Abstract
SUMMARYThe 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 lived an average of 126 days before death or removal from study because of clinical signs of abnormality or formation of tumors. Half of Tp53Δ11/+ were removed from study by 1 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 that this mutant rat line will be useful in studying cancer types rarely observed in mice and in carcinogenicity assays for drug development.
Highlights
The TP53 protein is indispensible for genomic integrity, the name ‘the guardian of the genome’ (Lane, 1992)
zinc finger nucleases (ZFNs) validation The TP53 ZFN target site is shown in supplementary material Fig. S1A
Activity was validated by the presence of genome modifications with a mutation detection assay in cells transfected with mRNA encoding for ZFN but not in cells transfected with a GFP-expressing plasmid as a negative control
Summary
The TP53 protein is indispensible for genomic integrity, the name ‘the guardian of the genome’ (Lane, 1992). Somatic mutations in the TP53 gene are responsible for the development of up to 50% of certain types of human cancer (Hollstein et al, 1991; Olivier et al, 2010). In the past three decades, various Trp loss-of-function mouse models have been developed (Clarke and Hollstein, 2003), including gene disruptions (Donehower et al, 1992; Jacks et al, 1994), humanization of the DNA binding domain (Luo et al, 2001) and a variety of point mutations (Petitjean et al, 2007), demonstrating good correlation between decreased TP53 activity and increased incidences of tumor formation. Mouse models have been used widely, despite limitations such as the underrepresentation of certain cancer types compared with humans. New models involving other species are needed to complement mouse studies and to advance the search for cures for cancer
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