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Abstract
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 TP53R167H (orthologous to human TP53R175H) in exon 5. Pigs with the unrecombined mutant allele (flTP53R167H) 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 flTP53R167H 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.
Highlights
In human, osteosarcomas (OS) is the major form of primary bone cancer [1]
Since our publication describing the generation of flTP53R167H pigs [20], a total of 29 flTP53R167H/+ heterozygous and 10 flTP53R167H/R167H homozygous pigs were examined by necropsy
The study of p53 isoforms and its involvement in tumorigenesis had been hampered by the fact that the main experimental mammal, the mouse, lacks internal P2 promoter activity [8]
Summary
Osteosarcomas (OS) is the major form of primary bone cancer [1]. It predominantly affects young people and is highly malignant, requiring aggressive surgical resection and cytotoxic chemotherapy [2]. The role of TP53 mutations in numerous cancers has been extensively documented [6]. Potentially important aspects of TP53 gene function still remain unclear, including the role of various p53 isoforms. Human TP53 is known to express at least 9 different mRNA transcripts [7] and at least 12 protein isoforms [8], with transcription initiated by two promoters: P1 at the 5’ end and P2 in intron 4; alternative splicing across introns 2 and 9; and alternative translation initiated at internal start codons 40, 133 and 160. The internal promoter P2 originates the Δ133p53 and Δ160p53 isoforms in humans. While the function of Δ160p53 is less studied, the Δ133p53 is involved in the regulation of replicative cellular senescence [9], angiogenesis, cytokine secretion/immune response and tumour progression in some cancer types [10]
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