返回Google圖書搜尋

Human Papillomavirus Oncoproteins Alter Genomic Stability and Regulate the Viral Life Cycle

出版	Northwestern University, 1999
URL	http://books.google.com.hk/books?id=YTAdAQAAMAAJ&hl=&source=gbs_api

註釋Understanding how human papillomaviruses (HPVs) induce the proliferative lesions associated with genital warts and cervical cancers relies on our appreciation of the functions of the E6 and E7 viral proteins. These "oncoproteins" of the high risk HPV types interfere with the activities of cellular tumor suppressor proteins; E7 proteins act by associating with members of the retinoblastoma family, while E6 increases the turnover of p53. This work describes studies which (1) demonstrate that E6 and E7 alter cell cycle control and contribute to genomic instability, (2) identify a previously unknown role for the oncoproteins in the productive viral life cycle, and (3) address differences between low and high risk viruses in their alteration of cell cycle regulators. By use of DNA content flow cytometric analyses, I found that E6 and E7 could independently induce the loss of mitotic spindle checkpoint activity in human keratinocytes upon treatment with a spindle inhibitor. E6 is able to bypass this checkpoint by degradation of p53, a component of the checkpoint, while E7 acts through the loss of Rb and possibly the increased expression of the cellular oncoprotein, MDM2. To address the role of these oncoproteins in the productive viral life cycle, I utilized a genetic system in which HPV 31 circular genomes are introduced into keratinocytes and examined for their ability to replicate in transient and stable assays. I determined that E6 and E7 are both required for the maintenance of stable viral episomes, but have no role in transient replication. Finally, I generated keratinocytes that maintain HPV 11 genomes episomally and mimic low risk infected cells in vivo . These cells exhibited extended lifespans and were used to examine the levels of cell cycle regulators in monolayer and differentiated cultures. I found distinct alterations in cell cycle control for high and low risk HPV types.