Human papillomavirus type 16 (HPV-16) is the most common cause of lower genital tract cancers. The virus replicates in the upper part of stratified epithelium, in cells which would normally be terminally differentiated. Since terminally differentiated cells will contain little or no replicative enzymes and the virus relies on the cell's replicative machinery for the propagation of the viral DNA, the virus must stimulate the epithelial cells into S-phase. We have shown that the E7 protein is able to stimulate S-phase progression in human keratinocytes, which are induced to differentiate. In this application I wish to investigate the activities of E7 that are required for stimulation of G1 progression. In particular, we will study the ability of the E7 protein to alter the transcriptional activity of cells through interaction with members of the Rb and AP-1 transcription factor families. Additionally, we will investigate the ability of E7 to increase cyclin/kinase activity in differentiating cells, which also contain high levels of kinase inhibitors.
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