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p53 Transdominance But No Gain of Function in Mouse Brain Tumor Model¹

Laboratory of Tumor Biology and Genetics, Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland [M. E. H., M-F. H.], Institute of Neuropathology, University Hospital of Zurich, 8091 Zurich, Switzerland [M. E. H., M. A. K., D. R., A. A.], and Oncology Department, Novartis, 4002 Basel, Switzerland [P. C.]

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, Y236) associated with a familial brain tumor syndrome. To determine whether this tissue-specific tumor predisposition reflects a gain-of-function activity of Y236 or an effect of genetic background we have developed a mouse brain tumor model. Primary neuroectodermal cells deficient for p53 (+/- or -/-) and transduced with Y236 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 Y236. In keeping with in vitro data showing that Y236 has dominant-negative activity, these tumors retained the endogenous wild-type p53 allele but accumulated high levels of Y236. However, the presence of Y236 in transplanted p53^-/- cells had no effect on the tumor frequency, 15% versus 27% without the mutant. In conclusion, Y236 is transdominant but exerts no gain-of-function activity mediating a more penetrant tumor phenotype.