The Function of Tribbles in the Pathogenesis of AML

Tribbles 在 AML 发病机制中的作用

• 批准号: 7313731
• 负责人: WARREN S PEAR
• 金额: $ 33.54万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7313731
• 关键词: Acute Myelocytic Leukemia; Address; Biochemical; C-terminal; C57BL/6 Mouse; CCAAT-Enhancer-Binding Proteins; Cells; Complex; Data; Development; Diagnosis; Disruption; Drosophila genus; Exhibits; Family member; Funding; Genes; Goals; Growth; Hematopoietic; Hematopoietic stem cells; Homeostasis; Homologous Gene; Human; Knockout Mice; Lead; Leukemic Cell; Link; Malignant Neoplasms; Metabolism; Molecular; Monitor; Mus; Mutate; Mutation; Myelogenous; Oncogenes; Pathogenesis; Patients; Phosphotransferases; Population; Property; Protein Family; Proteins; Research Personnel; Role; Sampling; Signal Pathway; Signal Transduction; Site; Structure; Surveys; Testing; Transcript; adapter protein; base; cell type; in vivo; leukemia; mRNA Expression; notch protein; progenitor; programs; protein degradation; reconstitution; research study; tumor

Tribbles proteins, of which three mammalian homologues are known, are poorly characterized proteins that have been implicated in protein degradation. They are characterized by a central non-functional kinase-like domain. We recently identified Tribbles homologue 2 (Trib2) as a Notch-regulated transcript in leukemic cells undergoing growth arrest. To investigate the in vivo function of Trib2, mice were reconstituted with hematopoietic stem cells retrovirally expressing Trib2. All Trib2 reconstituted mice developed clonal acute myelogenous leukemia (AMI) that could be serially transferred. Because Drosophila Tribbles negatively regulates slbo, the Drosophila homologue of C/EBP, we investigated the relationship between Trib2 and C/EBPa. We identified Trib2 in a complex with C/EBPa, which resulted in C/EBPa degradation. To determine the relevance of our findings to human AML, a survey of Trib2 mRNA expression in human AMI patient samples identified elevated Trib2 expression in a subset of samples. Together, our data identify Trib2 as an oncogene in the pathogenesis of AML that functions by inactivating C/EBPa. The goals of this proposal are to determine the mechanism by which Trib2 induces C/EBPa degradation, determine the mechanism by which Trib2 induces AML, to identify the Trib2-expressing hematopoietic progenitors that initiate AML, and to identify genes that cooperate with Trib2 in the pathogenesis of AML. These studies should not only lead to a better understanding of the pathogenesis of AML, but should have direct translational utility as they will identify new targets for diagnosing and treating AML. Experiments described in this project will greatly benefit from extensive interactions with the other Project Leaders and their projects and will also make extensive use of the scientific cores.

Tribbles蛋白质，其中三种哺乳动物同源物是已知的，它们的特征性蛋白质很差， 与蛋白质降解有关。它们的特征是中央非功能激酶样 领域。我们最近将Tribbles同源2（Trib2）确定为白血病细胞中的缺口调节的转录本 经历增长逮捕。为了调查部落2的体内功能，将小鼠与 造血干细胞逆转录病毒表达分子2。所有Trib2重组的小鼠都会发展出克隆急性 可以连续转移的脊髓性白血病（AMI）。因为果蝇构造了负面的 调节C/EBP的果蝇同源物SLBO，我们调查了Trib2与 C/EBPA。我们在与C/EBPA的综合体中确定了Trib2，从而导致C/EBPA降解。到 确定我们的发现与人类AML的相关性，人类AMI中的Trib2 mRNA表达的调查 患者样品在样本的一部分中鉴定出升高的Trib2表达。我们的数据一起识别部落2 作为AML发病机理中的癌基因，通过失活C/EBPA起作用。目标的目标 建议是确定Trib2诱导C/EBPA降解的机制，确定 Trib2诱导AML的机制，以识别表达Trib2的造血祖细胞 启动AML，并确定与AML发病机理中与Trib2合作的基因。这些研究 不仅应该更好地理解AML的发病机理，还应有直接的 转化实用程序将确定用于诊断和治疗AML的新目标。描述的实验 在这个项目中，将大大受益于与其他项目负责人及其项目的广泛互动 并将广泛使用科学核心。