C-MYC TARGETS IN THE PATHOGENESIS OF HUMAN CANCERS

C-MYC 人类癌症发病机制中的靶标

• 批准号: 2458079
• 负责人: CHI V. DANG
• 金额: $ 34.17万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2458079
• 关键词: antisense nucleic acid; apoptosis; cell cycle proteins; fibroblasts; gene induction /repression; gene targeting; laboratory rat; loss of heterozygosity; molecular oncology; neoplasm /cancer genetics; neoplastic transformation; oncogenes; transcription factor; tumor necrosis factor beta; tumor suppressor genes

DESCRIPTION: During the last funding period, the applicant has made a number of published as well as preliminary observations that suggest: 1) c-Myc mediated anchorage independent growth of rat fibroblast is associated with the deregulated expression of genes including cyclin A, ornithine decarboxylase and several genes that he has cloned and are as yet undefined, 2) Deregulated cyclin A expression induces anchorage independent growth and apoptosis of rat fibroblasts, 3) Chromosomal localization of the MXI-1 gene and loss of heterozygosity studies suggest that MXI-1 is a tumor suppressor gene in human prostate cancer and glioblastomas, and 4) TNFb (lymphotoxin) selectively induces apoptosis in Myc- overexpressing fibroblasts. A unique, rapid and efficient model and systematic approach to identify c-Myc responsive genes has been established. Based on these observations and to reach the long term goal of delineating the mechanisms by which c-Myc transform cells, experiments are proposed to answer the following questions: 1) What are the genes that are upregulated by c-Myc, and how do they contribute to neoplasia? 2) What are the genes that are downregulated by c-Myc and how do they participate in neoplasia? 3) What are the effects of Mxi-1 on the expression of c-Myc target genes? and 4) Which c-Myc target genes predispose fibroblasts to lymphotoxin-mediated apoptosis, and is this pathway exploitable for therapeutic purposes?

描述：在最后一个资金期间，申请人做了 已发表的数量以及提示的初步观察：1） C-Myc介导的大鼠成纤维细胞独立锚固生长与 具有包括细胞周期蛋白A的基因的不受管调的表达，鸟氨酸 他克隆并尚未定义的脱羧酶和几个基因， 2）放松管制的细胞周期蛋白A表达诱导锚定独立的生长和 大鼠成纤维细胞的凋亡，3）MXI-1基因的染色体定位 杂合性研究的丧失表明MXI-1是肿瘤抑制剂 人前列腺癌和胶质母细胞瘤中的基因，以及4）TNFB（淋巴毒素） 有选择地诱导MYC过表达的成纤维细胞凋亡。 一个独特的， 快速有效的模型和系统的方法来识别C-MYC 已经建立了响应基因。 基于这些观察和 达到描述C-MYC的机制的长期目标 转化细胞，提出了实验来回答以下问题： 1）C-MYC上调的基因是什么，它们如何 有助于肿瘤？ 2）被下调的基因是什么 C-MYC以及他们如何参与肿瘤？ 3）有什么影响 MXI-1关于C-MYC靶基因的表达？ 4）哪个C-MYC目标 基因使成纤维细胞易于淋巴毒素介导的细胞凋亡，这是 用于治疗目的的途径可利用？