Mutant p53 increases radioresistance in rat embryo fibroblasts simultaneously transfected with HPV16-E7 and/or activated H-ras.
Recently, it has been suggested that abrogation of the wild type p53 protein function may alter the cellular response to DNA damaging agents, including ionizing radiation. This study was designed to compre the relative radiosensitivity and tumorigenicity of rat embryo fibroblast (REF) cell lines transfected with a mutant form of the p53 gene (plasmid MTp53pro193), alone, or in combination, with the H-ras (plasmid pEJ6.6) and HPV16-E7 (plasmid pJ4 omega 16.E7) oncogenes. Transfection of the mutant p53pro193 gene alone resulted in selected clones having increased radioresistance in culture which correlated with increased mutant p53 expression in these clones. However, the co-transfection of mutant p53 and H-ras genes or triple transfection of mutant p53, H-ras and E7 genes resulted in clones with high mutant p53 expression, significantly increased radioresistance and uniform tumorigenicity. There was no correlation between intrinsic radioresistance and spontaneous metastasis in the tumorigenic REF transfectant clones. Stepwise acquisition of radioresistance and an aggressive tumor cell phenotype is observed when the mutant p53 gene and HPV E7 co-operate with the ras oncogene in transfection assays, and can be correlated to increases in mutant p53 expression.
Bristow
R G
RG
Department of Radiation Oncology and Research (Division of Experimental Therapeutics, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Canada.
Jang
A
A
Peacock
J
J
Chung
S
S
Benchimol
S
S
Hill
R P
RP
D000818:Animals; D002470:Cell Survival; D005347:Fibroblasts; D016158:Genes, p53; D011905:Genes, ras; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009374:Neoplasms, Experimental / Q000209:etiology; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D016283:Proto-Oncogene Proteins p21(ras) / Q000032:analysis; D011836:Radiation Tolerance; D051381:Rats; D011916:Rats, Inbred F344; D014162:Transfection
D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D016283:Proto-Oncogene Proteins p21(ras)