The Cdkn1aSUPER Mouse as a Tool to Study p53-Mediated Tumor Suppression

Cell Rep. 2018 Oct 23;25(4):1027-1039.e6. doi: 10.1016/j.celrep.2018.09.079.

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 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.

Keywords: Cdkn1a; apoptosis; cancer; cancer protection; cell cycle arrest; mouse model; p21; p53; tumor suppressor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Carcinogenesis / pathology
  • Cell Cycle Checkpoints
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Cytoprotection
  • DNA Damage
  • Drug Resistance, Neoplasm
  • Embryo, Mammalian / cytology
  • Epithelium / metabolism
  • Fibroblasts / metabolism
  • Gene Dosage
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Regeneration
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Tumor Suppressor Protein p53