The Howley laboratory studies the molecular biology of the papillomaviruses using the bovine papillomavirus (BPV) as well as the human papillomaviruses (HPVs). BPV is the most extensively studied of the papillomaviruses and has served as the model system for the analysis of viral transcription and of viral DNA replication. One focus of our studies has involved the viral E1 and E2 proteins and their roles in the regulation of viral transcription and DNA replication. We are conducting structure/function studies of the viral E1 and E2 proteins with the hope of developing inhibitors of their functions.
There are over 70 different HPVs, and some of them are associated with specific human cancers most notably human cervical cancer. We study the role of these HPVs in human neoplasia and the mechanisms by which these viruses contribute to cellular transformation. The virus encodes two proteins, E6 and E7, that have oncogenic properties and that contribute directly to HPV associated carcinogenesis. A particular focus of the laboratory is the study of the E6 gene, which has multiple functions, including the ability to functionally inactivate p53 by targeting its ubiquitination and proteolysis. This process is mediated by a cellular protein, E6AP, that binds to E6 and functions as a ubiquitin protein ligase in promoting the E6 dependent ubiquitination of p53. We are conducting structure/function studies on E6 and E6AP, and are studying additional functions of the papillomavirus E6 proteins. We have discovered that the BPV E6 protein binds to the cellular focal adhesion protein paxillin leading to a disruption of the actin cytoskeleton. We have also found that HPV16 E6 can bind IRF3 and inhibit its transcriptional activation function.