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

Guanglin Niu, Isabel Hellmuth, Tatiana Flisikowska, Hubert Pausch, Beate Rieblinger, Alexander Carrapeiro, Benjamin Schade, Brigitte Böhm, Eva Kappe, Konrad Fischer, Bernhard Klinger, Katja Steiger, Reiner Burgkart, Jean-Christophe Bourdon, Dieter Saur, Alexander Kind, Angelika Schnieke, Krzysztof Flisikowski (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)
4 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)1896-1908
Number of pages13
JournalOncogene
Volume40
Early online date18 Feb 2021
DOIs
Publication statusPublished - 10 Mar 2021

Keywords

  • Bone cancer
  • Gene regulation

Fingerprint

Dive into the research topics of 'Porcine model elucidates function of p53 isoform in carcinogenesis and reveals novel circTP53 RNA'. Together they form a unique fingerprint.

Cite this