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TARGET GENES ACTIVATED BY THE JUN ONCOGENE

由 Jun 癌基因激活的靶基因

基本信息

批准号：
2871748
负责人：
TIMOTHY J BOS
金额：
$ 21.86万
依托单位：
EASTERN VIRGINIA MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-08-01 至 2001-01-31
项目状态：
已结题

项目摘要

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.

癌症仍然是美国的主要死因。一个癌症研究的首要目标是开发有效的治疗方法旨在消除或抑制经济增长的战略癌细胞。实现这一目标的前提是理解肿瘤的发生、生长和发展涉及多种机制。这些机制的核心是……的行动、调节和功能原癌基因。改变原生物功能或调节的突变- 癌基因激活分子信号级联导致将正常细胞转化为癌细胞。Jun癌蛋白在这一进程中发挥核心作用，作为许多信号通路。它的功能是将这些信号转换为变化在基因表达上。由于它作为转录调节因子的作用， Jun癌蛋白为研究肿瘤发生发展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。整体而言这项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中的作用诱导细胞转化。 2.确定反式激活结构域在JUN诱导的细胞中的作用转型。] 3.分离和鉴定与JUN诱导相关的靶基因细胞转化。 4.确定Jun转化相关基因在小麦生长发育中的作用致癌转化。该提案分为三个部分。第一部分(目标1和2)涉及各种生化物质的作用。 Jun在致癌转化中的作用。我们已经概述了两个 Jun癌蛋白诱导致癌的可能模型转型。一项广泛的突变分析将用于区分这些型号。第二部分(目标30重点是确定基因表达的变化是由于 Jun的致癌转化。我们将分离和鉴定Jun 消减杂交法转化相关靶基因差异显示。这些靶标的分子表征将包括对结构、功能和调节的研究。第三部分 (目标4)涉及确定Jun转型的角色相关的目标在产生转化的表型中起作用。这将是通过确定对细胞转化的影响来实现，每个靶基因的过表达。这将确定每个目标是否足以诱导致癌转化。我们还将阻止表达式使用反义技术，以确定是否致癌所需的靶基因(不充分) 转换。