Homozygous and heterozygous p53 knockout rats develop metastasizing sarcomas with high frequency

R. van Boxtel, R. Kuiper, P.W. Toonen, S. van Heesch, R. Hermsen, A. de Bruin, E. Cuppen

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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.
Original languageEnglish
Pages (from-to)1616-1622
JournalAmerican Journal of Pathology
Volume179
Issue number4
DOIs
Publication statusPublished - 2011

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