TARGET GENES ACTIVATED BY THE JUN ONCOGENE

癌症仍然是美国的主要死亡原因。 一 癌症研究的主要目标是开发有效的治疗方法 针对消除或抑制生长的战略， 癌细胞 实现这一目标的先决条件是了解 参与肿瘤发生、生长和进展的多种机制。 这些机制的核心是以下方面的行动、管理和职能： 原癌基因 改变原核细胞功能或调节的突变 致癌基因激活分子信号级联，导致 正常细胞转化为癌细胞。 Jun癌蛋白 在这一过程中发挥着核心作用， 信号通路 它的功能是将这些信号转化为变化 in gene基因expression表达. 由于其作为转录调节因子的作用， Jun癌蛋白为研究肿瘤的发生过程提供了一个很好的模型。 在特定基因调控水平上的肿瘤发生。 整体 这一建议的目的是为了更好地了解 Jun癌蛋白介导这一过程的分子机制。 具体目标是： 1、确定特异性AP-1靶点识别在Jun 诱导细胞转化。 2. 确定转录激活结构域在Jun诱导的细胞凋亡中的作用， 转型 ] 3. 分离和表征与Jun诱导的细胞凋亡相关的靶基因， 细胞转化 4. 为了确定Jun转化相关基因在 致癌转化 该提案分为三个部分。 第一 第一部分（目标1和2）涉及各种生物化学物质的作用， Jun在致癌转化中的作用。 我们概述了两个 Jun癌蛋白诱导致癌的可能模型 转型 将使用广泛的突变分析来 区分这些模式。 第二部分（目标30侧重于 鉴定由于以下原因而发生的基因表达变化： 我们将分离和表征Jun 使用消减杂交转化相关靶基因， 差异显示 这些靶点的分子特征 将包括对结构、功能和监管的研究。 第三部分 (aim 4）涉及角色的确定，即君转型 相关的靶标在产生转化的表型中起作用。 这将 通过确定对细胞转化的影响来实现， 每个靶基因的过度表达。 这将决定每个目标是否 足以诱导致癌转化。 我们还将阻止表达 每个靶基因，使用反义技术，以确定是否 靶基因（是不够的）是致癌所必需的， 转换.

Cancer continues to be a major cause of death in the United States. A primary goal in cancer research is the development of effective treatment strategies targeted at the elimination or inhibition of the growth of cancer cells. A prerequisite to this goal is an understanding of the diverse mechanisms involved in tumor initiation, growth and progression. Central to these mechanisms are the actions, regulation and function of protooncogenes. Mutations which alter the function or regulation of proto- oncogenes activate molecular signaling cascades resulting in the transformation of normal cells into cancer cells. The Jun oncoprotein plays a central role in this process as the nuclear target of a number of signaling pathways. Its function is to convert these signals into changes in gene expression. Because of its role as a transcription regulator, the Jun oncoprotein provides an excellent model to study the process of tumorigenesis at the level of specific gene regulation. The overall objective of this proposal is to gain a better understanding of the molecular mechanisms by which the Jun oncoprotein mediates this process. The specific aims are; 1, To determine the role of specific AP-1 target recognition in Jun induced cell transformation. 2. To determine the role of the transactivation domain in Jun induced cell transformation. ] 3. To isolate and characterize target genes associated with Jun induced cell transformation. 4. To determine the role of Jun transformation associated genes in oncogenic conversion. The proposal is divided into three parts. The first part (aims 1 and 2) deals with the role of the various biochemical functions of Jun in oncogenic transformation. We have outlined two possible models by which the Jun oncoprotein induces oncogenic transformation. An extensive mutational analysis will be used to distinguish between these models. The second part (aim 30 focuses on identification of the changes in gene expression that occur as a result of oncogenic transformation by Jun. We will isolate and characterize Jun transformation associated target genes using subtractive hybridization and differential display. Molecular characterization of each of these targets will include studies on structure, function and regulation. The third part (aim 4) involves determination of the role that Jun transformation associated targets play in generating a transformed phenotype. This will be accomplished by determining the effect on cell transformation, of overexpression of each target gene. This will determine if each target is sufficient to induce oncogenic conversion. We will also block expression of each target gene, using antisense technology, in order to determine if target genes (that are not sufficient) are required for oncogenic conversion.