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Am J Pathol. 2011 Oct;179(4):1616-22. doi: 10.1016/j.ajpath.2011.06.036. Epub 2011 Aug 18.

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

Author information

  • 1Hubrecht Institute for Developmental Biology and Stem Cell Research, Cancer Genomics Center, KNAW and University Medical Center Utrecht, Utrecht, The Netherlands.

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.

Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

PMID:
21854749
[PubMed - indexed for MEDLINE]
PMCID:
PMC3181367
Free PMC Article

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