Molecular Mechanisms of Notch Signaling in Neoplasia

描述（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，包括淋巴系统肿瘤、胰腺肿瘤、乳腺肿瘤和CMS肿瘤等。然而，Notch功能的病理生理机制仍然知之甚少。Notch信号转导通路的失调可以驱动细胞的肿瘤转化，在转化状态的启动和维持中起重要作用。这种转化活性是Notch的固有特性，其通过转录级联介导其作用。该提议的基本假设是Notch是一种支架蛋白，其通过转录调控复合物的组装来介导其功能，所述转录调控复合物控制基因转录的变化。我们的目标是表征调节Notch复合物的组装和稳定性的分子机制，并鉴定介导和/或调节Notch功能的机制，以更好地理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到Notch多聚化、磷酸化和与其他蛋白质结合的调节。这些机制可以通过复合物组装的时机、蛋白质的稳定化和/或Notch靶标的差异活化来调节Notch活性。该提案的具体目标包括：i）表征调节Notch多聚化和转录复合物组装的关键参数，ii）表征新型Notch结合蛋白的作用， 称为NACK（Notch激活复合物激酶）的Notch活性，和iii）表征在其转录活性调节中起作用的Notch的翻译后修饰。这些研究的长期目标是全面了解Notch活性如何转化细胞，以促进癌症治疗的合理设计。

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.