title: Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome.
abstract: Individuals with Li-Fraumeni syndrome carry inherited mutations in the p53 tumor suppressor gene and are predisposed to tumor development. To examine the mechanistic nature of these p53 missense mutations, we generated mice harboring a G-to-A substitution at nucleotide 515 of p53 (p53+/515A) corresponding to the p53R175H hot spot mutation in human cancers. Although p53+/515A mice display a similar tumor spectrum and survival curve as p53+/- mice, tumors from p53+/515A mice metastasized with high frequency. Correspondingly, the embryonic fibroblasts from the p53515A/515A mutant mice displayed enhanced cell proliferation, DNA synthesis, and transformation potential. The disruption of p63 and p73 in p53-/- cells increased transformation capacity and reinitiated DNA synthesis to levels observed in p53515A/515A cells. Additionally, p63 and p73 were functionally inactivated in p53515A cells. These results provide in vivo validation for the gain-of-function properties of certain p53 missense mutations and suggest a mechanistic basis for these phenotypes.
authors.affiliation: Department of Molecular Genetics, Section of Cancer Genetics, The University of Texas MD Anderson Cancer Center and The University of Texas Graduate School of Biomedical Sciences, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Gene A
authors.initials: GA
authors.lastname: Lang
authors.forename: Tomoo
authors.initials: T
authors.lastname: Iwakuma
authors.forename: Young-Ah
authors.initials: YA
authors.lastname: Suh
authors.forename: Geng
authors.initials: G
authors.lastname: Liu
authors.forename: V Ashutosh
authors.initials: VA
authors.lastname: Rao
authors.forename: John M
authors.initials: JM
authors.lastname: Parant
authors.forename: Yasmine A
authors.initials: YA
authors.lastname: Valentin-Vega
authors.forename: Tamara
authors.initials: T
authors.lastname: Terzian
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Caldwell
authors.forename: Louise C
authors.initials: LC
authors.lastname: Strong
authors.forename: Adel K
authors.initials: AK
authors.lastname: El-Naggar
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004261:DNA Replication / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D016158:Genes, p53 / Q000235:genetics* / Q000502:physiology; D016864:Li-Fraumeni Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; C000606460:TP73 protein, human; D015534:Trans-Activators; C486419:Trp63 protein, mouse; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins