FUNCTION OF THE C-MYC ONCOGENE

破坏c-myc调控或表达水平的突变 基因常见于人类和动物的癌症中。异位表达 研究确定了c-myc基因的许多生物学活性，包括 转化、永生化、阻断细胞分化和 诱导细胞凋亡。由于Myc蛋白与特定的DNA结合 序列中，细胞转化的机制可以看作是 激活特定靶基因的转录因子。功能性 研究表明，c-Myc蛋白的两个特定结构域 是细胞转化所必需的：C末端100个氨基酸 它包括DNA结合区和一小段20个氨基酸的片段 从N-末端(称为Myc Box 2)，它在所有成员中保守 Myc基因家族。因为DNA结合区很好 C-Myc蛋白的主要功能结构域 仍未定义的是Myc Box 2。 这个项目将通过分析Myc Box 2的功能来解决 与这一区域结合的核蛋白也是必不可少的 致癌基因的转化活性。实验方法 是基于一项初步研究，这些显性干扰等位基因 C-Myc蛋白被证明形成依赖于 关于Myc Box 2的完整性及其与核因子的关系 这可能是c-Myc功能所必需的。具体目标如下 以下是： 1.一种必需的限速核因子(称为MB2F)，它结合 通过Myc Box 2连接到c-Myc氨基末端将被提纯 并将克隆相应的cDNA. 2.MB2F的功能将通过对潜力的研究来解决 转变活动和与核组件的相互作用。 3.其他癌基因转化对MB2F的要求为 评估过了。特别是，我们将测试MB2F是否对 另一种核癌基因，腺病毒E1a基因的转化，以及 酪氨酸激酶癌基因，bcr-abl。 4.c-Myc蛋白与MB2F相互作用的潜在调节 细胞外刺激或细胞周期进程的辅因子将是 学习。 这个项目的长期目标是确定细胞启动子 依赖于c-Myc和MB2F的激活，因此 代表细胞转化的下游效应器。

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.