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UV carcinogenesis
in heterozygous p53 knockout hairless mice; conversion to more malignant
tumors
van Kranen, Henk2,
Berg, Rob3, Westerman-de Vries, Anja2,
Rebel, Heggert1, Wester, Piet2
and de Gruijl, Frank1
Dermatology, Leiden Univ. Med. Ctr., Netherlands1
RIVM/Natl. Inst. for Health and the Environment, Netherlands2
Dermatolgy, Univ. med. Ctr. Utrecht, Netherlands3
Abstract-
Judging from its frequent mutation or loss in many types of cancers,
the p53 gene is a cellular Achilles' heel. Its product is
involved in various pathways that control the cell cycle, DNA repair
and apoptosis. In experimental UV carcinogenesis one allele is often
mutated while the other wildtype allele is still present. The (additional)
effect of allelic loss is not entirely clarified. Surprisingly, we found
that p53-mutant foci occurred earlier in heterozygous k.o. (p53+/-)
mice than in wildtypes (p53+/+), at both 1 MED and 0.5 MED/day,
in spite of the lack of one target allele in p53+/- cells. Correspondingly,
the tumors occurred significantly earlier in p53+/- mice (p<0.001,
t-median of 11 vs 14 weeks) at 1 MED/d, but not so much earlier at 0.5
MED/d (15 vs 16.5 weeks). Eventual tumor yields did , however, differ
significantly between p53+/- and p53+/+ mice at both dose
levels. Although the p53 mutations in the tumors showed the normal
UV hotspots, spindle cell carcinomas arose frequently in the p53+/-
mice; these tumors are hardly ever seen in wildtype hairless mice. These
data indicate that allelic loss may cause more rapid tumor induction
at high dosages (probably by weaker apoptotic responses), but not at
lower dosages. Allelic loss does, however, appear to have a dramatic
effect on conversion to malignancy, which may be due to a 'gain
of function' of mutated p53 in absence of wildtype p53.
Keywords: UV carcinogenesis,
p53+/- mice, p53 mutation, spindle cell carcinoma
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