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Role of E3 Ligase, UBR5, in Hematopoietic Differentiation and Lymphomagenesis

E3 连接酶 UBR5 在造血分化和淋巴瘤发生中的作用

基本信息

批准号：
9920178
负责人：
Shannon Buckley
金额：
$ 27.91万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9920178
关键词：
Address Affect Award B-Cell NonHodgkins Lymphoma B-Lymphocytes Basic Science Biological Assay CRISPR/Cas technology Cell Compartmentation Cell Line Cell Lineage Cells Centers of Research Excellence Cyclin D1 Cysteine DNA Damage Defect Development Disease Disease Progression Engineering Frameshift Mutation Future Genomics Hematopoiesis Hematopoietic Immune Immunoprecipitation In Vitro Knockout Mice Lymphoid Lymphoma Lymphomagenesis Maintenance Malignant Neoplasms Mantle Cell Lymphoma Mantle Zone Mass Spectrum Analysis Molecular Molecular Target Mutate Mutation Myelogenous Natural regeneration Nebraska Non-Hodgkin&apos s Lymphoma Nonsense Codon Normal Cell Nuclear Patients Play Population Proteins Proteomics Research Role System Testing Therapeutic Translational Research Ubiquitin Ubiquitination Validation Vascularization Yolk Sac cancer cell drug discovery embryonic stem cell experimental study hematopoietic differentiation high throughput screening in utero in vivo insight leukemia/lymphoma lymph nodes mortality mouse model multicatalytic endopeptidase complex mutant new therapeutic target next generation sequencing novel overexpression protein degradation recombinase-mediated cassette exchange self-renewal small hairpin RNA small molecule small molecule inhibitor stem cells therapeutic target transcription factor ubiquitin ligase ubiquitin-protein ligase

项目摘要

Project Summary/Abstract: Role of E3 Ligase, UBR5, in Hematopoietic Differentiation and Lymphomagenesis Mantle cell lymphoma (MCL) is a rare and aggressive non-Hodgkin's lymphoma. Unfortunately, limited therapies for MCL are currently available suggesting a need to further unravel molecular mechanisms regulating transformation and progression of the disease. The majority of MCL patients have mutations leading to overexpression of Cyclin D1 in the pre-B cell population, resulting in extensive proliferation and blocks in differentiation originating in the mantle zone of the lymph node. Recently, next generation sequencing has identified a number of novel mutations in MCL patients including the ubiquitin E3 ligase UBR5. E3 ubiquitin ligases serve as the substrate recognizing component for protein degradation by the ubiquitin proteasome system. Approximately 18% of MCL patients were found to have mutations within the HECT domain of UBR5, which can accept and transfer ubiquitin molecules to the substrate. Interestingly, in hematopoietic lineages the B-lymphoid populations including the pre-B cell compartment, highly express UBR5 compared to the myeloid and T-lymphoid compartments. These findings suggest that understanding the role and interacting proteins of UBR5 in hematopoiesis will provide insights to mantle cell lymphoma transformation, progression and possible future therapeutics targets, in addition to basic understanding of hematopoietic cell specification.

项目摘要/摘要：E3连接酶，UBR5，在造血分化和淋巴增生症套细胞淋巴瘤(MCL)是一种罕见的侵袭性非霍奇金淋巴瘤。不幸的是，有限的目前已有治疗MCL的方法，提示有必要进一步揭示分子机制。调节疾病的转化和发展。大多数MCL患者的突变导致在前B细胞群体中过表达Cyclin D1，导致广泛的增殖和阻断分化起源于淋巴结的外套膜带。最近，下一代测序已经在MCL患者中发现了一些新的突变，包括泛素E3连接酶UBR5。E3泛素连接酶是泛素蛋白酶体降解蛋白质的底物识别成分系统。大约18%的MCL患者被发现在UBR5的Hect结构域内存在突变，它可以接受泛素分子并将其转移到底物上。有趣的是，在造血系中与髓系相比，B淋巴系群体包括前B细胞室在内高表达UBR5 和T淋巴细胞室。这些发现表明，理解蛋白的作用和相互作用 UBR5在造血中的作用将为套细胞淋巴瘤的转化、发展和可能的研究提供线索未来的治疗目标，除了对造血细胞规格的基本了解。