Clarke A R, Howard L A, Harrison D J, Winton D J
Department of Pathology, University of Edinburgh, Scotland, UK.
Oncogene. 1997 May 1;14(17):2015-8. doi: 10.1038/sj.onc.1201040.
Normal function of the p53 gene is integral to the cellular response to genotoxic stress. One prediction arising from this is that p53 deficiency results in an increased mutation frequency. However, limited evidence has been produced in support of this idea. In order to further investigate the in vivo role of p53 in surveillance against mutation, and particularly to address the significance of p53-dependent apoptosis, we scored mutation frequency at the Dlb-1 locus within cells of the intestinal epithelium of animals which were wild type, heterozygous or null for p53 and heterozygous (a/b) at the Dlb-1 locus. Using this assay we have shown that loss of a p53-dependent apoptotic pathway is associated with the detectable acquisition of mutations, but only at high levels of DNA damage. These results question the significance of the immediate 'wave' of p53-dependent apoptosis seen in this tissue, particularly as there was a delayed p53-independent apoptotic pathway. We conclude that loss of p53 function only becomes relevant to the in vivo acquisition of mutations and thus tumorigenesis in certain circumstances.
p53基因的正常功能对于细胞对基因毒性应激的反应至关重要。由此产生的一个预测是，p53缺陷会导致突变频率增加。然而，支持这一观点的证据有限。为了进一步研究p53在体内监测突变中的作用，特别是为了探讨p53依赖性凋亡的意义，我们对p53野生型、杂合型或缺失型且Dlb-1位点为杂合型（a/b）的动物肠道上皮细胞中Dlb-1位点的突变频率进行了评分。通过该检测方法，我们发现p53依赖性凋亡途径的缺失与可检测到的突变获得有关，但仅在高水平DNA损伤时出现。这些结果对该组织中所见的p53依赖性凋亡的直接“浪潮”的意义提出了质疑，特别是因为存在延迟的p53非依赖性凋亡途径。我们得出结论，p53功能的丧失仅在某些情况下与体内突变的获得以及肿瘤发生相关。
