Molecular Mechanisms of Notch Signaling in Neoplasia

肿瘤中Notch信号传导的分子机制

• 批准号: 8451260
• 负责人: ANTHONY John CAPOBIANCO
• 金额: $ 24.63万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8451260
• 关键词: Affect; Affinity Chromatography; Binding; Binding Proteins; Breast; Cells; Complex; Data; Embryonic Development; Family member; Gene Expression Regulation; Gene Family; Genes; Genetic Transcription; Goals; Homo; Human; Lead; Maintenance; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Mediating; Molecular; Mus; Neoplasms; Neoplastic Cell Transformation; Output; Pancreas; Pathway interactions; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Post-Translational Protein Processing; Process; Property; Proteins; Regulation; Research Proposals; Resected; Role; Sampling; Scaffolding Protein; Signal Transduction; Signal Transduction Pathway; Specificity; System; Therapeutic; Time; Tissues; Transcriptional Regulation; Tumor Cell Line; Work; cell transformation; design; lymphoid neoplasm; mouse model; mutant; neoplastic; notch protein; novel; paralogous gene; public health relevance; tumor; tumorigenesis

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.

描述（由申请人提供）：大量证据表明，在多种人类癌症中，Notch基因家族的作用，包括淋巴系统，胰腺，乳腺癌和CMS等人的肿瘤。但是，Notch功能的病理生理机制仍然很少理解。放松调节Notch信号转导途径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的内在特性，它通过转录级联反应介导了其效果。该提议的基本假设是Notch是一种支架蛋白，通过组装转录调节复合物（S）来介导其功能，该复合物控制基因转录的变化。我们的目标是表征调节Notch复合物组装和稳定性的分子机制，并识别介导和/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活化复合物的组装和稳定性受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杂组装的时间，蛋白质的稳定和/或差分激活Notch靶标来调节Notch活性。该提案的具体目的包括： i）表征调节Notch多聚化和转录复合物组装的临界参数，ii）表征新型缺口结合蛋白的作用 在Notch活性中称为NACK（Notch活化复合激酶），iii）表征在其转录活性调节中起作用的Notch的翻译后修饰。这些研究的远距离目标是对Notch活性如何转化细胞的全面了解，以促进癌症治疗剂的合理设计。