Differential cell cycle checkpoint response in normal human keratinocytes and fibroblasts.
Differential cell cycle checkpoint response in normal human keratinocytes and fibroblasts.
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发表时间：
1998-07
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通讯作者：
P. Flatt;J. Price;A. Shaw;J. Pietenpol
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作者：
P. Flatt;J. Price;A. Shaw;J. Pietenpol
DNA突变的发生率和随后在不同类型的细胞中转化的风险可能取决于暴露于DNA损伤剂后细胞周期停滞的位置和持续时间的特定细胞类型的变化。为了确定是否存在细胞类型特异性检查点，从同一组织分离的正常人表皮角质形成细胞(HKS)和人真皮成纤维细胞(HFs)暴露于基因毒性物质。在暴露后，细胞周期停滞曲线、细胞增殖率以及选定的蛋白质水平和活性被分析并发现与细胞类型有关。暴露于伽玛射线或阿霉素后，HFs主要滞留在G1期，而HKS主要滞留在G2期。与观察到的G1期滞留的HFs相比，HKS的G1期停滞减弱与P53蛋白积聚减少有关。尽管辐照后的HFs不能重新进入细胞周期，但HKS在处理后72小时开始增殖。与观察到的细胞周期曲线一致，与HKS相比，HFS在伽玛射线照射后，细胞周期蛋白依赖的激酶活性被抑制的时间更长。结果表明，在任何给定的组织中，细胞周期检查点对遗传毒性侮辱的反应可能因细胞类型而异。在HKS观察到的减弱的G1期停滞可能是导致皮肤肿瘤的转化事件的重要因素。
The incidence of DNA mutation and subsequent risk of transformation in different cell types may depend on cell type-specific variation in position and duration of cell cycle arrest after exposure to DNA-damaging agents. To determine whether cell type-specific checkpoints occur, normal human epidermal keratinocytes (HKs) and human dermal fibroblasts (HFs), isolated from the same tissue, were exposed to genotoxic agents. Following exposure, cell cycle arrest profiles, cell proliferation rates, and select protein levels and activities were analyzed and found to be cell type dependent. After exposure to either gamma-radiation or Adriamycin, HFs arrested primarily in G1, whereas HKs arrested predominantly in G2. The attenuated G1 arrest in the HKs correlated with less p53 protein accumulation, as compared to that observed in G1-arrested HFs. Although gamma-irradiated HFs were unable to reenter the cell cycle, HKs began proliferating 72 h posttreatment. Consistent with the cell cycle profiles observed, cyclin-dependent kinase activities were inhibited for a longer duration in HFs as compared to HKs after gamma-irradiation. The results indicate that cell cycle checkpoint response to genotoxic insult may vary according to cell type within any given tissue. The attenuated G1 arrest observed in HKs may be an important factor in the transforming events leading to skin neoplasia.