Elucidating the regulation of RNA methylation by mTOR signaling in cancer

项目总结/摘要 在过去的十年里，我们对RNA化学修饰的了解，如N6-腺苷甲基化（m6 A） 由于全转录组测序技术的发展， 用于检测RNA修饰的测定。新出现的证据表明，m6 A修饰的mRNAs的改变 编码癌基因和肿瘤抑制因子的基因与癌症的发展和进展有关， 白血病神经胶质瘤乳腺癌和肺癌这些RNA修饰通过几种RNA结合进行处理， 蛋白质如RNA甲基转移酶和脱甲基酶。这些酶的表达和活性 在肿瘤发生过程中可能受到上游信号通路的调节，然而，我们的理解是， 关于信号转导通路如何控制这些酶以及随之而来的RNA修饰， 基本的通过对mTOR信号通路的磷酸化蛋白质组学和转录组学分析， 确定了mTOR信号传导和调节m6 A RNA甲基化的酶之间的联系。我的工作 得到初步数据支持假设是mTOR途径，通过调节mTOR的表达， m6 A甲基转移酶复合物的活性控制mRNA代谢。更重要的是，我的数据显示 这种mTOR-m6 A信号调节参与一碳代谢的酶的表达， 高增殖率和癌细胞存活所需的代谢途径。拟议的实验 这些策略将揭示mTOR信号传导如何通过以下途径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。成功完成本 该提案将为表征新的癌症生物标志物和靶向治疗提供理论基础。 致癌信号通路下游的RNA甲基化过程。

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.