The Cdkn1aSUPER Mouse as a Tool to Study p53-Mediated Tumor Suppression
| Autor: | Filippo Beleggia, Hendrik Nolte, Niklas Klümper, Vasiliki Liaki, Hans Christian Reinhardt, Lars Tharun, Alessandro Torgovnick, Florian Siedek, Sven Perner, Jörg Isensee, Jan Michel Heger, Lucie Laurien, Gero Knittel, Maike Wittersheim, Reinhard Büttner, Anna Schmitt, Manolis Pasparakis, Arina Riabinska, Uschi Leeser, Wenzel Vogel, Christian Jüngst, Roberta Castiglione, Thorsten Persigehl, Grit Herter-Sprie, Tim Hucho, Astrid Schauss, Björn Schumacher, Marcus Krüger |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Context (language use) Biology medicine.disease Phenotype General Biochemistry Genetics and Molecular Biology Transgenesis 03 medical and health sciences 030104 developmental biology 0302 clinical medicine lcsh:Biology (General) Apoptosis 030220 oncology & carcinogenesis medicine Cancer research Adenocarcinoma Allele Fibrosarcoma lcsh:QH301-705.5 |
| Zdroj: | Cell Reports, Vol 25, Iss 4, Pp 1027-1039.e6 (2018) |
| ISSN: | 2211-1247 |
| Popis: | Summary: Cdkn1a, which encodes p21, functions as a major route for p53-mediated cell-cycle arrest. However, the consequence of Cdkn1a gene dosage on tumor suppression has not been systematically investigated. Here, we employed BAC transgenesis to generate a Cdkn1aSUPER mouse, which harbors an additional Cdkn1a allele within its natural genomic context. We show that these mice display enhanced cell-cycle arrest and reduced apoptosis in response to genotoxic stress. Furthermore, using a chemically induced skin cancer model and an autochthonous Kras-driven lung adenocarcinoma model, we show that Cdkn1aSUPER mice display a cancer protection phenotype that is indistinguishable from that observed in Tp53SUPER animals. Moreover, we demonstrate that Tp53 and Cdkn1a cooperate in mediating cancer resistance, using a chemically induced fibrosarcoma model. Overall, our Cdkn1aSUPER allele enabled us to assess the contribution of Cdkn1a to Tp53-mediated tumor suppression. : Torgovnick et al. create a mouse model, carrying a third copy of Cdkn1a (p21), which shows enhanced cell-cycle arrest capacity and protection against DNA damage-induced apoptosis. The Cdkn1aSUPER animals display delayed epithelial regeneration and a robust cancer resistance phenotype, highlighting the importance of p21 in p53-dependent tumor suppression. Keywords: Cdkn1a, p21, p53, mouse model, cancer, tumor suppressor, cell cycle arrest, apoptosis, cancer protection |
| Databáze: | OpenAIRE |
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