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

基本信息

批准号：
10573149
负责人：
Joel Francis
金额：
$ 4.02万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
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/10573149
关键词：
Acceleration 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 Data Data Set Databases Defect Enzymes Event Gene Expression 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 Proliferating 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 mRNA Translation malignant stomach neoplasm mouse model mutant novel programs protein function reconstitution ribosome profiling tumorigenesis yeast protein

项目摘要

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.

项目摘要共价后翻译蛋白修饰有助于细胞生理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。异常法规这些修饰以及产生它们的酶是人类的共同特征疾病，包括癌症。在该中编码的150多个蛋白甲基转移酶人类基因组和越来越多的人类蛋白质，包括一些具有既定的人已知在信号传导和癌症中的作用，它们具有携带功能性后翻译后甲基化事件。大多数甲基化事件发生在赖氨酸或精氨酸残基上。但是，我们的实验室和其他人最近发现，组氨酸甲基化发生在200多种人蛋白上出色地。尽管如此，关于分子，信号传导和生物学后果知之甚少与蛋白质组氨酸甲基化有关。该提议重点是蛋白质组氨酸甲基转移酶（PHMT），METTL18及其在癌症中的作用。在初步工作中，我发现 mettl18在许多细胞系中的位置HIS245甲基甲基小鼠组织。我还有证据表明METTL18调节蛋白质的合成和肿瘤发生。在这里，我建议使用多学科方法，包括生化，蛋白质组学和细胞（1）研究mettl18催化的分子和生物学功能的生物学策略活性和（2）表征了Mettl18在胃癌中的生理作用。拟议的项目将在斯坦福大学的博士或Gozani博士实施大学。 Gozani博士是一位经验丰富的导师和领导者蛋白甲基化和癌症生物学。他和斯坦福大学生物学系非常适合支持我的研究项目和研究生教育。