MOLECULAR MECHANISMS OF NOTCH SIGNALING IN NEOPLASIA

肿瘤中Notch信号传导的分子机制

• 批准号: 6193488
• 负责人: ANTHONY John CAPOBIANCO
• 金额: $ 26.93万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-20 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6193488
• 关键词: acute lymphocytic leukemia; biological signal transduction; complementary DNA; estrogen receptors; gene deletion mutation; genetic library; immunofluorescence technique; intermolecular interaction; membrane proteins; mutant; neoplastic transformation; oncoproteins; protein structure function; receptor; reporter genes; tissue /cell culture; western blottings

DESCRIPTION: (Adapted from applicant's abstract) Notch genes play a central role in both development and disease. Notch proteins are large transmembrane receptors with no apparent enzymatic activity. Although ligands (Serrate) for Notch have been identified, the mechanism of ligand activation and downstream signaling remains poorly understood. Mutations in the Notch signal transduction family are implicated in a number of human disorders. In T-cell Acute Lymphoblastic Leukemia (T-ALL), the Notch 1 locus is involved in a chromosomal translocation with the T-cell recpetor B locus {t(7:9)(q34;q34.3)}. This translocation generates aberrant Notch proteins that lack most of the extracellular sequences. These mutant forms of Notch are thought to be constitutively active; however, the pathophysiological mechanism is unknown. In addition to the involvement of Notch in T-cell leukemia, expression studies have revealed aberrant expression of both Notch and Serrate proteins in other neoplasm including cervical and colorectal carcinoma. The long term goal of this laboratory is to elucidate the mechanisms of Notch signaling in neoplasia. The research proposed in this application is focused on the dissection of the Notch signaling pathway using molecular genetics and biochemistry. Their laboratory has developed an in vitro transformation model for Notch proteins. Activated mutants of Notch that resemble those found in T-ALL are capable of transforming cells in collaboration with E1A. Using this assay, a structure/function analysis will be performed to determine the domains of Notch required for transformation. Other aspects of this work will be directed toward identifying proteins that interact with Notch and determination of the role these proteins play in Notch-mediated transformation. Cellular transformation is a culmination of a number of defects in certain cellular processes, such as apoptosis and cell cycle control. To investigate the role of Notch in such processes a conditionally transforming allele of Notch will be created. A conditional allele of Notch will be useful in studying the early events in neoplastic conversion. Moreover, a conditional allele of Notch will allow us to address the requirement of Notch signaling events in the initiation and maintenance of transformation. The role that Serrate (Notch ligand) plays in activation of Notch and neoplastic transformation will also be studied.

描述：（改编自申请人的摘要）Notch基因发挥核心作用。 在发展和疾病中的作用。Notch蛋白是大跨膜蛋白， 没有明显酶活性的受体。虽然配体（锯齿） Notch已经被确定，配体激活的机制和下游 信号传导仍然知之甚少。Notch信号转导中的突变 家庭与许多人类疾病有关。急性T细胞 淋巴母细胞白血病（T-ALL），Notch 1基因座参与染色体异常。 与T细胞受体B基因座{t（7：9）（q34;q34.3）}易位。这 易位产生异常的Notch蛋白， 胞外序列这些突变形式的Notch被认为是 组成型活性;然而，病理生理机制是未知的。在 除了Notch在T细胞白血病中的作用外， 已经揭示了Notch和Serrate蛋白在其他细胞中的异常表达， 肿瘤包括宫颈癌和结肠直肠癌。 该实验室的长期目标是阐明Notch的机制 肿瘤形成中的信号传导。本申请中提出的研究重点是 使用分子遗传学对Notch信号通路的剖析， 生物化学他们的实验室已经开发出一种体外转化模型 Notch蛋白质Notch的激活突变体类似于 T-ALL能够与E1 A合作转化细胞。使用此 分析，将进行结构/功能分析以确定结构域 转换所需的Notch。这项工作的其他方面将 旨在鉴定与Notch相互作用的蛋白质， 这些蛋白质在Notch介导的转化中发挥的作用。蜂窝 转化是某些细胞中许多缺陷的顶点， 过程，如细胞凋亡和细胞周期控制。调查的作用 Notch在这样的过程中，Notch的条件转化等位基因将是 创造Notch的条件等位基因将有助于研究早期 肿瘤转化中的事件。此外，Notch的条件等位基因将 使我们能够解决Notch信号传导事件的要求， 和保持转化。Serrate（Notch ligand）的作用 还将研究Notch的活化和肿瘤转化。