FUNCTION OF THE C-MYC ONCOGENE

C-MYC 癌基因的功能

• 批准号: 2414226
• 负责人: MICHAEL David COLE
• 金额: $ 29.57万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-01 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2414226
• 关键词: DNA binding protein; cell growth regulation; gene expression; genetic promoter element; genetic transcription; laboratory rabbit; molecular cloning; neoplastic transformation; nucleic acid sequence; oncogenes; oncoproteins; phosphorylation

Mutations that disrupt the regulation or expression level of the c-myc gene are frequently found in human and animal cancers. Ectopic expression studies define numerous biological activities of the c-myc gene, including transformation, immortalization, blockage of cell differentiation and induction of apoptosis. Since the Myc proteins bind to specific DNA sequences, the mechanisms of cell transformation can be viewed as that of a transcription factor that activates specific target genes. Functional studies have demonstrated that two specific domains of the c-Myc protein are essential for cell transformation: the C-terminal 100 amino acids which encompass the DNA binding region, and a small 20 amino acid segment from the N-terminus (called Myc Box 2) that is conserved in all members of the myc family of genes. Since the DNA binding region is well characterized, the major functional domain of the c-Myc protein that remains undefined is Myc Box 2. This project will address the function of Myc Box 2 through an analysis of the nuclear proteins that bind to this region and which are also essential for the transforming activity of the oncogene. The experimental approach is based on preliminary studies i which dominant interfering alleles of the c-Myc protein were shown to form protein complexes that are dependent on the integrity of Myc Box 2 and hence correlate with nuclear factors that may be essential for c-Myc function. The specific aims are as follows: 1. An essential, rate-limiting nuclear factor (termed MB2F) which binds to the c-Myc amino terminus through Myc Box 2 will be purified biochemically and the corresponding cDNA will be cloned. 2. The function of MB2F will be addressed through studies of potential transforming activity and interactions with nuclear components. 3. The requirement of MB2F for transformation by other oncogenes will be assessed. In particular, we will test if MB2F is essential for transformation by another nuclear oncogene, the adenovirus E1a gene, and a tyrosine kinase oncogene, BCR-abl. 4. The potential regulation of c-Myc protein interaction with the MB2F cofactor by either extracellular stimuli or cell cycle progression will be studied. The long range goal of this project is to identify cellular promoters that are dependent on both c-Myc and MB2F for their activation and hence represent the downstream effectors of cell transformation.

破坏C-MYC调节或表达水平的突变 基因经常在人类和动物癌中发现。 异位表达 研究定义了C-MYC基因的众多生物学活性，包括 转化，永生化，细胞分化的阻塞和 诱导凋亡。 由于MYC蛋白与特定DNA结合 序列，细胞转化的机制可以看作是 激活特定靶基因的转录因子。 功能 研究表明，C-MYC蛋白的两个特定结构域 对于细胞转化至关重要：C末端100氨基酸 包含DNA结合区域和一个小20氨基酸段 来自N端（称为Myc Box 2） MYC家族的基因家族。 由于DNA结合区域很好 表征是C-Myc蛋白的主要功能结构域 Myc Box 2仍然不确定。 该项目将通过分析MYC Box 2的功能 与该区域结合的核蛋白，也是必不可少的 用于转化癌基因。 实验方法 基于初步研究I，主要干扰等位基因 C-Myc蛋白显示出形成依赖性的蛋白质复合物 关于MYC Box 2的完整性，因此与核因子相关 这对于C-MYC功能可能至关重要。 具体目的是 以下内容： 1。限制的必不可少的，限制核因子（称为MB2F） 通过MYC Box 2到达C-MYC氨基终端将被净化 生化和相应的cDNA将被克隆。 2。MB2F的功能将通过潜在的研究来解决 改变活动和与核成分的相互作用。 3。MB2F对其他癌基因转化的要求将是 评估。 特别是，我们将测试MB2F是否对 另一个核癌基因，腺病毒E1A基因和转化 酪氨酸激酶癌，BCR-ABL。 4。c-myc蛋白与MB2F的潜在调节 通过细胞外刺激或细胞周期进程的辅助因子将是 研究。 该项目的远距离目标是确定蜂窝启动子 取决于C-MYC和MB2F的激活，因此 表示细胞转化的下游效应子。