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Common tumour p53 mutations in immortalized cells from Hupki mice heterozygous at codon 72

Item Type:Article
Title:Common tumour p53 mutations in immortalized cells from Hupki mice heterozygous at codon 72
Creators Name:Reinbold, M. and Luo, J.L. and Nedelko, T. and Jerchow, B. and Murphy, M.E. and Whibley, C. and Wei, Q. and Hollstein, M.
Abstract:Codon 72 of human p53 gene is polymorphic, encoding arginine or proline. Here we report construction of a human p53 knock-in (Hupki) mouse encoding the codon 72(pro) variant. The new strain was crossed with the original Hupki mice (codon 72(arg/arg)) to obtain primary embryonic fibroblasts polymorphic at codon 72 or homozygous for codon 72(pro). The fibroblasts, cultured under standard conditions, immortalized within 12 weeks and acquired p53 mutations similarly to Hupki codon 72(arg/arg) cells investigated previously. Sequencing of human p53 exons 4-9 in immortalized cultures revealed missense mutations found repeatedly in human tumours. In cell lines ensuing from benzo(a)pyrene-treated cultures the combined p53 mutation pattern from experiments with the 3 codon 72 genotypes showed a predominance of strand-biased G to T transversions (18 of 36 mutations), and mutations recurring at smokers' lung tumour hotspot codons 157 and 273, supporting involvement of tobacco carcinogens in shaping the mutation signature in lung cancers of smokers. Mutations in cell lines from unexposed cultures did not cluster at these codons and G to T transversions were uncommon (2 of 52 mutations) (Fisher's exact test P<0.0001). Most mutations (13/16) in cell lines derived from cells polymorphic at codon 72 were found on the proline allele, with loss of the arginine allele.
Keywords:Lung Cancer, Mutation Hotspot, Embryonic Fibroblasts, Senescence, Polymorphism, Animals, Mice
Publisher:Nature Publishing Group (U.K.)
Page Range:2788-2794
Date:24 April 2008
Official Publication:https://doi.org/10.1038/sj.onc.1210932
PubMed:View item in PubMed

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