PDZ-dependent jagged 1 signaling in tumorigenesis

肿瘤发生中 PDZ 依赖性锯齿状 1 信号传导

• 批准号: 8211066
• 负责人: ANTHONY John CAPOBIANCO
• 金额: $ 30.8万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8211066
• 关键词: Animal Model; Apoptosis; Biological Models; Cancerous; Cell Maintenance; Cell physiology; Cells; Cervix carcinoma; Colon Carcinoma; Communication; Complex; Data; Disease; Environment; Event; Exhibits; Family; Family member; Gene Expression; Gene Targeting; Genes; Goals; Health; Human; Integral Membrane Protein; Laboratories; Lead; Ligands; MCF7 cell; Maintenance; Mediating; Mediator of activation protein; Modeling; Multiple Myeloma; Neoplasms; Oncogenic; Pathway interactions; Play; Process; Protein Family; Proteins; Reporting; Role; Signal Pathway; Signal Transduction; Squamous cell carcinoma; System; Tissues; Transgenic Mice; Tumor Cell Line; Up-Regulation; Work; base; cell motility; cell transformation; insight; jagged1 protein; leukemia; member; meningioma; metaplastic cell transformation; mouse model; neoplastic; neoplastic cell; new therapeutic target; notch protein; novel; prototype; receptor; tumor; tumorigenesis

DESCRIPTION (provided by applicant): A developing paradigm in signal transduction is that of the importance of cell-to-cell mediated signaling. How cells communicate between each other to develop and maintain specific cellular environments remains a poorly understood problem. Moreover, it is becoming increasingly clear that cellular microenvironments are critical to the initiation and maintenance of tumorigenesis. The Notch/DSL (Delta/Serrate/Lag-2) system is an excellent prototype for this type of signaling because it primarily mediates communication between adjacent non-equivalent cells. Jagged1 (Jag1), a member of the DSL family, is an evolutionarily conserved transmembrane protein that regulates cell fate decisions in numerous tissues. Additionally, aberrant misexpression of Jagged1 has been documented in several human tumors such as colon and cervical carcinomas; however, a causal role in oncogenesis has not been demonstrated. The current Notch/DSL signaling model proposes that a DSL protein on one cell is presented to a Notch protein on an adjacent cell thereby initiating signaling in the Notch-expressing cell. However, data from our laboratory indicates an alternative model whereby signaling is actually bi-directional. That is, we have demonstrated that expression of Jagged1 in RKE cells results in alterations in gene expression and cellular transformation. These activities are dependent on the presence of a PDZ-ligand domain at the C-terminus of Jagged1. Therefore, our underlying hypothesis is that Jagged1 induces intrinsic PDZ-dependent signaling events that can lead to oncogenic transformation of cells. The outlined experimental strategy will employ the use of cell-based and animal model systems to help elucidate the mechanism(s) through which Jagged1 induces transformation. The aims of this study are: (1) Determine the role of Jagged1-mediated signaling in cellular transformation and in tumor formation and maintenance, including defining the significance of the PDZ-ligand and other functional domains of Jagged1, (2) Elucidate the mechanism of Jagged1 downstream signaling events. Jagged1 interacting proteins (JIPs) and the importance of cell-to-cell signaling will be investigated, (3) Determine Jagged1-mediated changes in gene expression and investigate subsequent effects on cellular processes. These studies will establish a novel signaling paradigm in the Notch/DSL signaling mechanism and provide insights into complex cell-to-cell signaling in tumor microenvironments, which may provide novel therapeutic targets. PUBLIC HEALTH RELEVANCE: Notch is a gene that has been determined to contribute to the formation of leukemia and much work has been done to define the cellular events mediated by Notch that lead to changes in the cell that make them cancerous. We have shown that Notch's ligand, Jagged1, may also contribute to cellular transformation. It is essential to determine how this novel signaling mechanism in the Notch/DSL pathway may contribute to tumorigenesis.

描述（由申请人提供）：信号转导的发展范式是细胞到细胞介导的信号传导的重要性。 细胞之间如何相互交流以发展和维持特定的细胞环境仍然是一个知之甚少的问题。 此外，越来越清楚的是，细胞微环境对于肿瘤发生的开始和维持至关重要。 Notch/DSL（Delta/Serrate/Lag-2）系统是此类信号传导的极好原型，因为它主要介导相邻的非等效细胞之间的通信。 DSL家族成员JAGGED1（JAG1）是一种进化保守的跨膜蛋白，可调节许多组织中的细胞命运决策。 此外，在几种人类肿瘤（例如结肠和宫颈癌）中已经记录了JAGGED1的异常变形。但是，尚未证明因果发生在肿瘤发生中的作用。 当前的Notch/DSL信号传导模型提出，将一个细胞上的DSL蛋白呈现给相邻细胞上的Notch蛋白，从而启动表达缺口的细胞中的信号传导。 但是，我们实验室的数据表明信号实际上是双向的替代模型。 也就是说，我们已经证明了RKE细胞中JAGGED1的表达会导致基因表达和细胞转化的改变。 这些活性取决于锯齿状1的C末端的PDZ-rigand域的存在。 因此，我们的基本假设是JAGGED1诱导固有的PDZ依赖性信号传导事件，这可能导致细胞的致癌转化。 概述的实验策略将采用基于细胞和动物模型系统的使用来帮助阐明锯齿状1诱导转化的机制。 这项研究的目的是：（1）确定JAGGED1介导的信号在细胞转化以及肿瘤形成和维持中的作用，包括定义PDZ-Ligand和Jagged1的其他功能域的重要性，（2）阐明机制JAGGED1下游信号事件。 将研究JAGGED1相互作用蛋白（JIP）和细胞对细胞信号传导的重要性，（3）确定基因表达的JAGGED1介导的变化，并研究随后对细胞过程的影响。 这些研究将在Notch/DSL信号传导机制中建立新的信号范式，并为肿瘤微环境中的复杂细胞到细胞信号传导提供见解，这可能提供新的治疗靶标。 公共卫生相关性：Notch是一个决定为白血病形成做出贡献的基因，并且已经做出了许多工作来定义Notch介导的细胞事件，从而导致细胞变化，从而使它们变化。 我们已经表明，Notch的配体Jagged1也可能有助于细胞转化。 必须确定Notch/DSL途径中这种新型信号传导机制如何有助于肿瘤发生。