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 DeltaNp73 gene. Expression of HPV38 E6 and E7 in mouse skin also promotes p53 and DeltaNp73 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 DeltaNp73 expression and lack of the UV response are directly linked. Loss of p53 gene in HPV38 E6/E7 transgenic mice abolished DeltaNp73 expression and partially restored the UV-activated cell cycle checkpoints. Similarly, loss of p73, and consequently DeltaNp73, led to restoration of the p53 pathways. In fact, keratinocytes of p73-/- HPV38 E6/E7 transgenic mice upon UV irradiation express high levels of p21(WAF1) and are cell cycle arrested. Thus, HPV38 E6 and E7, via DeltaNp73 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.
Dong
W
W
International Agency for Research on Cancer, World Health Organization, Infections and Cancer Biology Group, Lyon, France.
Arpin
C
C
Accardi
R
R
Gissmann
L
L
Sylla
B S
BS
Marvel
J
J
Tommasino
M
M
D000818:Animals; D052686:Betapapillomavirus / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D016158:Genes, p53; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics*; D050725:Papillomavirus E7 Proteins / Q000235:genetics*; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics*; D014466:Ultraviolet Rays
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D050725:Papillomavirus E7 Proteins; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human