Loss of p53 or p73 in human papillomavirus type 38 E6 and E7 transgenic mice partially restores the UV-activated cell cycle checkpoints

We have previously shown that human keratinocytes expressing E6 and E7 from the cutaneous human papillomavirus (HPV) type 38 have high levels of a specific form of p53, which in turn activate the transcription of ΔNp73 gene. Expression of HPV38 E6 and E7 in mouse skin also promotes p53 and ΔNp73 accumulation. Interestingly, keratinocytes of these mice do not undergo cell cycle arrest after skin ultraviolet (UV) irradiation. Here, we provide several lines of evidence that ΔNp73 expression and lack of the UV response are directly linked. Loss of p53 gene in HPV38 E6/E7 transgenic mice abolished ΔNp73 expression and partially restored the UV-activated cell cycle checkpoints. Similarly, loss of p73, and consequently ΔNp73, led to restoration of the p53 pathways. In fact, keratinocytes of p73−/− HPV38 E6/E7 transgenic mice upon UV irradiation express high levels of p21WAF1 and are cell cycle arrested. Thus, HPV38 E6 and E7, via ΔNp73 accumulation, are able to alter the regulation of cell cycle checkpoints activated by UV radiation. These data suggest that UV and HPV may cooperate in skin carcinogenesis.