title: A functionally inactive p53 Li-Fraumeni syndrome mutant.
abstract: Germline mutations in the tumor-suppressor p53 have been recently identified in Li-Fraumeni syndrome patients. We analysed the function of one of these mutations, an arg-to-trp substitution at amino acid 245 in the murine p53 gene. This p53LFS mutant could not, unlike wild-type p53, suppress foci formation of rat embryo-fibroblasts. Like other p53 mutants it cooperated with activated ras to transform rat embryo fibroblasts. Overexpression of p53LFS thus resulted in a phenotype similar to other mutant p53s. The p53LFS protein was also transcriptionally inactive in contrast to previous studies using a p53LFS/GAL4 fusion protein. To better understand the functional domain disrupted in p53LFS, we developed a dimerization assay and showed that p53LFS still dimerized. In addition, p53LFS retained its ability to bind SV40 large T antigen and not hsc70, both characteristics of wild-type p53. Using immunofluorescence, we localized p53LFS to the nucleus. From these results we conclude that p53LFS represents an unusual p53 mutant in that it retains many characteristics of wild-type p53, however activities critical for growth suppression are lost.
authors.affiliation: Department of Molecular Genetics, University of Texas M. D. Anderson Cancer Center, Houston 77030.
authors.forename: M
authors.initials: M
authors.lastname: Hao
authors.forename: C A
authors.initials: CA
authors.lastname: Finlay
authors.forename: G
authors.initials: G
authors.lastname: Lozano
mesh_terms: D002467:Cell Nucleus / Q000737:chemistry; D003402:Creatine Kinase / Q000235:genetics; D004247:DNA / Q000378:metabolism; D016158:Genes, p53; D006367:HeLa Cells; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D009154:Mutation; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000737:chemistry
chemical_list: D016159:Tumor Suppressor Protein p53; D004247:DNA; D003402:Creatine Kinase