title: Homozygous and heterozygous p53 knockout rats develop metastasizing sarcomas with high frequency.
abstract: The TP53 tumor suppressor gene is mutated in the majority of human cancers. Inactivation of p53 in a variety of animal models results in early-onset tumorigenesis, reflecting the importance of p53 as a gatekeeper tumor suppressor. We generated a mutant Tp53 allele in the rat using a target-selected mutagenesis approach. Here, we report that homozygosity for this allele results in complete loss of p53 function. Homozygous mutant rats predominantly develop sarcomas with an onset of 4 months of age with a high occurrence of pulmonary metastases. Heterozygous rats develop sarcomas starting at 8 months of age. Molecular analysis revealed that these tumors exhibit a loss-of-heterozygosity of the wild-type Tp53 allele. These unique features make this rat highly complementary to other rodent p53 knockout models and a versatile tool for investigating tumorigenesis processes as well as genotoxic studies.
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, Cancer Genomics Center, KNAW and University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ruben
authors.initials: R
authors.lastname: van Boxtel
authors.forename: Raoul V
authors.initials: RV
authors.lastname: Kuiper
authors.forename: Pim W
authors.initials: PW
authors.lastname: Toonen
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: van Heesch
authors.forename: Roel
authors.initials: R
authors.lastname: Hermsen
authors.forename: Alain
authors.initials: A
authors.lastname: de Bruin
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D005260:Female; D055786:Gene Knockout Techniques; D016678:Genome / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009362:Neoplasm Metastasis; D051381:Rats; D011922:Rats, Mutant Strains; D012509:Sarcoma / Q000235:genetics* / Q000473:pathology*; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53