Development; Diabetes Mellitus; Disease; Drug Targeting; Environment; Enzymes; Epigenetic Process; Essential Amino Acids; Exhibits; FRAP1 gene; Genetic Transcription; Glucose; Glutamine; Goals; Growth; Growth Factor; Hela Cells; Homeostasis; Human; Human Cell Line; Immunosuppression; Introns; Isotope Labeling; Lead; Link; Lipids; MEL Gene; Malignant Neoplasms; Mammalian Cell; Measures; Messenger RNA; Metabolic; Metabolic Pathway; Metabolic syndrome; Metabolism; Methionine; Methionine Metabolism Pathway; Methylation; Methyltransferase; Modification; Molecular; Mutate; Neurodegenerative Disorders; Nutrient; Obesity; Organ; PC3 cell line; Pathologic; Pathway interactions; Patients; Phosphorylation Site; Phosphotransferases; Physiological; Positioning Attribute; Process; Protein Biosynthesis; Proteins; Proteomics; RNA; RNA Interference; RNA methylation; Reaction; Regulation; Reporting; Ribosomal RNA; Role; S-Adenosylmethionine; Signal Pathway; Signal Transduction; Syndrome; System; Therapeutic; Therapeutic Intervention; Tissues; Tracer; Transcriptional Regulation; base; c-myc Genes; cell growth; cell motility; chemical genetics; dietary; drug discovery; histone methylation; inhibitor/antagonist; insight; macromolecule; metabolic rate; metabolomics; methionine adenosyltransferase; mouse model; neoplastic cell; nervous system disorder; novel; nucleotide metabolism; pre-clinical; side effect; stable isotope; targeted treatment; therapeutic target; tumor; tumor growth

SUMMARY The mechanistic target of rapamycin complex 1 (mTORC1) senses and integrates diverse environmental signals to control energy and nutrient-consuming biosynthetic processes, such as protein, lipid, and nucleotide synthesis. mTORC1 stimulates anabolic cell growth through posttranslational and transcriptional mechanisms leading to increased macromolecule synthesis a prerequisite to augment cellular biomass priming cells for growth and division. In many diseases, the prominence of mTORC1 signaling reinforces the importance of considering targeting mTORC1 signaling in several diseases including neurodegenerative disorders, diabetes, tumor syndromes, and aging. However, direct mTORC1 targeted therapies, being conceptually and preclinically a promising target, displayed only limited efficacy in human patients. Therefore, a better understanding of the biology downstream of mTORC1 and the development of more effective and specific therapeutic strategies in the treatment of mTORC1-driven diseases are needed. To achieve the biosynthetic demands accompanying proliferation, cells must increase the transport of nutrients from the environment. Glucose, lactate, and glutamine are the principal nutrients that promote biosynthesis and survival in mammalian cells. An emerging aspect of nutrient utilization in aging and proliferative diseases includes the role of dietary methionine restriction, which was recently explored in the context of obesity, metabolic syndrome, and cancer. Methionine is an essential amino acid that is catabolized and recycled in a sequence of metabolic reactions designated as the methionine cycle. Methionine and ATP are converted into the universal methyl donor S-adenosylmethionine (SAM) via the methionine adenosyltransferase 2 alpha (MAT2A) enzyme. Under this proposal, we propose to study the influence of mTORC1 signaling on S-adenosylmethionine (SAM) synthesis and the subsequent methylation processes supporting anabolic metabolism. We have identified that mTORC1 stimulates SAM synthesis in various cell settings through direct transcriptional control of MAT2A expression by c-MYC. We propose to evaluate the influence of mTORC1 signaling on SAM synthesis in a variety of human cells (Specific Aim1). Will identify the mechanisms by which mTORC1 signaling promotes RNA methylation, particularly the N6- methyladenosine (m6A) mark. We will determine the role of m6A on RNA downstream of mTORC1 in the control of cell growth (Specific Aim2). Furthermore, we will determine the implication of the mTORC1-MAT2A axis on tumor growth and the potential therapeutic strategy derived from this mechanism (Specific Aim3). Thus, the overall goal of this proposal is to decipher the molecular mechanisms by which mTORC1 controls RNA methylation in normal and pathological settings. We anticipate that the proposed studies will yield new insights into how SAM levels alter anabolic metabolism and will uncover therapeutic targets to perturb mTORC1-driven diseases.

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