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

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

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  • Medientyp: E-Artikel
  • Titel: Porcine model elucidates function of p53 isoform in carcinogenesis and reveals novel circTP53 RNA
  • Beteiligte: Niu, Guanglin; Hellmuth, Isabel; Flisikowska, Tatiana; Pausch, Hubert; Rieblinger, Beate; Carrapeiro, Alexander; Schade, Benjamin; Böhm, Brigitte; Kappe, Eva; Fischer, Konrad; Klinger, Bernhard; Steiger, Katja; Burgkart, Reiner; Bourdon, Jean-Christophe; Saur, Dieter; Kind, Alexander; Schnieke, Angelika; Flisikowski, Krzysztof
  • Erschienen: Springer Science and Business Media LLC, 2021
  • Erschienen in: Oncogene
  • Sprache: Englisch
  • DOI: 10.1038/s41388-021-01686-9
  • ISSN: 0950-9232; 1476-5594
  • Schlagwörter: Cancer Research ; Genetics ; Molecular Biology
  • Entstehung:
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>Recent years have seen an increasing number of genetically engineered pig models of human diseases including cancer. We previously generated pigs with a modified <jats:italic>TP53</jats:italic> allele that carries a Cre-removable transcriptional stop signal in intron 1, and an oncogenic mutation <jats:italic>TP53</jats:italic><jats:sup><jats:italic>R167H</jats:italic></jats:sup> (orthologous to human <jats:italic>TP53</jats:italic><jats:sup><jats:italic>R175H</jats:italic></jats:sup>) in exon 5. Pigs with the unrecombined mutant allele (fl<jats:italic>TP53</jats:italic><jats:sup><jats:italic>R167H</jats:italic></jats:sup>) develop mainly osteosarcoma but also nephroblastomas and lymphomas. This observation suggested that <jats:italic>TP53</jats:italic> gene dysfunction is itself the key initiator of bone tumorigenesis, but raises the question which aspects of the <jats:italic>TP53</jats:italic> regulation lead to the development of such a narrow tumour spectrum. Molecular analysis of p53 revealed the presence of two internal <jats:italic>TP53</jats:italic> promoters (Pint and P2) equivalent to those found in human. Consequently, both pig and human express <jats:italic>TP53</jats:italic> 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 <jats:italic>circTP53</jats:italic> determine the tumour spectrum and play a critical role in the malignant transformation in fl<jats:italic>TP53</jats:italic><jats:sup><jats:italic>R167H</jats:italic></jats:sup> 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 <jats:italic>TP53</jats:italic>. Considering the similarities of <jats:italic>TP53</jats:italic> regulation between pig and human, these observations provide useful pointers for further investigation into isoform function including the novel <jats:italic>circTP53</jats:italic> in both the pig model and human patients.</jats:p>