Schwartz J L, Jordan R
Department of Radiation Oncology, University of Washington, Seattle 98195, USA.
Carcinogenesis. 1997 Jan;18(1):201-5. doi: 10.1093/carcin/18.1.201.
Alterations in p53 expression are associated with genomic instability, presumably because loss of p53 leads to an inability to eliminate damaged and therefore potentially unstable cells by apoptosis or by induced cell cycle block. We tested this hypothesis by examining the influence of apoptosis on X-ray-induced chromosome aberration frequency in two isogenic human B-lymphoblastoid cell lines; TK6, which is sensitive to the induction of apoptosis, and WI-L2-NS, a p53 mutant resistant to apoptosis induction. While TK6 was more sensitive than WI-L2-NS cells to the cytotoxic effects of X-rays, it showed fewer induced chromosome aberrations. Inhibition of apoptosis in TK6 cells with phorbol 12-myristate 13-acetate (PMA) resulted in X-ray-induced aberration frequencies similar in magnitude to WI-L2-NS. The results support the hypothesis that apoptosis acts to selectively remove damaged cells. The reduction in aberration frequency associated with apoptosis was seen primarily for unstable types of aberrations; acentric chromosome fragments and dicentric chromosomes. There was no effect on the induced frequency of balanced translocations, the stable counterpart to dicentrics. The failure to remove cells with unstable types of aberrations is consistent with the genomic instability that accompanies loss of p53 activity.
p53表达的改变与基因组不稳定相关，推测是因为p53缺失导致无法通过凋亡或诱导细胞周期阻滞来清除受损从而可能不稳定的细胞。我们通过检测凋亡对两种同基因人B淋巴母细胞系X射线诱导的染色体畸变频率的影响来验证这一假说；TK6细胞对凋亡诱导敏感，WI-L2-NS细胞是对凋亡诱导有抗性的p53突变体。虽然TK6细胞比WI-L2-NS细胞对X射线的细胞毒性作用更敏感，但它诱导产生的染色体畸变较少。用佛波酯12-肉豆蔻酸酯13-乙酸酯（PMA）抑制TK6细胞的凋亡，导致X射线诱导的畸变频率在幅度上与WI-L2-NS细胞相似。这些结果支持了凋亡作用是选择性清除受损细胞的假说。与凋亡相关的畸变频率降低主要见于不稳定类型的畸变；无着丝粒染色体片段和双着丝粒染色体。对双着丝粒染色体的稳定对应物平衡易位的诱导频率没有影响。无法清除具有不稳定类型畸变的细胞与p53活性丧失伴随的基因组不稳定是一致的。
