Role of Protein Methylation in Cell Mitosis and Glioblastoma

蛋白质甲基化在细胞有丝分裂和胶质母细胞瘤中的作用

基本信息

批准号：
10322748
负责人：
Shi-Yuan Cheng
金额：
$ 42.96万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322748
关键词：
Address Affect Arginine Biological Cell Shape Cell division Cell physiology Cells Chromatin Chromosome Condensation Chromosomes Clinical Combined Modality Therapy DNA Damage Enzymes Epigenetic Process Event Gene Expression Genetic Glioblastoma Goals Growth Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Histones In Vitro Knock-out Knowledge Learning Malignant - descriptor Malignant Neoplasms Messenger RNA Methylation Methyltransferase Mitosis Mitotic Molecular Nuclear Organelles Patient-Focused Outcomes Patients Phenotype Phosphorylation Phosphotransferases Physical condensation Play Post-Translational Protein Processing Process Prognostic Marker Property Protein Analysis Protein Family Protein Inhibition Protein Methylation Protein-Arginine N-Methyltransferase Protein-Serine-Threonine Kinases Proteins RNA Splicing Radiation therapy Regulation Role Signal Pathway Signal Transduction Substrate Interaction Testing Threonine Transferase Tumor Biology Tumorigenicity antitumor effect casein kinase II clinical application enzyme substrate experimental study improved in silico in vivo innovation non-histone protein novel pre-clinical research protein arginine methyltransferase 2 protein function radiation response recruit response small molecule standard care standard of care temozolomide therapeutic target treatment response treatment strategy tumor tumor growth

项目摘要

Methylation on histone and non-histone proteins is a common and important post-translational modification (PTM) that controls protein functions and activities in modulating cancer tumorigenicity and responses to therapies. In this project, we will investigate the mechanism for protein arginine (R) methylation regulation of GBM tumorigenicity by elucidating the role of protein arginine methyltransferase 6 (PRMT6) on cell mitosis through specific arginine methylation of regulator of chromosome condensation 1 (RCC1), thereby regulating GBM phenotype and responses to therapies. We provide novel evidence that PRMT6 regulates RCC1 activity through methylation of RCC1 at R214, the arginine residue required for RCC1 activation of Ran GTPase through association with histones in chromosome, thereby affecting cell mitotic process, GBM tumorigenicity and responses to therapies. We demonstrate that casein kinase 2 (CK2), a ubiquitously expressed and constitutively active serine/threonine kinase that is important in cancers stimulates PRMT6 methyltransferase activity by phosphorylating threonine 21 of PRMT6 protein. Additionally, genetic depletions or small molecule targeting of PRMT6, RCC1 or CK2 inhibited GBM tumorigenicity in vitro and in vivo, and enhanced anti-tumor effects by radiation therapy (RT). These strong scientific premises provide the basis for the overarching hypothesis of this proposal: CK2-activated PRMT6 induces asymmetric dimethylation (aDMA) of RCC1, thereby regulating cell mitosis, GBM tumorigenicity as well as GBM responses to RT. We will address this hypothesis in the context of three specific aims: 1) Determine how PRMT6-induced R214 aDMA of RCC1 affects cell mitotic process as well as GBM tumor biologic properties in vitro and in vivo; 2) Define mechanisms by which CK2 regulates PRMT6 activity, and the relationships between CK2-associated phosphorylation of PRMT6, RCC1 function, cell mitosis, GBM tumor phenotypes, and association with GBM patient outcome; and 3) Determine whether PRMT6 and CK2 directed combination therapy is more effective than corresponding monotherapies, and whether such combination therapy enhances the anti-tumor activity of RT and temozolomide (TMZ) treatment. At the completion of this project, we will learn how PRMT6-catayzed aDMA of RCC1 shapes of cell mitosis, GBM phenotype and response to therapy. Our proposed studies will be the first to address the role of PRMT activity on non-histone aDMA of RCC1 in cell mitosis, GBM tumor biology and responses to therapies. This knowledge, in turn, will provide clear indication of the potential benefit of including combination of inhibition of PRMT6 and CK2 with RT and TMZ as part of treatment strategy for patient with GBM.

在组蛋白和非历史蛋白上的甲基化是翻译后的常见且重要的控制蛋白质功能和活性调节癌症肿瘤性和活性的修饰（PTM）对疗法的反应。在这个项目中，我们将研究蛋白精氨酸（R）甲基化的机制通过阐明蛋白精氨酸甲基转移酶6（PRMT6）在细胞上的作用来调节GBM肿瘤性。通过染色体凝结1（RCC1）调节剂的特异性精氨酸甲基化的有丝分裂，从而调节GBM表型和对疗法的反应。我们提供了PRMT6调节RCC1的新颖证据通过R214的RCC1的甲基化活性，RCC1激活RAN GTPase所需的精氨酸残基通过与染色体中的组蛋白关联，从而影响细胞有丝分裂过程，GBM肿瘤性和对疗法的反应。我们证明了酪蛋白激酶2（CK2），一种无处不在的表达和组成性的在癌症中很重要的活性丝氨酸/苏氨酸激酶可通过刺激PRMT6甲基转移酶活性。 PRMT6蛋白的磷酸化苏氨酸21。另外，遗传耗竭或小分子靶向 PRMT6，RCC1或CK2在体外和体内抑制了GBM肿瘤性，并通过放射疗法（RT）。这些强大的科学前提为总体假设提供了基础建议：CK2激活的PRMT6诱导RCC1的不对称二甲基化（ADMA），从而调节细胞有丝分裂，GBM肿瘤性以及对RT的GBM反应。我们将在三个具体目的：1）确定pRMT6诱导的RCC1的R214 ADMA如何影响细胞有丝分裂过程作为体外和体内的GBM肿瘤生物学特性； 2）定义CK2调节PRMT6的机制活性以及CK2相关的PRMT6磷酸化，RCC1功能，细胞有丝分裂， GBM肿瘤表型，并与GBM患者结局相关； 3）确定PRMT6和是否是否 CK2定向组合疗法比相应的单一疗法更有效，并且是否存在联合疗法增强了RT和Temozolomide（TMZ）治疗的抗肿瘤活性。在完成该项目的完成，我们将了解如何prmt6-catayz-catayzed Adma RCC1细胞有丝分裂形状，GBM 表型和对治疗的反应。我们提出的研究将是第一个解决PRMT活动的作用的研究在细胞有丝分裂，GBM肿瘤生物学和对疗法的反应中，RCC1的非历史ADMA上。这个知识，反过 CK2与RT和TMZ是GBM患者的治疗策略的一部分。