Molecular mechanisms of notch signaling in neoplasia

大量证据表明，Notch基因家族在多种人类癌症中发挥了作用，包括 淋巴系统、胰腺、乳腺和CMS等肿瘤。然而， Notch功能的病理生理机制尚不清楚。潜在的假设是 这一建议是Notch信号转导通路的放松调控推动了肿瘤转化 在转化状态的启动和维持中起着重要的作用。这 转化活性是Notch的固有属性，Notch通过信号转导来调节其作用 复合体(S)。 我的实验室已经开发出体外策略来研究哺乳动物Notch的作用机制 细胞癌变过程中的信号转导途径。本文提出的研究是设计的 为了更好地了解Notch的分子本质以及Notch的激活如何颠覆 细胞的正常生理和放松对生长的控制。这项建议的具体目标包括； Notch的结构和功能分析，Notch信号复合体的特性，细胞机制 周期调控和Notch对基因表达的调控。这些研究的长期目标是 全面了解Notch活动是如何转化细胞的，以便为 癌症治疗药物的合理设计。

Substantial evidence has demonstrated a role for the Notch gene family in multiple human cancers, including neoplasms of the lymphoid system, pancreas, breast and CMS, among others. However, the pathophysiological mechanism of Notch function remains poorly understood. The underlying hypothesis of this proposal is that deregulation of the Notch signal transduction pathway drives the neoplastic conversion of cells, playing an important role in both the initiation and maintenance of the transformed state. This transforming activity is an intrinsic property of Notch and Notch mediates its effects through a signaling complex(s). My laboratory has developed in vitro strategies to study the mechanism of action of the mammalian Notch signal transduction pathway in the neoplastic transformation of cells. Research proposed herein is designed to seek a better understanding of the molecular nature of Notch and how activation of Notch subverts the normal physiology of the cell and deregulates growth controls. Specific aims for this proposal include; structure and function analysis of Notch, characterization of the Notch signaling complex, mechanism of cell cycle regulation and regulation of gene expression by Notch. The long-range goal for these studies is to obtain a comprehensive understanding of how Notch activity transforms cells in order to contribute to the rational design of cancer therapeutics.