Nucleostemin (NS) protects the genome from replication-induced DNA damage and plays an indispensable role in maintaining the continuous proliferation of both p53-wildtype and mutant cells. Yet, some outcomes of NS-deficient cells appear to be shaped by their p53 status, which stimulates conflicting claims on the role of p53 in executing the NS function. This disparity was conveniently attributed to the usual suspect of cell-type variations. To provide a definitive resolution, we investigated the interplay between NS and p53 in two pairs of isogenic cells, i.e. genetically modified mouse embryonic fibroblast (MEF) cells and HCT116 human colon cancer cells. In MEF cells, p53 deletion further compromises rather than rescues the proliferative potential of NS-depleted cells without changing their G2/M arrest fate before prophase entry. The detrimental effect of p53 loss in NS-depleted MEF cells correlates with a dramatic increase of polyploid giant cells (PGCs) (up to 24%), which indicates aberrant mitosis. To determine how p53 shapes the response of cells to NS depletion at the molecular level, we showed that p53 turns on the expression of reprimo and MDM2 in NS-deficient MEF cells. In the absence of p53, NS-deficient MEF cells exhibit increased levels of phosphorylated cdc2 (Y15) protein and cyclin B1. In cancer (HCT116) cells, NS loss leads to G2/M arrest under both p53wt and p53ko conditions and increases phosphorylated cdc2 more in p53ko than in p53wt cells, as it does in MEF cells. Unlike its effect in MEF cells, NS depletion decreases tumor growth and increases the expression of reprimo and cyclin B1 in a p53-independent manner in HCT116 cells. Our data indicate that the p53 status of NS-deficient cells orchestrates how they respond to G2/M arrest in a normal vs. cancer cell distinct fashion.

中文翻译：

---

p53配置了缺乏核糖蛋白的细胞的G2 / M阻滞反应。

核糖蛋白（NS）保护基因组免受复制诱导的DNA损伤，并在维持p53野生型和突变细胞的持续增殖中起不可或缺的作用。然而，NS缺陷细胞的某些结果似乎受其p53状态的影响，这激发了关于p53在执行NS功能中作用的矛盾主张。这种差异方便地归因于通常怀疑的细胞类型变异。为了提供确定的分辨率，我们研究了两对同基因细胞（即基因修饰的小鼠胚胎成纤维细胞（MEF）和HCT116人结肠癌细胞）中NS和p53之间的相互作用。在MEF细胞中，p53的缺失会进一步损害而不是挽救NS耗竭细胞的增殖潜能，而不改变前期进入前其G2 / M阻滞作用。NS缺失的MEF细胞中p53的有害影响与多倍体巨细胞（PGC）的急剧增加（高达24％）有关，这表明有丝分裂异常。为了确定p53在分子水平上如何塑造细胞对NS耗竭的反应，我们证明了p53可以打开NS缺失的MEF细胞中reprimo和MDM2的表达。在不存在p53的情况下，NS缺失的MEF细胞显示出增加的磷酸化cdc2（Y15）蛋白和细胞周期蛋白B1水平。在癌细胞（HCT116）中，NS丢失会导致在p53wt和p53ko条件下G2 / M停滞，并且p53ko中的磷酸化cdc2比p53wt细胞中的磷酸化cdc2增加更多，就像在MEF细胞中一样。与它在MEF细胞中的作用不同，NS耗竭以不依赖p53的方式在HCT116细胞中减少肿瘤的生长并增加reprimo和cyclin B1的表达。