The Cdkn1a Mouse as a Tool to Study p53-Mediated Tumor Suppression

Torgovnick A, Heger JM, Liaki V, Isensee J, Schmitt A, Knittel G, Riabinska A, Beleggia F, Laurien L, Leeser U, Jüngst C, Siedek F, Vogel W, Klümper N, Nolte H, Wittersheim M, Tharun L, Castiglione R, Krüger M, Schauss A, Perner S, Pasparakis M, Büttner R, Persigehl T, Hucho T, Herter-Sprie GS, Schumacher B, Reinhardt HC

Cell Rep 2018 Oct;25(4):1027-1039.e6

PMID: 30355482

Abstract

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 Cdkn1a 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 Cdkn1a mice display a cancer protection phenotype that is indistinguishable from that observed in Tp53 animals. Moreover, we demonstrate that Tp53 and Cdkn1a cooperate in mediating cancer resistance, using a chemically induced fibrosarcoma model. Overall, our Cdkn1a allele enabled us to assess the contribution of Cdkn1a to Tp53-mediated tumor suppression.

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