Elucidating the regulation of RNA methylation by mTOR signaling in cancer

阐明癌症中 mTOR 信号传导对 RNA 甲基化的调节

• 批准号: 10693796
• 负责人: Gina Lee
• 金额: $ 25.78万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693796
• 关键词: 5' Untranslated Regions; Adenosine; Autophagocytosis; Biological Assay; Carbon; Catalytic Domain; Cell Adhesion; Cell Proliferation; Cell Survival; Chemicals; Complex; DHFR gene; DNA Methylation; Data; Deposition; Development; Enzymes; FRAP1 gene; Folic Acid; Folic Acid Antagonists; Genes; Glioma; Growth; Growth Factor; Initiator Codon; Knowledge; Link; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Methionine; Methylation; Modification; Nephroblastoma; Nucleotides; Oncogenes; Oncogenic; Oxidation-Reduction; Pathway interactions; Phosphorylation; Process; Proliferating; Proteins; Proteome; RNA; RNA Helicase; RNA Splicing; RNA methylation; RNA-Binding Proteins; RNA-targeting therapy; Regulation; Resolution; Ribosomes; S-Adenosylhomocysteine; S-Adenosylmethionine; Scanning; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Sodium Chloride; Structure; Technology; Transcript; Transferase; Translations; Tumor Suppressor Proteins; c-myc Genes; cancer biomarkers; cancer cell; cancer survival; cancer therapy; cell growth; differential expression; enzyme activity; epitranscriptome; intermolecular interaction; leukemia; mTOR Signaling Pathway; mTOR inhibition; mTOR protein; malignant breast neoplasm; metabolome; nucleotide metabolism; phosphoproteomics; protein expression; targeted agent; transcriptome; transcriptome sequencing; transcriptomics; tumor; tumor growth; tumor progression; tumorigenesis

PROJECT SUMMARY/ABSTRACT Over the past decade, our knowledge of RNA chemical modifications such as N6-adenosine methylation (m6A) on mRNAs has increased due to the development of transcriptome-wide sequencing technologies and several assays to detect RNA modifications. Emerging evidence shows that alteration of m6A modification on mRNAs encoding oncogenes and tumor suppressors is linked to cancer development and progression including leukemia, glioma, breast and lung cancers. These RNA modifications are processed by several RNA binding proteins such as RNA methyl transferases and demethylases. The expression and activities of these enzymes are likely to be modulated by upstream signaling pathways during tumorigenesis, however, our understanding of how signal transduction pathway controls these enzymes and the consequent RNA modifications is still rudimentary. Through phosphoproteomic and transcriptomic analysis of the mTOR signaling pathway, I have identified links between the mTOR signaling and enzymes that regulate m6A RNA methylation. My working hypothesis, which is supported by preliminary data, is that mTOR pathway, by regulating the expression and activities of m6A methyl transferase complex, controls mRNA metabolism. More importantly, my data suggest that this mTOR-m6A signaling regulates the expression of enzymes involved in one-carbon metabolism, a metabolic pathway required for high proliferation rate and survival of cancer cells. The proposed experimental strategies will reveal how mTOR signaling controls expression of oncogenes and tumor suppressors through RNA methylation, and its connection to one-carbon metabolism in cancer. Successful completion of this proposal will provide a rationale for the characterization of new cancer biomarkers and therapeutics targeting RNA methylation process downstream of oncogenic signaling pathways.

项目概要/摘要 在过去的十年中，我们对 RNA 化学修饰（如 N6-腺苷甲基化 (m6A)）的了解 由于全转录组测序技术的发展和一些 检测 RNA 修饰的测定。新出现的证据表明 mRNA 上 m6A 修饰的改变 编码癌基因和肿瘤抑制因子与癌症的发生和进展有关，包括 白血病、神经胶质瘤、乳腺癌和肺癌。这些 RNA 修饰是通过多种 RNA 结合处理的 蛋白质，例如RNA甲基转移酶和去甲基酶。这些酶的表达和活性 在肿瘤发生过程中很可能受到上游信号通路的调节，但是，我们的理解 信号转导途径如何控制这些酶以及随后的 RNA 修饰仍然是一个谜 简陋的。通过 mTOR 信号通路的磷酸化蛋白质组学和转录组学分析，我得到了 确定了 mTOR 信号传导与调节 m6A RNA 甲基化的酶之间的联系。我的工作 初步数据支持的假设是，mTOR 通路通过调节表达和 m6A 甲基转移酶复合物的活性控制 mRNA 代谢。更重要的是，我的数据表明 mTOR-m6A 信号调节参与一碳代谢的酶的表达， 癌细胞高增殖率和存活所需的代谢途径。拟议的实验 策略将揭示 mTOR 信号如何通过以下方式控制癌基因和肿瘤抑制因子的表达 RNA 甲基化及其与癌症中一碳代谢的联系。顺利完成本次 该提案将为新的癌症生物标志物和治疗靶向的表征提供理论依据 致癌信号通路下游的 RNA 甲基化过程。