Role of the candidate protein methyltransferase METTL18 in cancer biology

候选蛋白甲基转移酶 METTL18 在癌症生物学中的作用

• 批准号: 10388029
• 负责人: Joel Francis
• 金额: $ 3.92万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-10 至 2025-02-09
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10388029
• 关键词: Agar; Anchorage-Independent Growth; Antibodies; Arginine; Biochemical; Biological; Biological Assay; Biological Process; Biology; Cancer Biology; Cancer Patient; Cancer cell line; Cell Line; Cell physiology; Cells; Collaborations; Consequentialism; Data; Data Set; Databases; Defect; Enzymes; Event; Gene Expression; Genetic Translation; Graduate Education; Histidine; Human; Human Genome; In Vitro; Investigation; Knock-out; Knowledge; Laboratories; Letters; Luciferases; Lysine; Malignant Neoplasms; Mammals; Measures; Mentors; Methylation; Methyltransferase; Modification; Molecular; Mus; Neoplasm Metastasis; Normal tissue morphology; Pathway interactions; Patients; Phenotype; Physiological; Polyribosomes; Positioning Attribute; Post-Translational Protein Processing; Primary Neoplasm; Protein Biosynthesis; Protein Methylation; Protein Methyltransferases; Proteins; Proteome; Proteomics; Publications; Regulation; Research Project Grants; Ribosomal Proteins; Role; Sampling; Signal Transduction; Source; Stomach; TP53 gene; Testing; Tissues; Translation Initiation; Universities; Variant; Work; antibody libraries; cancer cell; clinically actionable; experience; experimental study; gastric cancer cell; human disease; in vivo; interdisciplinary approach; mRNA Expression; malignant stomach neoplasm; mouse model; mutant; novel; programs; protein function; reconstitution; ribosome profiling; tumorigenesis; yeast protein

Project Summary Covalent post-translational protein modifications contribute to all aspects of cell physiology and are a primary source of protein functional diversity in mammals. The aberrant regulation of these modifications, as well as the enzymes that generate them, is a common feature of human disease, including cancer. There are more than 150 protein methyltransferases encoded in the human genome, and a growing number of human proteins, including several with established roles in signaling and cancer, are known to harbor functional post-translational methylation events. Most methylation events occur on either lysine or arginine residues; however, our lab and others have recently discovered that histidine methylation occurs on over 200 human proteins as well. Still, very little is known about the molecular, signaling and biological consequences associated with protein histidine methylation. This proposal focuses on a protein histidine methyltransferase (PHMT), METTL18, and its role in cancer. In preliminary work I found that METTL18 methylates the ribosomal protein rpL3 at position His245 in numerous cell lines and mouse tissue. I also have evidence that METTL18 regulates protein synthesis and oncogenesis. Here I propose to use multi-disciplinary approaches, including biochemical, proteomic and cell biological strategies to (1) investigate the molecular and biological function of METTL18 catalytic activity and (2) characterize the physiologic role of METTL18 in gastric cancer. The proposed project will be executed in the laboratory of Dr. Or Gozani at Stanford University. Dr. Gozani is an experienced mentor and a leader at the intersection of the fields of protein methylation and cancer biology. He and the Stanford University Department of Biology are well-suited to support my research project and graduate education.

项目摘要 共价翻译后蛋白质修饰有助于细胞生理学的各个方面 并且是哺乳动物中蛋白质功能多样性的主要来源。异常调节 这些修饰以及产生它们的酶是人类细胞的共同特征， 疾病，包括癌症。有超过150种蛋白质甲基转移酶编码的蛋白质 人类基因组，以及越来越多的人类蛋白质，包括几种已建立的 在信号传导和癌症中的作用，已知具有功能性翻译后甲基化 事件大多数甲基化事件发生在赖氨酸或精氨酸残基上;然而，我们的实验室和 其他人最近发现组氨酸甲基化发生在200多种人类蛋白质上， 好.尽管如此，人们对这种疾病的分子、信号和生物学后果仍知之甚少。 与蛋白质组氨酸甲基化有关。这项提案的重点是一种蛋白质组氨酸 甲基转移酶（PHMT），胃L18及其在癌症中的作用。在初步工作中，我发现， 胃L18在许多细胞系中甲基化核糖体蛋白rpL 3的位置His 245， 小鼠组织。我也有证据表明，胃L18调节蛋白质合成和肿瘤发生。 在这里，我建议使用多学科的方法，包括生物化学，蛋白质组学和细胞 生物学策略：（1）研究胃L18催化的分子和生物学功能 活性和（2）描述胃L18在胃癌中的生理作用。 拟议的项目将在斯坦福大学的Or Gozani博士的实验室执行 大学Gozani博士是一位经验丰富的导师，也是以下领域的领导者： 蛋白质甲基化和癌症生物学。他和斯坦福大学生物系 非常适合支持我的研究项目和研究生教育。