title: Codon 249 of the human TP53 tumor suppressor gene is no hot spot for aflatoxin B1 in a heterologous background.
abstract: Mutations in the TP53 tumor suppressor gene are the most common alteration in cancer, and human primary liver cancers related to previous dietary exposure to the mycotoxin aflatoxin B1 (AFB1) exhibit a specific hot spot mutation at TP53 codon 249. We have asked whether the 249 hot spot is related to a particular susceptibility to AFB1 of this TP53 region or whether it is related to a phenotype of the 249S p53 mutant protein. This was addressed by constructing a metabolically competent variant of Saccharomyces cerevisiae strain yIG397 expressing human cytochrome P450 1A2 and P450-reductase and isolating AFB1-induced mutants that failed to express the genomic ADE2 reporter gene. Molecular analysis revealed that only 8/40 mutants had a mutation in the TP53 target gene, whereas 32/40 mutants were due to a recombination event eliminating the ADE2 reporter gene. None of 19 mutations identified in the eight mutant TP53 plasmids altered codon 249, thus this codon was no hot spot if the TP53 gene was in the heterologous background yeast. The genotoxic action of AFB1 was completely different from that of the alkylating agent ethyl-methane-sulfonate, where 28/30 induced mutations were linked to the TP53 target gene.
authors.affiliation: Department of Genetics, Institute of Toxicology, Swiss Federal Institute of Technology, Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland. sengstag@diz.ethz.ch
authors.forename: C
authors.initials: C
authors.lastname: Sengstag
authors.forename: J L
authors.initials: JL
authors.lastname: Mörbe
authors.forename: B
authors.initials: B
authors.lastname: Weibel
mesh_terms: D016604:Aflatoxin B1 / Q000235:genetics / Q000633:toxicity*; D002262:Carboxy-Lyases / Q000235:genetics; D003001:Cloning, Molecular; D003062:Codon / Q000235:genetics* / Q000378:metabolism; D005020:Ethyl Methanesulfonate / Q000633:toxicity; D016147:Genes, Tumor Suppressor / Q000235:genetics*; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D016296:Mutagenesis / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D003062:Codon; D005020:Ethyl Methanesulfonate; D016604:Aflatoxin B1; D002262:Carboxy-Lyases; C022378:phosphoribosylaminoimidazole carboxylase