PDZ-dependent jagged 1 signaling in tumorigenesis

描述（由申请人提供）：信号转导的一个发展范例是细胞间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，细胞微环境对肿瘤发生的开始和维持至关重要。Notch/DSL （Delta/Serrate/Lag-2）系统是这种类型信号的优秀原型，因为它主要介导相邻非等效细胞之间的通信。Jagged1 （Jag1）是DSL家族的一员，是一种进化保守的跨膜蛋白，在许多组织中调节细胞命运决定。此外，Jagged1的异常错误表达已在几种人类肿瘤中得到证实，如结肠癌和宫颈癌；然而，在肿瘤发生中的因果作用尚未得到证实。目前的Notch/DSL信号模型提出，一个细胞上的DSL蛋白被呈递给相邻细胞上的Notch蛋白，从而在表达Notch的细胞中启动信号。然而，我们实验室的数据表明了另一种模型，即信号实际上是双向的。也就是说，我们已经证明了Jagged1在RKE细胞中的表达会导致基因表达和细胞转化的改变。这些活性依赖于Jagged1 c端pdz -配体结构域的存在。因此，我们的基本假设是Jagged1诱导内在的pdz依赖性信号事件，从而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来帮助阐明Jagged1诱导转化的机制。本研究的目的是：(1)确定Jagged1介导的信号在细胞转化和肿瘤形成和维持中的作用，包括确定Jagged1的pdz配体和其他功能域的意义；(2)阐明Jagged1下游信号事件的机制。将研究Jagged1相互作用蛋白（jip）和细胞间信号传导的重要性。(3)确定Jagged1介导的基因表达变化，并研究随后对细胞过程的影响。这些研究将在Notch/DSL信号机制中建立一个新的信号范式，并为肿瘤微环境中复杂的细胞间信号传导提供见解，从而可能提供新的治疗靶点。公共卫生相关性：Notch是一种被确定有助于白血病形成的基因，并且已经做了很多工作来确定由Notch介导的细胞事件，这些细胞事件导致细胞发生癌变。我们已经证明Notch的配体Jagged1也可能有助于细胞转化。确定Notch/DSL通路中这种新的信号机制如何促进肿瘤发生是至关重要的。

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.