FUNCTION OF THE ADENOVIRUS E1B ONCOGENE

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.Description