London Regional Cancer Program, Lawson Health Research Institute, London, Ontario, Canada.
Department of Biochemistry, Western University, London, Ontario, Canada.
PLoS One. 2019 Jan 31;14(1):e0203577. doi: 10.1371/journal.pone.0203577. eCollection 2019.
RB-E2F transcriptional control plays a key role in regulating the timing of cell cycle progression from G1 to S-phase in response to growth factor stimulation. Despite this role, it is genetically dispensable for cell cycle exit in primary fibroblasts in response to growth arrest signals. Mice engineered to be defective for RB-E2F transcriptional control at cell cycle genes were also found to live a full lifespan with no susceptibility to cancer. Based on this background we sought to probe the vulnerabilities of RB-E2F transcriptional control defects found in Rb1R461E,K542E mutant mice (Rb1G) through genetic crosses with other mouse strains. We generated Rb1G/G mice in combination with Trp53 and Cdkn1a deficiencies, as well as in combination with KrasG12D. The Rb1G mutation enhanced Trp53 cancer susceptibility, but had no effect in combination with Cdkn1a deficiency or KrasG12D. Collectively, this study indicates that compromised RB-E2F transcriptional control is not uniformly cancer enabling, but rather has potent oncogenic effects when combined with specific vulnerabilities.
RB-E2F 转录控制在响应生长因子刺激时，从 G1 期到 S 期的细胞周期进程中起着关键作用。尽管具有这种作用，但在响应生长抑制信号时，RB-E2F 转录控制对于原代成纤维细胞的细胞周期退出在遗传上是可有可无的。在细胞周期基因中具有 RB-E2F 转录控制缺陷的工程改造的小鼠也被发现具有完整的寿命，并且不易患癌症。基于这一背景，我们试图通过与其他小鼠品系的遗传杂交来探测 Rb1R461E，K542E 突变小鼠（Rb1G）中发现的 RB-E2F 转录控制缺陷的脆弱性。我们生成了 Rb1G/G 小鼠，与 Trp53 和 Cdkn1a 缺陷以及与 KrasG12D 相结合。Rb1G 突变增强了 Trp53 的癌症易感性，但与 Cdkn1a 缺陷或 KrasG12D 结合时没有影响。总之，这项研究表明，受损的 RB-E2F 转录控制并非普遍具有致癌作用，而是与特定脆弱性结合时具有强烈的致癌作用。
