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Differentiation-dependent up-regulation of the human papillomavirus E7 gene reactivates cellular DNA replication in suprabasal noncycling epithelial cells
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Differentiation-dependent up-regulation of the human papillomavirus E7 gene reactivates cellular DNA replication in suprabasal noncycling epithelial cells
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Differentiation-dependent up-regulation of the human papillomavirus E7 gene reactivates cellular DNA replication in suprabasal noncycling epithelial cells
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Dissertation
Differentiation-dependent up-regulation of the human papillomavirus E7 gene reactivates cellular DNA replication in suprabasal noncycling epithelial cells
1996
Overview
Messenger RNA transcription, DNA amplification and progeny production of human papillomaviruses (HPVs) are closely linked to epithelial cell differentiation in patient papillomas. Since these cells have exited the cell cycle for weeks and viral DNA replication requires the host DNA replication machinery, HPVs must have a mechanism to reactivate these host genes. In this thesis, I show via retrovirus-mediated gene transfer that an intact E7 gene of high-risk or of low-risk HPV genotypes, each under the control of its respective native enhancer-E6 promoter, induced proliferating cell nuclear antigen (PCNA) expression in the suprabasal cells of epithelial raft cultures of acutely infected primary human foreskin keratinocytes. The differentiation program of the infected cells was not only unaltered, it was essential for high activity of the E6 promoter. I also show that extensive host DNA replication took place in differentiating cells of E7-containing raft cultures and of patient papillomas. These results suggest that the main function of the E7 protein is to reactivate host DNA replication machinery to support viral replication in differentiated, noncycling cells. I infer that the family of retinoblastoma proteins which E7 proteins inactivate play key roles in controlling all the cellular DNA replication genes. Their inactivation did not however promote progression through mitosis.
Publisher
ProQuest Dissertations & Theses
Subject
ISBN
9798641437910
