The p53-mediated G1 checkpoint is retained in tumorigenic rat embryo fibroblast clones transformed by the human papillomavirus type 16 E7 gene and EJ-ras.
Rat embryo fibroblast clones transformed with the human papillomavirus type 16 E7 gene and the H-ras oncogene (ER clones) fall into two groups on the basis of endogenous p53 genotype, wild type or mutant. We have compared these clones with the aim of indentifying physiological differences that could be attributed to p53 protein function. We show that all ER clones, regardless of p53 gene status, are tumorigenic and metastatic in severe combined immunodeficiency mice. We demonstrate that only the wild-type p53 protein expressed in ER clones is functional on the basis of its site-specific double-stranded DNA-binding activity and its ability to confer a G1 delay on cells following treatment with ionizing radiation. These data indicate that disruption of the p53 growth-regulatory pathway is not a prerequisite for the malignant conversion of rat embryo fibroblasts expressing the E7 gene and mutant ras. Differences in phenotype that were correlated with loss of p53 protein function included the following: serum-independent growth of ER clones in culture, decreased tumor doubling time in vivo, and increased radioresistance. In addition, we demonstrate the p53-dependent G1 checkpoint alone does not determine radiosensitivity.
Peacock
J W
JW
Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Canada.
Chung
S
S
Bristow
R G
RG
Hill
R P
RP
Benchimol
S
S
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002453:Cell Cycle / Q000528:radiation effects; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic; D002999:Clone Cells; D016384:Consensus Sequence; D004622:Embryo, Mammalian; D005347:Fibroblasts; D005434:Flow Cytometry; D016193:G1 Phase / Q000502:physiology*; D005720:Gamma Rays; D016158:Genes, p53; D011905:Genes, ras; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis / Q000473:pathology; D009368:Neoplasm Transplantation; D009838:Oligodeoxyribonucleotides; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D027383:Papillomaviridae / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D051381:Rats; D014157:Transcription Factors / Q000235:genetics; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D009838:Oligodeoxyribonucleotides; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16