Lessons from the small DNA tumour viruses


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Daniel DiMaio1
1Yale University School of Medicine, New Haven, CT, USA

Abstract

Tumor viruses exploit crucial regulatory nodes in the cell in order to replicate and persist in their hosts. Because these same nodes regulate cell proliferation and survival, these viruses can cause cancer. Furthermore, because of their intimate association with this central cellular machinery, tumor viruses have proven to be prime tools for unraveling the complexities of all human cancers, not just those induced by viruses themselves. The small DNA tumor viruses, because of their limited genome size, have been a particularly fertile area to study the molecular basis of cancer. Studies of these viruses elucidated intracellular signal transduction pathways and highlighted the importance of these pathways in cell cycle control and cancer. Studies of these viruses also revealed the identity and function of tumor suppressor proteins such as p53 and the retinoblastoma family. Surprisingly, diverse tumor viruses modulate the activity of a common set of cellular proteins, indicating the central importance of these targets in controlling cell proliferation and death. Some of these virus-host interactions are important in human carcinogenesis, and sustained inactivation of cellular tumor suppressor pathways by viral oncoproteins is required to maintain the survival and proliferative state of cancer cells, suggesting novel rational approaches to treat cancer. In addition to teaching us about cancer and cell biology, viruses can also teach us how to manipulate cell behavior. Based on our analysis of cell transformation by bovine papillomavirus, we have developed genetic techniques to reprogram a very unusual viral protein to allow it to interact with novel cellular targets. We will describe how we used this approach to construct a series of artificial, small transmembrane proteins that can activate specific cellular growth factor receptors or inhibit infection by human immunodeficiency virus.