持续的 ERK 信号转导促进 G2 细胞周期退出并为细胞进行全基因组复制做好准备。
Sustained ERK signaling promotes G2 cell cycle exit and primes cells for whole-genome duplication.
机构信息
Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Biochemistry, Cellular and Molecular Biology Graduate Program, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
出版信息
Dev Cell. 2024 Jul 8;59(13):1724-1736.e4. doi: 10.1016/j.devcel.2024.03.032. Epub 2024 Apr 18.
Whole-genome duplication (WGD) is a frequent event in cancer evolution that fuels chromosomal instability. WGD can result from mitotic errors or endoreduplication, yet the molecular mechanisms that drive WGD remain unclear. Here, we use live single-cell analysis to characterize cell-cycle dynamics upon aberrant Ras-ERK signaling. We find that sustained ERK signaling in human cells leads to reactivation of the APC/C in G2, resulting in tetraploid G0-like cells that are primed for WGD. This process is independent of DNA damage or p53 but dependent on p21. Transcriptomics analysis and live-cell imaging showed that constitutive ERK activity promotes p21 expression, which is necessary and sufficient to inhibit CDK activity and which prematurely activates the anaphase-promoting complex (APC/C). Finally, either loss of p53 or reduced ERK signaling allowed for endoreduplication, completing a WGD event. Thus, sustained ERK signaling-induced G2 cell cycle exit represents an alternative path to WGD.
全基因组复制（WGD）是癌症进化中频繁发生的事件，它会引发染色体不稳定。WGD 可能源于有丝分裂错误或内复制，但驱动 WGD 的分子机制仍不清楚。在这里，我们使用活细胞单细胞分析来描述异常 Ras-ERK 信号转导后细胞周期的动力学。我们发现，人类细胞中持续的 ERK 信号转导导致 APC/C 在 G2 中重新激活，导致处于 WGD 预备状态的四倍体 G0 样细胞。这个过程不依赖于 DNA 损伤或 p53，但依赖于 p21。转录组学分析和活细胞成像显示，组成性 ERK 活性促进了 p21 的表达，这对于抑制 CDK 活性是必要且充分的，并且可以提前激活后期促进复合物（APC/C）。最后，要么缺失 p53 要么降低 ERK 信号转导，都可以完成内复制，完成 WGD 事件。因此，持续的 ERK 信号诱导的 G2 细胞周期退出代表了 WGD 的另一种途径。
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