학술논문
The Cdkn1aSUPERMouse as a Tool to Study p53-Mediated Tumor Suppression
Document Type
Article
Author
Torgovnick, Alessandro; Heger, Jan Michel; Liaki, Vasiliki; Isensee, Jörg; Schmitt, Anna; Knittel, Gero; Riabinska, Arina; Beleggia, Filippo; Laurien, Lucie; Leeser, Uschi; Jüngst, Christian; Siedek, Florian; Vogel, Wenzel; Klümper, Niklas; Nolte, Hendrik; Wittersheim, Maike; Tharun, Lars; Castiglione, Roberta; Krüger, Marcus; Schauss, Astrid; Perner, Sven; Pasparakis, Manolis; Büttner, Reinhard; Persigehl, Thorsten; Hucho, Tim; Herter-Sprie, Grit Sophie; Schumacher, Björn; Reinhardt, Hans Christian
Source
Cell Reports; October 2018, Vol. 25 Issue: 4 p1027-1039.e6
Subject
Language
ISSN
22111247
Abstract
Cdkn1a, which encodes p21, functions as a major route for p53-mediated cell-cycle arrest. However, the consequence of Cdkn1agene dosage on tumor suppression has not been systematically investigated. Here, we employed BAC transgenesis to generate a Cdkn1aSUPERmouse, which harbors an additional Cdkn1aallele 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 Cdkn1aSUPERmice display a cancer protection phenotype that is indistinguishable from that observed in Tp53SUPERanimals. Moreover, we demonstrate that Tp53and Cdkn1acooperate in mediating cancer resistance, using a chemically induced fibrosarcoma model. Overall, our Cdkn1aSUPERallele enabled us to assess the contribution of Cdkn1ato Tp53-mediated tumor suppression.