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; Institute for Genome Stability in Aging and Disease, Medical Faculty, University of Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany.
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.
Cell Rep. 2018 Oct 23;25(4):1027-1039.e6. doi: 10.1016/j.celrep.2018.09.079.
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.
Cdkn1a 基因编码 p21，是 p53 介导的细胞周期阻滞的主要途径。然而，Cdkn1a 基因剂量对肿瘤抑制的影响尚未系统研究。在这里，我们利用 BAC 转基因技术生成了一种 Cdkn1a 小鼠，其在天然基因组背景中携带额外的 Cdkn1a 等位基因。我们表明，这些小鼠在应对遗传毒性应激时表现出增强的细胞周期阻滞和减少的细胞凋亡。此外，我们使用化学诱导的皮肤癌模型和自发的 Kras 驱动的肺腺癌模型表明，Cdkn1a 小鼠表现出与 Tp53 动物观察到的相似的癌症保护表型。此外，我们使用化学诱导的纤维肉瘤模型证明，Tp53 和 Cdkn1a 合作介导癌症抵抗。总之，我们的 Cdkn1a 等位基因使我们能够评估 Cdkn1a 对 Tp53 介导的肿瘤抑制的贡献。
