Analysis of viral-host protein interactions and tumorigenesis in transgenic mice

Transgenic mice provide a valuable system with which to explore mechanisms that regulate cell growth and differentiation. The ability to target the expression of test genes to specific cell types and developmental stages facilitates the rigorous assessment of regulatory pathways operative in each cell type in vivo. The natural induction of neoplasia clearly involves multiple genetic events which include alterations both in cellular protooncogenes (dominant events) and in tumor suppressor genes (recessive events). Transgenic mice have long been used to explore the mechanism of dominant oncogene action, and continue to provide an avenue for experimentation. Recent developments in the study of DNA tumor virus oncoproteins suggest their usefulness in probing the function of certain tumor suppressors. The transforming proteins from three DNA tumor viruses, adenovirus, simian virus 40, and human papillomaviruses 16 and 18, interact with a common subset of cellular proteins to disrupt normal cellular growth regulation. The discovery that two of these proteins, pRB and p53, are tumor suppressors not only emphasizes the importance of these cellular proteins in growth regulatory processes, but also provides an approach to understanding the function of these cellular targets in vivo. Analysis of the DNA virus oncoproteins in transgenic mice has recently begun to yield insight into the role of these tumor suppressors and other cellular functions in development and tumorigenesis of a variety of cell types. This approach and recent findings which it has yielded are reviewed here.