MOLECULAR MECHANISMS OF NOTCH SIGNALING IN NEOPLASIA

描述：(改编自申请者的摘要)Notch基因发挥着核心作用 在发育和疾病中的作用。Notch蛋白是一种大跨膜蛋白 没有明显酶活性的受体。尽管配体(锯齿状) Notch已被确定，配体激活的机制和下游 人们对信号仍然知之甚少。Notch信号转导中的突变 家庭与许多人类疾病有牵连。在急性T细胞中 淋巴母细胞性白血病(T-ALL)，Notch 1基因涉及一条染色体 T细胞受体B位点易位{t(7：9)(q34；q34.3)}。这 易位会产生异常的Notch蛋白，这种蛋白缺乏大多数 胞外序列。这些Notch的突变形式被认为是 结构性活跃；然而，其病理生理机制尚不清楚。在……里面 除了Notch参与T细胞白血病，表达研究 已发现Notch和Serrate蛋白在其他 肿瘤，包括宫颈癌和结直肠癌。 本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 Notch信号通路的分子遗传学和分子生物学研究进展 生物化学。他们的实验室已经开发出一种体外转化模型 用于Notch蛋白质。Notch的激活突变体，与在 T-ALL能够与E1a合作转化细胞。使用这个 活性，将进行结构/功能分析以确定结构域 转换所需的Notch的。这项工作的其他方面将是 针对识别与Notch相互作用的蛋白质和测定 这些蛋白质在Notch介导的转化中所起的作用。蜂窝 转化是某些细胞中许多缺陷的顶峰 过程，如细胞凋亡和细胞周期控制。调查……的作用 在这样的过程中，Notch的条件转化等位基因将是 已创建。Notch的条件等位基因将在早期研究中有用 肿瘤转化中的事件。此外，Notch的条件等位基因将 允许我们在启动过程中满足Notch信令事件的要求 和保持转型。Serrate(Notch配体)的作用 在Notch的激活和肿瘤转化方面也将进行研究。

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.