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Recent years have seen an increasing number of genetically engineered pig models of human diseases including cancer. We previously generated pigs with a modified  TP53  allele that carries a Cre-removable transcriptional stop signal in intron 1, and an oncogenic mutation  TP53   R167H   (orthologous to human  TP53   R175H  ) in exon 5. Pigs with the unrecombined mutant allele (fl TP53   R167H  ) develop mainly osteosarcoma but also nephroblastomas and lymphomas. This observation suggested that  TP53  gene dysfunction is itself the key initiator of bone tumorigenesis, but raises the question which aspects of the  TP53  regulation lead to the development of such a narrow tumour spectrum. Molecular analysis of p53 revealed the presence of two internal  TP53  promoters (Pint and P2) equivalent to those found in human. Consequently, both pig and human express  TP53  isoforms. Data presented here strongly suggest that P2-driven expression of the mutant R167H-Δ152p53 isoform (equivalent to the human R175H-Δ160p53 isoform) and its circular counterpart  circTP53  determine the tumour spectrum and play a critical role in the malignant transformation in fl TP53   R167H   pigs. The detection of Δ152p53 isoform mRNA in serum is indicative of tumorigenesis. Furthermore, we showed a tissue-specific p53-dependent deregulation of the p63 and p73 isoforms in these tumours. This study highlights important species-specific differences in the transcriptional regulation of  TP53 . Considering the similarities of  TP53  regulation between pig and human, these observations provide useful pointers for further investigation into isoform function including the novel  circTP53  in both the pig model and human patients.

Porcine model elucidates function of p53 isoform in carcinogenesis and reveals novel circTP53 RNA