Study of a Novel Deubiquitylase in Medulloblastoma

髓母细胞瘤中新型去泛素化酶的研究

• 批准号: 8528745
• 负责人: Vidya Gopalakrishnan
• 金额: $ 33.35万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8528745
• 关键词: Address; Adverse effects; Apoptosis; Behavior; Biology; Brain; Cell Cycle; Cell Proliferation; Cells; Childhood Brain Neoplasm; Clinical Research; Complex; Cyclin-Dependent Kinase Inhibitor; Cytoplasmic Granules; Data; Defect; Desmoplastic; Development; Disease; Endocrine; Epigenetic Process; Equilibrium; Etiology; Event; Exhibits; Face; Failure; Future; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Histology; Histone Deacetylation; Human; In Vitro; Knockout Mice; Link; Maintenance; Malignant - descriptor; Mediating; Methylation; Modeling; Molecular; Mus; Neuronal Differentiation; Oncogenic; Pathway interactions; Patients; Process; Prognostic Marker; Proteins; Quality of life; RE1-silencing transcription factor; Recurrence; Repression; Risk; Role; Sampling; Staging; Stem cells; Survivors; Testing; Toxic effect; Transcription Repressor/Corepressor; Tumor Biology; Tumor Tissue; Ubiquitination; Work; base; cyclin-dependent kinase inhibitor 1B; high risk; improved; in vivo; medulloblastoma; mouse model; mutant; neoplastic cell; nerve stem cell; neurogenesis; new therapeutic target; novel; pre-clinical; prognostic; promoter; research study; small molecule; smoothened signaling pathway; therapeutic target; tumor; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Medulloblastoma is the most common malignant pediatric brain tumor. While current treatments have improved survival, survivors face high risk of recurrence and significant long-term quality of life issues. These side effects result from a failure of the current treatment approaches to target tumor cells and spare the normal brain of young patients. Thus, targeted therapies are desperately needed. However, this requires a better understanding of disease biology and the identification of disease-specific molecular events. Medulloblastomas arise from a developmental imbalance between proliferation and neuronal differentiation in cerebellar progenitor cells. Medulloblastomas often show abnormally high expression of the RE1 Silencing Transcription Factor (REST), a repressor of neuronal differentiation. REST expression is associated with blockade of neuronal differentiation and a poor prognostic significance for patients. The requirement for REST in medulloblastoma progression and maintenance was shown in murine orthotopic models. However, mechanistic details were lacking. REST was recently implicated in the control of cell proliferation in medulloblastoma and in cerebellar progenitor cells. An increase in REST expression facilitated excessive degradation of the cyclin dependent kinase inhibitor (CDKI) p27 in tumor cells by repressing the transcription of a novel p27-specific deubiquitylase, USP37. The expression of p27 was significantly correlated with USP37 and REST in human medulloblastoma samples. Constitutive expression of wild type USP37, but not a catalytically inactive mutant rescued defects in p27 behavior, blocked proliferation and promoted neuronal differentiation in medulloblastoma cells. These data not only link REST to p27 and the control of cell proliferation in vitro, but also implicate USP37 in this process. The current application will study this newly identified pathway in deregulation of cell proliferation and tumor development in mouse models. The overall hypothesis of this proposal is that REST-mediated repression of USP37 and the consequent decline in p27 levels contributes to medulloblastoma development by causing a failure of cell cycle exit and perturbing the balance between cell proliferation and neuronal differentiation. Aim1 of the proposed studies will determine if REST and USP37 are important for loss of proliferative control and tumor formation in mice with p27- deficiency. Aim 2, will assess if p27 is necessary and sufficient for USP37-dependent brake on cell proliferation and tumor development. Aim 3 will examine the mechanism by which REST controls USP37 transcription. These studies will provide a better understanding of the newly identified relationship between REST, USP37 and p27 in the control of cell proliferation and medulloblastoma development and set the stage for future therapeutic targeting of this pathway.

描述（由申请人提供）：髓母细胞瘤是最常见的恶性儿童脑肿瘤。虽然目前的治疗方法提高了生存率，但幸存者面临着复发的高风险和严重的长期生活质量问题。这些副作用是由于目前的治疗方法未能靶向肿瘤细胞并保护年轻患者的正常大脑而造成的。因此，迫切需要靶向治疗。然而，这需要更好地了解疾病生物学和识别疾病特异性分子事件。髓母细胞瘤是由小脑祖细胞增殖和神经元分化之间的发育不平衡引起的。髓母细胞瘤通常表现出异常高的 RE1 沉默转录因子 (REST) 表达，这是一种神经元分化的抑制因子。 REST 表达与神经元分化的阻断有关，并且对患者的预后意义不佳。小鼠原位模型显示了髓母细胞瘤进展和维持对休息的要求。然而，缺乏机械细节。最近，REST 被认为参与髓母细胞瘤和小脑祖细胞细胞增殖的控制。 REST 表达的增加通过抑制新型 p27 特异性去泛素化酶 USP37 的转录，促进肿瘤细胞中细胞周期蛋白依赖性激酶抑制剂 (CDKI) p27 的过度降解。人髓母细胞瘤样本中 p27 的表达与 USP37 和 REST 显着相关。野生型USP37（而非催化失活突变体）的组成型表达挽救了p27行为缺陷，阻止增殖并促进髓母细胞瘤细胞中的神经元分化。这些数据不仅将 REST 与 p27 以及体外细胞增殖的控制联系起来，而且还表明 USP37 参与了这一过程。目前的应用将研究这一新发现的小鼠模型中细胞增殖和肿瘤发展失调的途径。该提议的总体假设是，REST 介导的 USP37 抑制以及随之而来的 p27 水平下降，通过导致细胞周期退出失败并扰乱细胞增殖和神经元分化之间的平衡，从而促进髓母细胞瘤的发展。拟议研究的目标1将确定REST和USP37对于p27缺陷小鼠的增殖控制丧失和肿瘤形成是否重要。目标 2 将评估 p27 对于 USP37 依赖性抑制细胞增殖和肿瘤发展是否是必要和充分的。目标 3 将检查 REST 控制 USP37 转录的机制。这些研究将有助于更好地理解新发现的 REST、USP37 和 p27 在控制细胞增殖和髓母细胞瘤发展方面的关系，并为该通路的未来治疗靶向奠定基础。