Low levels of p53 are associated with resistance to tetrachlorodibenzo-p-dioxin toxicity in DBA/2 mice.
We show here that DBA/2 strain mice have a complex mutation/polymorphism in the promoter region of the Trp53 locus (the mouse p53 locus). This region has previously been shown to be essential for p53 expression. We further show that the DBA/2 mutation is associated with approximately fourfold lower p53 levels in thymocytes treated with the DNA-damaging agent etoposide in-vitro, and with relative resistance of these thymocytes to apoptosis induced by the DNA-damaging agent etoposide compared with C57BL/6 mice. When part of the promoter containing this mutation was inserted into a plasmid containing a luciferase reporter gene but lacking eukaryote promoter sequences and transfected into MCF-7 human breast cell line cells, the mean luciferase activity was slightly less with the DBA/2 than with the C57BL/6 promoter-reporter construct (p < 0.01). We found that DBA/2xC57BL/6 F2 hybrid mice with the DBA/2 genotype at the Trp53 locus were relatively resistant to tetrachlorodibenzo-p-dioxin toxicity, and this resistance was additive with resistance associated with the Ahr locus. DBA/2 mice are long-lived and do not have particularly high levels of cancer, suggesting either that they carry other compensatory tumour resistance alleles (such as Ahr(d)), or that, while there may be a p53 protein dosage effect for acute toxicity, lower than normal levels of p53 may still be sufficient to protect against cancer. In evolutionary terms, it may be better to maintain low levels of p53 in order to avoid death from acute toxicity, even at the expense of a higher incidence of cancer in later life.
Yang
A L
AL
MRC Toxicology Unit, University of Leicester, UK.
Smith
A G
AG
Akhtar
R
R
Clothier
B
B
Robinson
S
S
MacFarlane
M
M
Festing
M F
MF
D000818:Animals; D001483:Base Sequence; D001835:Body Weight / Q000187:drug effects; D004247:DNA; D005047:Etoposide / Q000494:pharmacology; D016158:Genes, p53; D005838:Genotype; D006720:Homozygote; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009929:Organ Size / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000072317:Polychlorinated Dibenzodioxins; D005047:Etoposide; D004247:DNA