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

项目摘要/摘要：E3连接酶UBR 5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， 目前已有MCL的治疗方法，这表明需要进一步阐明其分子机制 调节疾病的转化和进展。大多数MCL患者的突变导致 细胞周期蛋白D1在前B细胞群中的过度表达，导致广泛的增殖和阻断， 淋巴结的分化起源于淋巴结的套区。最近，下一代测序已经 在MCL患者中鉴定了许多新的突变，包括泛素E3连接酶UBR 5。E3泛素 连接酶作为底物识别组分，用于泛素蛋白酶体降解蛋白质 系统发现大约18%的MCL患者在UBR 5的HECT结构域内具有突变， 其可以接受泛素分子并将其转移到基底上。有趣的是，在造血谱系中， 与髓样细胞相比，B淋巴细胞群（包括前B细胞区室）高度表达UBR 5。 和T淋巴区室。这些发现表明，了解蛋白质的作用和相互作用， UBR 5在造血中的作用将为套细胞淋巴瘤的转化、进展和可能的 未来的治疗目标，除了造血细胞的规范的基本理解。

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.