Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
Platform Bioinformatics and Biostatistics, University of Veterinary Medicine, Vienna, Austria.
Cancer Discov. 2018 Jul;8(7):884-897. doi: 10.1158/2159-8290.CD-17-0912. Epub 2018 Jun 13.
Tumor formation is a multistep process during which cells acquire genetic and epigenetic changes until they reach a fully transformed state. We show that CDK6 contributes to tumor formation by regulating transcriptional responses in a stage-specific manner. In early stages, the CDK6 kinase induces a complex transcriptional program to block p53 in hematopoietic cells. Cells lacking CDK6 kinase function are required to mutate (encoding p53) to achieve a fully transformed immortalized state. CDK6 binds to the promoters of genes including the p53 antagonists , and The findings are relevant to human patients: Tumors with low levels of CDK6 have mutations in significantly more often than expected. CDK6 acts at the interface of p53 and RB by driving cell-cycle progression and antagonizing stress responses. While sensitizing cells to p53-induced cell death, specific inhibition of CDK6 kinase activity may provoke the outgrowth of p53-mutant clones from premalignant cells. .
肿瘤形成是一个多步骤的过程，在此过程中细胞获得遗传和表观遗传改变，直到它们达到完全转化的状态。我们表明 CDK6 通过以特定阶段的方式调节转录反应来促进肿瘤形成。在早期阶段，CDK6 激酶诱导复杂的转录程序以阻止造血细胞中的 p53。缺乏 CDK6 激酶功能的细胞需要突变 (编码 p53) 以达到完全转化的永生化状态。CDK6 结合到包括 p53 拮抗剂在内的基因的启动子上，和 这些发现与人类患者有关：CDK6 水平低的肿瘤中， 突变的频率明显高于预期。CDK6 通过驱动细胞周期进程和拮抗应激反应，在 p53 和 RB 之间发挥作用。虽然使细胞对 p53 诱导的细胞死亡敏感，但 CDK6 激酶活性的特异性抑制可能会促使 p53 突变克隆从癌前细胞中生长出来。
