p 53 Transdominance But No Gain of Function in Mouse Brain Tumor Model 1

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-linep53 mutation (deletion of codon 236, Y236D) associated with a familial brain tumor syndrome. To determine whether this tissue-specific tumor predisposition reflects a gain-of-function activity of Y236D or an effect of genetic background we have developed a mouse brain tumor model. Primary neuroectodermal cells deficient for p53 (1/2 or 2/2) and transduced with Y236Dusing 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-linep53 deficiency. Brain tumors arising in this mouse model were highly invasive, reflecting an important feature of the human disease. Tumors arose fromp53 cells only when transduced with Y236D. In keeping within vitro data showing that Y236D has dominant-negative activity, these tumors retained the endogenous wild-typep53allele but accumulated high levels of Y236D. However, the presence of Y236Din transplanted p53 cells had no effect on the tumor frequency, 15%versus27% without the mutant. In conclusion, Y236Dis transdominant but exerts no gain-of-function activity mediating a more penetrant tumor phenotype.