Virus-mediated killing of cells that lack p53 activity

Abstract

A major goal of molecular oncology is to identify means to kill cells lacking p53 function. Most current cancer therapy is based on damaging cellular DNA by irradiation or chemicals. Recent reports support the notion that, in the event of DNA damage, the p53 tumour-suppressor protein is able to prevent cell death by sustaining an arrest of the cell cycle at the G2 phase. We report here that adeno-associated virus (AAV) selectively induces apoptosis in cells that lack active p53. Cells with intact p53 activity are not killed but undergo arrest in the G2 phase of the cell cycle. This arrest is characterized by an increase in p53 activity and p21 levels and by the targeted destruction of CDC25C. Neither cell killing nor arrest depends upon AAV-encoded proteins. Rather, AAV DNA, which is single-stranded with hairpin structures at both ends, elicits in cells a DNA damage response that, in the absence of active p53, leads to cell death. AAV inhibits tumour growth in mice. Thus viruses can be used to deliver DNA of unusual structure into cells to trigger a DNA damage response without damaging cellular DNA and to selectively eliminate those cells lacking p53 activity.

Viral oncoapoptosis of human tumor cells

“…Recently, adeno-associated virus was also shown to target selectively cultured cells lacking p53 activity. 72 We present data showing an alternative and novel strategy for the selective killing of tumor cells that we have termed viral oncoapoptosis. In our system, a virus that is unable to complete its replication cycle initiates an abortive infection that triggers tumor cells to undergo apoptosis.…”

p14ARF Triggers G2 Arrest Through ERK-Mediated Cdc25C Phosphorylation, Ubiquitination and Proteasomal Degradation

“…Downregulation of Cdc25C has been previously reported in response to UVB exposure, 38 γ radiations, 39 BRCA1 expression 34 or infection by adenovirus 40 and related either with a decrease of transcription 39 or a proteasomal degradation. 22,34,40 Interestingly, Singh and colleagues recently proposed that serine 216 could control Cdc25C stability. 22 Consistent with such idea, we demonstrate that phosphorylation at serine 216 by active ERK1/2 targets Cdc25C for ubiquitination and further proteasomal degradation in response to p14 ARF .…”

In situ Detection of Specific DNA Double Strand Breaks using Rolling Circle Amplification

“…Both results suggest that infection with these DNA viruses induces a DNA damage response, as has also been observed for other DNA viruses. 22,23 Adenovirus has a linear double-stranded DNA genome. It is possible that infected cells sense large amounts of exogenous viral DNA as DSBs, thus activating the response pathway, including the phosphorylation of histone H2AX.…”