Effect of high-risk human papillomavirus oncoproteins on p53R2 gene expression after DNA damage.
The p53R2 protein is a p53-inducible small subunit of ribonucleotide reductase. It plays a crucial role in p53-dependent cellular response to DNA damage and oxidative stress by providing deoxyribonucleotides (dNTPs) to the DNA repair machinery and by scavenging reactive oxygen species (ROS). To investigate the effects of high-risk human papillomavirus (HPV) oncoproteins on p53R2 expression after DNA damage, we analyzed the p53R2 protein levels in human cells ectopically expressing the HPV-16 E6 and E7 genes, and in the HPV-positive cancer cell lines SiHa, CaSki and HeLa, exposed to adriamycin or to H(2)O(2). We found that in normal cells, p53R2 expression is efficiently induced by both H(2)O(2) and adriamycin, supporting the role of p53R2 in cellular response to oxidative stress. Ectopic expression of E6 impaired p53 and p53R2 induction after DNA damage in human fibroblasts. Moreover, SiHa, CaSki and HeLa cells were unresponsive to H(2)O(2) exposure, and adriamycin induced p53R2 levels only in SiHa cells. Our results imply that high-risk HPV infection may suppress the p53R2-dependent dNTPs supply to the DNA repair system and the ROS scavenging activity; they also suggest that an altered p53R2 response to genotoxins and to oxidative stress may contribute to HPV-induced genetic instability and carcinogenesis.
Lembo
David
D
Department of Public Health and Microbiology, University of Turin, Via Santena 9, 10126 Turin, Italy. david.lembo@unito.it
Donalisio
Manuela
M
Cornaglia
Maura
M
Azzimonti
Barbara
B
Demurtas
Anna
A
Landolfo
Santo
S
D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D005347:Fibroblasts / Q000821:virology; D005786:Gene Expression Regulation; D052162:Human papillomavirus 16; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D016877:Oxidants / Q000494:pharmacology; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins / Q000502:physiology*; D012264:Ribonucleotide Reductases / Q000096:biosynthesis* / Q000235:genetics; D014161:Transduction, Genetic
D018797:Cell Cycle Proteins; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D016877:Oxidants; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D004317:Doxorubicin; D006861:Hydrogen Peroxide; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases