The Functional Analysis of the Coactivator CARM1

共激活子CARM1的功能分析

基本信息

批准号：
7414139
负责人：
MARK T. BEDFORD
金额：
$ 7.7万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-08-01 至 2007-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7414139
关键词：
Affect Alleles Alternative Splicing Arginine Bacteria Binding Binding Proteins Biological CD44 gene Candidate Disease Gene Cell Line Cells Cellularity Class Complex Coupled Cytoplasmic Protein Defect Depth Development Disease EP300 gene Embryo Enzymes Event Exons Family Fetal Liver Funding Future Gene Targeting Genes Genomics Goals Growth Hematopoietic Hepatocyte Heterogeneous Nuclear RNA Histone H3 Immune system Investigation Kidney Knock-out Knockout Mice Knowledge Lead Mammalian Cell Mammals Mature T-Lymphocyte Mediating Messenger RNA Methylation Methyltransferase Molecular Mus Nuclear Nude Mice Numbers Peptides Phenotype Play Post-Translational Protein Processing Protein Binding Protein Splicing Protein-Arginine N-Methyltransferase Proteins Proteomics RNA Splicing Recruitment Activity Reporter Role Signal Transduction Specificity Spliced Genes Staging T-Cell Development T-Lymphocyte Tertiary Protein Structure Thymocyte Development Thymus Gland Transcript Transcription Coactivator Upper arm Yeasts capsule coactivator-associated arginine methyltransferase 1 drug development fetal in vivo mRNA Precursor man member mouse model mutant novel progenitor promoter protein function protein protein interaction reconstitution research study scaffold thymocyte tool

项目摘要

Arginine methylation is a widespread posttranslational modification found on both nuclear and cytoplasmic proteins. The methylation of arginine residues is catalyzed by the protein arginine N-methyltransferase (PRMT) family of enzymes, of which there are at least nine members in mammals. PRMTs are evolutionarily conserved and are found from yeast to man, but not in bacteria. The biological consequences of arginine methylation are largely unknown, although with the identification of specific substrates and the recent development of mouse models, functions are emerging. Our goal is to elucidate the biological role of coactivator-associated arginine methyltransferasel (CARM1), which is a transcriptional coactivator. How CARM1 functions as a coactivator is unclear. It methylates histone H3, p300, PABP1 and a subset of splicing factors. We plan to identify and characterize proteins that are recruited to the CARM1 methylated motifs and evaluate the role of CARM1 in splicing. We have generated CARM1 knockout mice, and cells derived from mutant embryos will provide a genetically controlled tool for the in vivo analysis of putative substrates, methyl-dependent binding proteins and splicing studies. Knockin CARM1 mice will also be generated and analyzed to evaluate the importance of this molecules enzymatic activity as opposed to its scaffolding functions. Ultimately, this in-depth analysis of CARM1 function will lead to the mechanistic understanding of a novel class of deregulated enzymes that play a role in a number of disease states and are new targets for drug development.

精氨酸甲基化是在核和细胞质上发现的广泛的翻译后修饰蛋白质。精氨酸残基的甲基化由蛋白质氨酸N-甲基转移酶催化（PRMT）酶家族，其中至少有9个成员。 PRMT在进化上保守，从酵母到人发现，但在细菌中却没有。精氨酸的生物学后果甲基化在很大程度上是未知的，尽管鉴定了特定底物和最近小鼠模型的开发，功能正在出现。我们的目标是阐明共激活剂相关的精氨酸甲基转移素（CARM1），它是转录共激活剂。如何 CARM1充当共激活因子尚不清楚。它甲基化组蛋白H3，P300，PABP1和一个子集剪接因子。我们计划识别和表征被募集到CARM1甲基化的蛋白质主题并评估Carm1在剪接中的作用。我们已经产生了CARM1敲除小鼠，并且细胞源自突变胚胎将为假定的体内分析提供遗传控制的工具底物，依赖甲基的结合蛋白和剪接研究。敲打Carm1小鼠也将是生成和分析以评估该分子酶活性的重要性脚手架功能。最终，对CARM1功能的深入分析将导致机械了解一类新型放松管制的酶，该酶在许多疾病状态和是药物开发的新目标。