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 在造血分化和淋巴瘤发生套细胞淋巴瘤（MCL）是一种罕见的侵袭性非霍奇金淋巴瘤。不幸的是，有限目前已有针对 MCL 的治疗方法，这表明需要进一步阐明分子机制调节疾病的转化和进展。大多数 MCL 患者都有突变导致前 B 细胞群中 Cyclin D1 的过度表达，导致广泛增殖并阻断分化起源于淋巴结的外套区。最近，二代测序已在 MCL 患者中发现了许多新的突变，包括泛素 E3 连接酶 UBR5。 E3泛素连接酶作为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 结构域内有突变，它可以接受泛素分子并将其转移到底物上。有趣的是，在造血谱系中与骨髓细胞相比，包括前 B 细胞区室在内的 B 淋巴细胞群高度表达 UBR5 和 T 淋巴室。这些发现表明，了解蛋白质的作用和相互作用造血作用中的 UBR5 将为套细胞淋巴瘤的转化、进展和可能的进展提供见解除了对造血细胞规范的基本了解之外，未来的治疗目标。