title: p53 transdominance but no gain of function in mouse brain tumor model.
abstract: Although p53 mutations in tumors typically result in loss of transactivation of p53 target genes some mutants display gain-of-function activity. The latter has important implications for the design of rational cancer therapy. We previously described a germ-line p53 mutation (deletion of codon 236, Y236delta) associated with a familial brain tumor syndrome. To determine whether this tissue-specific tumor predisposition reflects a gain-of-function activity of Y236delta or an effect of genetic background we have developed a mouse brain tumor model. Primary neuroectodermal cells deficient for p53 (+/- or -/-) and transduced with Y236delta using a retroviral vector were transplanted into the brain of adult wild-type mice. This neurografting paradigm circumvents the problem of early lethal tumors at extracerebral sites associated with germ-line p53 deficiency. Brain tumors arising in this mouse model were highly invasive, reflecting an important feature of the human disease. Tumors arose from p53+/- cells only when transduced with Y236delta. In keeping with in vitro data showing that Y236delta has dominant-negative activity, these tumors retained the endogenous wild-type p53 allele but accumulated high levels of Y236delta. However, the presence of Y236delta in transplanted p53-/- cells had no effect on the tumor frequency, 15% versus 27% without the mutant. In conclusion, Y236delta is transdominant but exerts no gain-of-function activity mediating a more penetrant tumor phenotype.
authors.affiliation: Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Monika.Hegi@chuv.hospvd.ch
authors.forename: M E
authors.initials: ME
authors.lastname: Hegi
authors.forename: M A
authors.initials: MA
authors.lastname: Klein
authors.forename: D
authors.initials: D
authors.lastname: Rüedi
authors.forename: P
authors.initials: P
authors.lastname: Chène
authors.forename: M F
authors.initials: MF
authors.lastname: Hamou
authors.forename: A
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D000483:Alleles; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005260:Female; D005799:Genes, Dominant; D016158:Genes, p53 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D010957:Plasmids; D011233:Precipitin Tests; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53