Absence of p53 permits propagation of mutant cells following genotoxic damage
Absence of p53 permits propagation of mutant cells following genotoxic damage
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DOI：
10.1038/sj.onc.1200871
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发表时间：
1997-02-06
期刊：
影响因子：
8
通讯作者：
Greaves, M
中科院分区：
文献类型：
--
作者：
Griffiths, SD;Clarke, AR;Greaves, M
已经收集了许多证据支持p53在细胞对DNA损伤的反应中的关键作用。p53功能障碍与许多人类癌症的进展和不良预后相关，并且与p53敲除小鼠中肿瘤的高发病率相关。缺乏促进DNA修复或凋亡的p53依赖性G（1）阻滞可能以两种方式对临床癌症产生关键影响。第一，通过消除对通过遗传毒性损伤和细胞凋亡起作用的治疗的影响;第二，通过诱导基因组不稳定性和DNA错误修复或允许突变体存活来鼓励进展。然而，研究p53缺陷和突变频率之间关系的实验迄今未能证实这些预测。因此，p53的确切作用尚不清楚。我们现在报告使用一个短期的体外方法来评估的影响，p53对辐射诱导的突变在hprt基因座在小鼠B细胞前体，通常是辐射超敏感，我们发现了大量的hprt突变体之间的X射线照射p53空细胞，这是由于优先生存的克隆突变体，而不是从p53依赖的突变率增加。这一结果对遗传毒性癌症治疗具有重要意义。
Much evidence has been gathered in support of a critical role for p53 in the cellular response to DNA damage. p53 dysfunction is associated with progression and poor prognosis of many human cancers and with a high incidence of tumours in p53 knockout mice. The absence of a p53-dependent G(1) arrest that facilitates DNA repair or apoptosis might impact critically on clinical cancer in two ways. First, by abrogating the impact on therapy that operates via genotoxic damage and apoptosis; and second, by encouraging progression either by inducing genomic instability and DNA mis-repair or by permitting survival of mutants. However, experiments examining the relationship between p53 deficiency and mutation frequency have so far failed to confirm these predictions. The precise role played by p53 is therefore unclear. We now report use of a short term in vitro approach to assess the influence of p53 on radiation-induced mutations at the hprt locus in murine B cell precursors that are normally radiation ultrasensitive, We find a high number of hprt mutants among X-irradiated p53 null cells, which results from preferential survival as clonogenic mutants rather than from a p53-dependent increase in mutation rate. This result has important implications for genotoxic cancer therapy.