Role of the METTL13 Lysine Methyltransferase in Signaling and Cancer

METTL13 赖氨酸甲基转移酶在信号传导和癌症中的作用

基本信息

批准号：
10116173
负责人：
Or P. Gozani
金额：
$ 47.73万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116173
关键词：
Ablation Attenuated Biochemical CRISPR/Cas technology Cancer Biology Cancer Etiology Cancer cell line Cell Proliferation Cell Survival Cells Cytoplasmic Protein Data Data Set Development Disease Elongation Factor Engineering Enzymes Excision FRAP1 gene Family Foundations Genes Genomics Goals Growth Growth and Development function Guanosine Triphosphate Phosphohydrolases Human In Vitro KRAS oncogenesis KRAS2 gene Knowledge Link Lung Adenocarcinoma Lysine Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mammalian Cell Messenger RNA Meta-Analysis Methylation Methyltransferase Modeling Modification Molecular Molecular Genetics Mus Neoplasms Orphan PI3K/AKT Pancreatic Ductal Adenocarcinoma Pathologic Pathway interactions Patients Pharmaceutical Preparations Phenotype Physiological Post-Translational Protein Processing Pre-Clinical Model Protein Biosynthesis Protein Kinase Protein Methyltransferases Proteins Proteome Proteomics Regulation Reporting Role Signal Transduction Substrate Specificity System Testing Translations Up-Regulation Work base cancer cell cancer initiation cell growth experimental study human model human tissue in vitro activity in vivo inhibitor/antagonist mRNA Expression mouse model multidisciplinary novel novel therapeutic intervention overexpression pancreatic cancer model pancreatic ductal adenocarcinoma model patient derived xenograft model pre-clinical synergism therapeutic candidate therapeutic target translational approach tumor tumorigenesis tumorigenic

项目摘要

ABSTRACT Our overarching goal is to better understand the role of post-translational modifications (PTMs) of cellular proteins in cancer with the underlying assumption that the enzymes that catalyze the addition or the removal of these PTMs are candidate therapeutic targets in cancer. While enzymes such as protein kinases have been extensively studied in cancer, new classes of enzymes have recently emerged as potential cancer targets. In particular, more than 100 lysine methyltransferases (KMTs) are predicted to be present in the human proteome and many are implicated in cancer etiology. However, the catalytic activity and substrate specificity for many of these enzymes remains unknown. In particular, functions for the vast majority of the large family of seven β- strand KMTs are not known. A central hypothesis to be tested here is that uncovering the activities of these orphan KMTs may provide new links between protein lysine methylation signaling and cancer biology. Here we focus on the candidate KMT METTL13 (Methyltransferase-like protein 13) as a potential critical regulator of tumorigenesis. The METTL13 gene is amplified in many cancers and METTL13 mRNA is over- expressed in diverse tumor types, including several were METTL13 expression negatively correlates with patient survival. However, METTL13 is an orphan enzyme and knowledge of any potential substrates and the overall mode of action of this protein in cells and in vivo is obscure. Based on preliminary observations, we hypothesize that METTL13 up-regulates protein translation to promote tumorigenesis. In Aim 1 we characterize the physiologic catalytic activity of METTL13 and the molecular functions of METTL13 in the regulation of eEF1A activity in vitro and in protein synthesis in cells. We will also investigate METTL13 and methylated eEF1A interacting partners and how these pathways intersect to influence cancer cell phenotypes. The goal of Aim 2 is to elucidate the role of METTL13 in tumors driven by oncogenic KRAS. We will test the hypothesis that METTL13, via its methylation activity, cooperates with KRAS signaling to promote the unlimited expansion of cancer cells in vivo using mouse models of pancreatic ductal adenocarcinoma and lung adenocarcinoma, in which the RAS pathway is frequently activated. We will also investigate the tumorigenic role of METTL13 in human tissue using patient-derived xenograft (PDX) models. We will assess the effects of METTL13 loss on protein translation in vivo. Finally, we will explore potential synergies of METTL13 ablation in combination with inhibitors of cell survival and growth pathways in pre- clinical models of pancreatic and lung cancers.

抽象的我们的首要目标是更好地了解细胞翻译后修饰 (PTM) 的作用癌症中的蛋白质，其基本假设是催化添加或去除蛋白质的酶这些 PTM 是癌症的候选治疗靶点，而蛋白激酶等酶则是癌症的候选治疗靶点。经过对癌症的广泛研究，新一类酶最近已成为潜在的癌症靶标。特别是，预计人类蛋白质组中存在超过 100 种赖氨酸甲基转移酶 (KMT) 许多与癌症病因学有关，然而，许多的催化活性和底物特异性。这些酶的功能尤其是七个β-大家族中的绝大多数仍然未知。这里要检验的一个中心假设是揭露这些国民党的活动。孤儿 KMT 可能提供蛋白质赖氨酸甲基化信号传导与癌症生物学之间的新联系。在这里，我们重点关注候选 KMT METTL13（甲基转移酶样蛋白 13）作为潜在的关键蛋白 METTL13 基因在许多癌症中扩增，并且 METTL13 mRNA 过度表达。在多种肿瘤类型中表达，其中一些肿瘤类型与 METTL13 表达呈负相关然而，METTL13 是一种孤儿酶，并且了解任何潜在的底物和根据初步观察，该蛋白质在细胞和体内的总体作用模式尚不清楚。其次，METTL13 上调蛋白质翻译以促进肿瘤发生。在目标 1 中，我们表征了 METTL13 的生理催化活性以及我们还将研究 METTL13 在体外调节 eEF1A 活性和细胞内蛋白质合成中的作用。 METTL13 和甲基化 eEF1A 伙伴以及这些途径如何交叉影响癌症目标 2 的目标是阐明 METTL13 在致癌 KRAS 驱动的肿瘤中的作用。我们将测试 METTL13 通过其甲基化活性与 KRAS 信号传导合作的假设利用小鼠胰腺导管模型促进体内癌细胞无限增殖腺癌和肺腺癌，其中 RAS 通路经常被激活。使用患者来源的异种移植（PDX）模型研究 METTL13 在人体组织中的致瘤作用。我们将评估 METTL13 缺失对体内蛋白质翻译的影响最后，我们将探索潜力。 METTL13 消融与细胞存活和生长途径抑制剂相结合的协同作用胰腺癌和肺癌的临床模型。