Mechanisms of human papillomavirus-induced malignancy


Year:

Session type:

Lawrence Banks1
1International Centre for Genetic Engineering and Biotechnology, Trieste, Italy

Abstract

Human Papillomaviruses (HPVs) are the causative agents of a large number of human cancers, with cervical cancer being the most prevalent. Two viral oncoproteins, E6 and E7 directly contribute to the development of the malignancy and both proteins are required for the maintenance of the transformed phenotype. Therefore these viral oncoproteins represent ideal targets for therapeutic intervention.

Much is known about the mechanisms by which the viral oncoproteins drive tumourigenesis. This involves perturbation of diverse cellular regulatory pathways, including cell cycle control and inhibition of apoptosis. A great deal of effort has been placed in understanding why only a small subset of HPV types, so-called ‘high risk' viruses cause cancer, whilst ‘low risk' virus types do not. One unique molecular marker of the high-risk virus E6 protein is its capacity to target cellular PDZ domain containing proteins. Many of these proteins are involved in the regulation of cell signaling pathways and have also been implicated in the control of cell polarity. The three most well-characterised PDZ targets of E6 are Discs Large (Dlg), Scribble (Scrib) and MAGI-1, although many others have also been reported. We have been interested in dissecting which of these substrates are true in vivo targets of the different HPV E6 oncoproteins, whilst also aiming to uncover what roles these proteins may play both in the development of malignancy and also in the context of the normal viral life cycle. Data will be presented implicating Scrib as being an inhibitor of cell invasion, whilst Dlg regulates the susceptibility of cells to undergo anoikis. Using structural data on the E6-PDZ recognition coupled with substrate modification, we provide compelling evidence that inhibition of some of these E6-PDZ interactions has therapeutic potential. Furthermore we can begin to answer questions about why these proteins are targeted by the virus, both during the viral life cycle and during the development of malignancy.