Linke S P, Clarkin K C, Wahl G M
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Cancer Res. 1997 Mar 15;57(6):1171-9.
A new technique that monitors cell cycle progression over multiple cycles was used to gain insight into how p53 limits the emergence of variants with structural chromosome alterations following gamma-irradiation. G0-synchronized, p53+ (with a functional p53 pathway) normal human fibroblast and epithelial strains underwent a dose-dependent permanent arrest in the initial G0-G1 phase after irradiation. The dose-response curves indicate that a single event, such as an irreparable DNA break, may be sufficient to induce arrest. p53+ cells that escaped the initial G0-G1 phase after irradiation entered S phase in at least two waves. However, many of these cells underwent long-term arrest in subsequent phases. In contrast, virtually all of the cells in isogenic p53- (with a nonfunctional p53 pathway) strains escaped from the first G0-G1 phase without delay, regardless of the dose. p53- cells were also eliminated in subsequent phases but at significantly lower frequencies. Consistent with these findings, the reproductive viability of p53- cells was higher than p53+ cells. The nonclonogenic fraction appeared to be eliminated within three cycles for both cell types. In addition, artificial holding in G0 after irradiation, which allows for the repair of potentially lethal damage, led to similar increases in survival in p53+ and p53- cells. These data are inconsistent with the hypothesis that the primary function of p53-dependent G0-G1 arrest in response to gamma-irradiation is to allow additional time for DNA repair. Rather, they indicate that p53 helps maintain genetic stability by eliminating cells with damaged chromosomes from the reproductively viable population.
一种监测多个细胞周期中细胞周期进程的新技术被用于深入了解p53如何限制γ射线照射后具有染色体结构改变的变异体的出现。G0期同步化的、p53 +（具有功能性p53通路）的正常人成纤维细胞和上皮细胞系在照射后的初始G0 - G1期经历了剂量依赖性的永久性停滞。剂量反应曲线表明，单个事件，如不可修复的DNA断裂，可能足以诱导停滞。照射后逃脱初始G0 - G1期的p53 +细胞至少分两波进入S期。然而，这些细胞中的许多在随后的阶段经历了长期停滞。相比之下，几乎所有同基因p53 -（具有无功能p53通路）细胞系中的细胞都毫无延迟地从第一个G0 - G1期逃脱，无论剂量如何。p53 -细胞在随后的阶段也被清除，但频率明显较低。与这些发现一致，p53 -细胞的生殖活力高于p53 +细胞。两种细胞类型的非克隆形成部分似乎在三个周期内被清除。此外，照射后人工滞留在G0期，这允许修复潜在的致死性损伤，导致p53 +和p53 -细胞的存活率有类似的增加。这些数据与以下假设不一致：即p53依赖的G0 - G1期停滞对γ射线照射的主要功能是为DNA修复提供额外时间。相反，它们表明p53通过从生殖存活群体中清除具有受损染色体的细胞来帮助维持遗传稳定性。
