NF-κB is a family of transcription factors that regulate gene expression involved in many processes， such as the inflammatory response and cancer progression. Little is known about associations of NF-κB with the human papillomavirus (HPV) life cycle. We have developed a tissue culture system to conditionally induce E1-dependent replication of the human papillomavirus 16 (HPV16) genome in human cervical keratinocytes and found that expression of HPV16 E1， a viral helicase， results in reduction of IκBα and subsequent activation of NF-κB in a manner dependent on helicase activity. Exogenous expression of a degradation-resistant mutant of IκBα， which inhibits the activation of NF-κB， enhanced E1-d... More
NF-κB is a family of transcription factors that regulate gene expression involved in many processes， such as the inflammatory response and cancer progression. Little is known about associations of NF-κB with the human papillomavirus (HPV) life cycle. We have developed a tissue culture system to conditionally induce E1-dependent replication of the human papillomavirus 16 (HPV16) genome in human cervical keratinocytes and found that expression of HPV16 E1， a viral helicase， results in reduction of IκBα and subsequent activation of NF-κB in a manner dependent on helicase activity. Exogenous expression of a degradation-resistant mutant of IκBα， which inhibits the activation of NF-κB， enhanced E1-dependent replication of the viral genome. Wortmannin， a broad inhibitor of phosphoinositide 3-kinases (PI3Ks)， and， to a lesser extent， VE-822， an ATR kinase inhibitor， but not KU55933， an ATM kinase inhibitor， suppressed the activation of NF-κB and augmented E1-dependent replication of the HPV16 genome. Interestingly， the enhancement of E1-dependent replication of the viral genome was associated with increased stability of E1 in the presence of wortmannin as well as the IκBα mutant. Collectively， we propose that expression of E1 induces NF-κB activation at least in part through the ATR-dependent DNA damage response and that NF-κB in turn limits E1-dependent replication of HPV16 through degradation of E1， so that E1 and NF-κB may constitute a negative feedback loop.
