FUNCTION OF THE ADENOVIRUS E1B ONCOGENE

人腺病毒是一种DNA肿瘤病毒，能够诱导恶性 转化不允许的啮齿动物细胞，从而作为一个模型 用来研究癌症发展的系统。病毒编码的 使病毒介导转化的癌基因是E1a和E1B 致癌基因。这些病毒基因产物通过改变正常细胞新陈代谢 相互作用和干扰关键宿主细胞调节功能 蛋白质。E1a基因产物与视网膜母细胞瘤的产物结合 易感基因，该基因的失活会导致 癌症。同样，两个E1B编码的癌蛋白之一，E1B 55K 蛋白，与p53抑癌基因的产物结合，突变 其中与恶性转化有关。因此，至少 三种腺病毒转化蛋白中的两种靶向于 细胞抗癌基因。这是剩下的腺病毒的功能 转化蛋白，E1B 19K蛋白，这是这一点的焦点 求婚。 E1B 19K蛋白与E1a的产物共表达 癌基因，刺激病灶形成，并允许锚定独立 转化细胞的生长。因为19K蛋白与 其他已知的癌蛋白，它可能通过一种独特的机制发挥作用。 最近，与19K蛋白相关的一种新的生物学活性已经 已经发现，中间细丝的断裂。这引发了 销毁中间长丝的可能性可能是通过 其中19K蛋白在转化中起作用。这一假设将是 通过以下方式进行测试。首先，19K蛋白的遗传分析 将会被承担。这将允许识别重要的 19K蛋白中的功能结构域并使之能够相互关联 生物活性，中间丝破坏，与 变换函数。第二，细胞蛋白质，可能是 中间细丝的成分，与19K物理上相互作用 蛋白质将被鉴定出来。第三，19K蛋白能够 补充其他病毒和细胞的转化能力 癌蛋白将被确定。这些实验的目标是 确定这种病毒癌蛋白导致正常细胞的机制 变得致癌转化。

Human adenoviruses are DNA tumor viruses able to induce malignant transformation of non-permissive rodent cells, and thus serve as a model system with which to study the development of cancer. The virally encoded oncogenes that enable virus-mediated transformation are the E1A and E1B oncogenes. These viral gene products modify normal cell metabolism by interacting and interfering with the function of key host cell regulatory proteins. The E1A gene products bind to the product of the retinoblastoma susceptibility gene, the inactivation of which causes the development of cancer. Similarly, one of the two E1B encoded oncoproteins, the E1B 55K protein, binds to the product of the p53 tumor suppressor genes, mutations in which have been associated with malignant transformation. Thus, at least two of the three adenovirus transforming proteins target the products of cellular anti-oncogenes. It is the function of the remaining adenovirus transforming protein, the E1B 19K protein, that is the focus of this proposal. The E1B 19K protein can, when coexpressed with the products of the E1A oncogene, stimulate focus formation, and permit anchorage independent growth of transformed cells. Since the 19K protein bears no resemblence to other known oncoproteins, it likely functions by a unique mechanism. Recently, a novel biological activity associated with the 19K protein has been discovered, the disruption of intermediate filaments. This raises the possibility that destruction of intermediate filaments may be the means by which the 19K protein functions in transformation. This hypothesis will be tested in the following ways. First, a genetic analysis of the 19K protein will be undertaken. This will permit the identification of important functional domains within the 19K protein and enable correlation of biological activity, intermediate filament disruption, with the transformation function. Second, the cellular proteins, perhaps the components of intermediate filaments, that physically interact with the 19K protein will be identified. Third, the ability of the 19K protein to complement the transforming ability of other viral and cellular oncoproteins will be determined. The goal of these experiments is to determine the mechanism by which this viral oncoprotein causes normal cells to become oncogenically transformed.