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

Cell Rep 2018 10;25(4):1027-1039.e6

Department I of Internal Medicine, University Hospital Cologne, Weyertal 115b, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Straße 26, 50931 Cologne, Germany; Center for Molecular Medicine, University Hospital Cologne, Robert Koch Straße 21, 50931 Cologne. Electronic address:

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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https://linkinghub.elsevier.com/retrieve/pii/S22111247183153
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http://dx.doi.org/10.1016/j.celrep.2018.09.079DOI Listing
October 2018
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