Is p53 haploinsufficient for tumor suppression? Implications for the p53+/- mouse model in carcinogenicity testing.
The p53 tumor suppressor gene has been shown to be critical in preventing cancer in humans and mice. We have generated and extensively characterized p53-deficient mice lacking one (p53+/-) or both (p53-/-) p53 alleles. The p53-deficient mice are much more susceptible to an array of different tumor types than their wild-type (p53+/+) littermates. The enhanced tumor susceptibility of the p53+/- mice has made them one of several transgenic mouse models that are being considered as substitutes for standard 2-year rodent carcinogenicity assays. In order to fully exploit this model, it will be important to understand some of the basic biological and molecular mechanisms that underlie its enhanced tumor susceptibility. With this in mind, we have explored the fate of the remaining wild-type p53 allele in spontaneously arising p53+/- tumors and have shown that over half of these tumors retain an intact, functional wild-type p53 allele. This suggests that p53 is haploinsufficient for tumor suppression and that mere reduction in p53 dosage is sufficient to promote cancer formation. To support the idea that p53 is indeed a haploinsufficient tumor suppressor, we show here that normal p53+/- cells exhibit reduced parameters of growth control and stress response compared to their p53+/- counterparts. We hypothesize that the reduced p53 dosage in the p53+/- cells provides an environment more conducive to the development of further oncogenic lesions and the initiation of a tumor. Finally, we have assessed p53 loss of heterozygosity (LOH) in carcinogen-induced p53+/- tumors and have found that some agents induce tumors that almost invariably exhibit p53 LOH, whereas other agents induce tumors that often retain the wild-type p53 allele. Our preliminary data suggest that LOH is dependent on both the mechanism of genotoxicity of the agent utilized and the tissue type targeted.
Venkatachalam
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S
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
Tyner
S D
SD
Pickering
C R
CR
Boley
S
S
Recio
L
L
French
J E
JE
Donehower
L A
LA
D000826:Animal Testing Alternatives; D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods*; D002273:Carcinogens / Q000633:toxicity*; D018628:Gene Dosage; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D005838:Genotype; D019656:Loss of Heterozygosity; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009153:Mutagens / Q000633:toxicity*; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics
D002273:Carcinogens; D009153:Mutagens