Department of Radiology, University of Massachusetts Medical School, Worcester, MA 01655.
Mol Biol Cell. 2018 Nov 1;29(22):2632-2643. doi: 10.1091/mbc.E18-01-0026. Epub 2018 Aug 22.
When untransformed human cells spend >1.5 h in prometaphase under standard culture conditions, all daughters arrest in G1 despite normal division of their mothers. We investigate what happens during prolonged prometaphase that leads to daughter cell arrest in the absence of DNA damage. We find that progressive loss of anti-apoptotic MCL-1 activity and oxidative stress act in concert to partially activate the apoptosis pathway, resulting in the delayed death of some daughters and senescence for the rest. At physiological oxygen levels, longer prometaphase durations are needed for all daughters to arrest. Partial activation of apoptosis during prolonged prometaphase leads to persistent caspase activity, which activates the kinase cascade mediating the post-mitotic activation of p38. This in turn activates p53, and the consequent expression of p21stops the cell cycle. This mechanism can prevent cells suffering intractable mitotic defects, which modestly prolong mitosis but allow its completion without DNA damage, from producing future cell generations that are susceptible to the evolution of a transformed phenotype.
当未经转化的人类细胞在标准培养条件下处于前期超过 1.5 小时时，尽管其母细胞正常分裂，所有子细胞仍会在 G1 期停滞。我们研究了在没有 DNA 损伤的情况下，导致子细胞停滞的前期延长过程中发生了什么。我们发现，抗凋亡 MCL-1 活性的逐渐丧失和氧化应激协同作用，部分激活了凋亡途径，导致一些子细胞延迟死亡，其余子细胞衰老。在生理氧水平下，所有子细胞都需要更长的前期时间才能停滞。在前期延长过程中，凋亡的部分激活会导致持续的半胱天冬酶活性，从而激活激酶级联反应，介导有丝分裂后 p38 的激活。这反过来又激活了 p53，随后表达的 p21 阻止了细胞周期。这种机制可以防止那些受到难以解决的有丝分裂缺陷的细胞产生未来的细胞世代，这些细胞的有丝分裂略有延长，但允许其完成而不会造成 DNA 损伤，从而避免了发生转化表型的进化。
