Cell Cycle, Stem Cell Fate and Cancer Laboratory, Institute for Research Marqués de Valdecilla (IDIVAL), 39011, Santander, Spain.
Cell Cycle & Cancer Biomarkers Group, Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBm) CSIC-UAM, 28029, Madrid, Spain.
Cell Death Differ. 2020 Aug;27(8):2451-2467. doi: 10.1038/s41418-020-0515-2. Epub 2020 Feb 20.
The cellular mechanisms controlling cell fate in self-renewal tissues remain unclear. Cell cycle failure often leads to an apoptosis anti-oncogenic response. We have inactivated Cdk1 or Polo-like-1 kinases, essential targets of the mitotic checkpoints, in the epithelia of skin and oral mucosa. Here, we show that inactivation of the mitotic kinases leading to polyploidy in vivo, produces a fully differentiated epithelium. Cells within the basal layer aberrantly differentiate and contain large or various nuclei. Freshly isolated KO cells were also differentiated and polyploid. However, sustained metaphase arrest downstream of the spindle anaphase checkpoint (SAC) due to abrogation of CDC20 (essential cofactor of anaphase-promoting complex), impaired squamous differentiation and resulted in apoptosis. Therefore, upon prolonged arrest keratinocytes need to slip beyond G2 or mitosis in order to initiate differentiation. The results altogether demonstrate that mitotic checkpoints drive squamous cell fate towards differentiation or apoptosis in response to genetic damage.
细胞命运控制的细胞机制在自我更新组织中仍然不清楚。细胞周期失败常常导致凋亡抗肿瘤反应。我们已经使皮肤和口腔黏膜上皮细胞中的细胞周期蛋白激酶 1 或 Polo 样激酶 1 失活，这是有丝分裂检查点的关键靶标。在这里，我们表明，有丝分裂激酶的失活导致体内多倍体的产生，产生完全分化的上皮细胞。基底细胞层中的细胞异常分化，包含大的或各种细胞核。新分离的 KO 细胞也分化和多倍体化。然而，由于纺锤体后期检查点 (SAC)下游的 CDC20（后期促进复合物的必需辅助因子）的破坏，中期停滞持续存在，这损害了鳞状分化，并导致细胞凋亡。因此，在长时间的阻滞中，角质形成细胞需要滑过 G2 期或有丝分裂才能开始分化。总之，这些结果表明，有丝分裂检查点在应对遗传损伤时驱动鳞状细胞命运向分化或凋亡。
