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Genetic mechanisms of tumor suppression by the human p53 gene
P L Chen1, Y M Chen, R Bookstein
1Department of Pathology, School of Medicine, University of California, San Diego, La Jolla 92093-0612.
Abstract:
Mutations of the gene encoding p53, a 53-kilodalton cellular protein, are found frequently in human tumor cells, suggesting a crucial role for this gene in human oncogenesis. To model the stepwise mutation or loss of both p53 alleles during tumorigenesis, a human osteosarcoma cell line, Saos-2, was used that completely lacked endogenous p53. Single copies of exogenous p53 genes were then introduced by infecting cells with recombinant retroviruses containing either point-mutated or wild-type versions of the p53 cDNA sequence. Expression of wild-type p53 suppressed the neoplastic phenotype of Saos-2 cells, whereas expression of mutated p53 conferred a limited growth advantage to cells in the absence of wild-type p53. Wild-type p53 was phenotypically dominant to mutated p53 in a two-allele configuration. These results suggest that, as with the retinoblastoma gene, mutation of both alleles of the p53 gene is essential for its role in oncogenesis.
Insights
Mutations in the p53 gene are common in human tumors. Both p53 gene copies must be inactivated for cancer development, similar to the retinoblastoma gene.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- The p53 gene, encoding a 53-kilodalton protein, is frequently mutated in human tumors.
- These mutations suggest a critical role for p53 in human oncogenesis.
Purpose of the Study:
- To model the stepwise mutation or loss of both p53 alleles during tumorigenesis.
- To investigate the functional consequences of wild-type versus mutated p53 expression.
Main Methods:
- Utilized a human osteosarcoma cell line (Saos-2) lacking endogenous p53.
- Introduced single copies of exogenous p53 genes (wild-type and point-mutated) via recombinant retroviruses.
Main Results:
- Wild-type p53 expression suppressed the neoplastic phenotype of Saos-2 cells.
- Mutated p53 conferred a limited growth advantage in the absence of wild-type p53.
- Wild-type p53 demonstrated phenotypic dominance over mutated p53 in a two-allele system.
Conclusions:
- Inactivation of both p53 alleles appears essential for its role in oncogenesis.
- This mechanism parallels the tumor suppressor function observed for the retinoblastoma gene.