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.
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