Molecular Mechanisms of Notch Signaling in Neoplasia

描述（由申请人提供）：大量证据表明Notch基因家族在多种人类癌症中发挥作用，包括淋巴系统、胰腺、乳腺癌和CMS等肿瘤。然而，Notch功能的病理生理机制尚不清楚。Notch信号转导通路的解除可以驱动细胞的肿瘤转化，在转化状态的启动和维持中都起着重要作用。这种转化活动是Notch的固有特性，它通过转录级联介导其作用。该建议的基本假设是Notch是一种支架蛋白，通过转录调节复合物的组装来调节其功能，从而控制基因转录的变化。我们的目标是表征调节Notch复合物组装和稳定性的分子机制，并确定介导和/或调节Notch功能的机制，以更好地了解正常和病理条件下的Notch信号传导。我们的初步数据表明，Notch激活复合物的组装和稳定性受Notch多聚、磷酸化和与其他蛋白质结合的调节。这些机制可能通过复合物组装的时间、蛋白质的稳定和/或Notch靶点的差异激活来调节Notch活性。本建议的具体目标包括：i)表征调节Notch多聚和转录复合体组装的关键参数，ii)表征一种新的Notch结合蛋白的作用

DESCRIPTION (provided by applicant): 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. Deregulation of the Notch signal transduction pathway can drive 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, which mediates its effects through a transcriptional cascade. The underlying hypothesis of this proposal is that Notch is a scaffold protein that mediates its function through the assembly of a transcriptional regulatory complex(s), which governs changes in gene transcription. Our goal is to characterize the molecular mechanisms regulating the assembly and stability of Notch complexes and Identifying mechanisms that mediate and/or regulate Notch function to better understand Notch signaling in normal and pathological conditions. Our preliminary data demonstrate that assembly and stability of Notch activation complex is regulated by Notch multimerization, phosphorylation and binding to other proteins. These mechanisms may regulate Notch activity through timing of the complex assembly, stabilization of the protein and/or differential activation of Notch targets. Specific aims for this proposal include; i) characterization of the critical parameters that regulate Notch multimerization and transcriptional complex assembly, ii) characterization of the role of a novel Notch-binding protein termed NACK (Notch Activation Complex Kinase) in Notch activity, and iii) characterization of posttranslational modifications of Notch that play a role in its transcriptional activity regulatio. 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.