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Cdk2 and Cdk4 Activities Are Dispensable for Tumorigenesis Caused by the Loss of p53

机译：Cdk2和Cdk4活性对于p53丢失引起的肿瘤发生是必不可少的

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The loss of p53 induces spontaneous tumors in mice, and p53 mutations are found in approximately 50% of human tumors. These tumors are generally caused by a number of events, including genomic instability, checkpoint defects, mitotic defects, deregulation of transcriptional targets, impaired apoptosis, and G1 deregulation or a combination of these effects. In order to determine the role of proteins involved in G1 control in tumorigenesis, we focused on Cdk2 and Cdk4, two cyclin-dependent kinases that in association with cyclin E and cyclin D promote the G1/S phase transition. We analyzed the consequence of loss of Cdk2 in p53-null animals by generating Cdk2?/? p53?/? mice. These mice are viable and developed spontaneous tumors, predominantly lymphoblastic lymphomas, similar to p53?/? mice. In contrast, the genotypes Cdk4?/? p53?/? were mostly lethal, with few exceptions, and Cdk2?/? Cdk4?/?p53?/? mice die during embryogenesis at embryonic day 13.5. To study the oncogenic potential, we generated mouse embryonic fibroblasts (MEFs) and found that p53?/?, Cdk2?/? p53?/?, Cdk4?/? p53?/?, and Cdk2?/? Cdk4?/? p53?/? MEFs grew at similar rates without entering senescence. Ras-transformed MEFs of these genotypes were able to form colonies in vitro and induce tumors in nude mice. Our results suggest that tumorigenicity mediated by p53 loss does not require either Cdk2 or Cdk4, which necessitates considering the use of broad-spectrum cell cycle inhibitors as a means of effective anti-Cdk cancer therapy.
机译：p53的缺失会诱发小鼠自发性肿瘤，在约50％的人类肿瘤中发现p53突变。这些肿瘤通常是由许多事件引起的，包括基因组不稳定性，检查点缺陷，有丝分裂缺陷，转录靶标失调，细胞凋亡受损以及G 1 失调或这些作用的组合。为了确定参与G 1 调控的蛋白在肿瘤发生中的作用，我们集中于Cdk2和Cdk4，这两种细胞周期蛋白依赖性激酶与细胞周期蛋白E和细胞周期蛋白D结合，促进G 1 / S相变。我们通过产生 Cdk2 ？ / ？ 来分析p53无效动物中Cdk2丢失的后果。 p53 ？ / ？小鼠。这些小鼠是存活且自发的肿瘤，主要是淋巴母细胞淋巴瘤，类似于 p53 ？ / ？小鼠。相比之下， Cdk4 ？ / ？ p53 ？< / sup> / ？大多具有致命性，只有少数例外，而 Cdk2 ？ / ？ Cdk4 ？ / ？ p53 ？ / ？小鼠在胚胎第13.5天的胚胎发生过程中死亡。为了研究致癌潜力，我们生成了小鼠胚胎成纤维细胞（MEF），发现 p53 ？ / ？， Cdk2 ？ / ？ p53 ？ / ？， Cdk4 ？ / ？ p53 ？ / ？和 Cdk2 ？ / ？ Cdk4 ？ / ？ p53 < / em> ？ / ？ MEF的生长速率相似，但未进入衰老状态。这些基因型的经Ras转化的MEF能够在体外形成集落并在裸鼠中诱发肿瘤。我们的结果表明，由p53缺失介导的致癌性不需要Cdk2或Cdk4，因此有必要考虑使用广谱细胞周期抑制剂作为有效的抗Cdk癌症疗法的手段。

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