Creation and preliminary characterization of a Tp53 knockout rat

Abstract

Summary The tumor suppressor TP53 plays a crucial role in cancer biology, and the TP53 gene is the most mutated gene in human cancer. Trp53 knockout mouse models have been widely used in cancer etiology studies and in search for a cure of cancer with some limitations that other model organisms might help overcome. Via pronuclear microinjection of zinc finger nucleases (ZFNs), we created a Tp53 knockout rat that contains an 11 bp deletion in exon 3, resulting in a frameshift and premature terminations in the open reading frame. In cohorts of 25 homozygous (Tp53Δ11/Δ11), 37 heterozygous (Tp53Δ11/+) and 30 wild type rats, the Tp53Δ11/Δ11 rats had an average life span of 126 daysbefore death or removal from study for clinical signs of abnormality or formation of tumors. Half of Tp53Δ11/+ were removed from study by one year of age because of tumor formation. Both Tp53Δ11/+ and Tp53Δ11/Δ11 rats developed a wide spectrum of tumors, most commonly sarcomas. Interestingly, there was a strikingly high incidence of brain lesions, especially in Tp53Δ11/Δ11 animals. We believe this mutant rat line will be useful in studying cancer types rarely observed in mice and in carcinogenicity assays for drug development.