p53: Guardian of the genome and policeman of the oncogenes
p53: Guardian of the genome and policeman of the oncogenes
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DOI：
10.4161/cc.6.9.4211
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发表时间：
2007-05-01
期刊：
影响因子：
4.3
通讯作者：
Serrano, Manuel
中科院分区：
文献类型：
--
作者：
Efeyan, Alejo;Serrano, Manuel
恶性转化过程普遍涉及遗传损伤和致癌信号传导，这两种应激通过不同的遗传途径向 p53 发出信号。基于此，可以区分 p53 的两种作用：“基因组守护者”，包括通过 ATM/ATR 和 Chk1/Chk2 激酶感知 DNA 损伤并做出反应；以及“癌基因警察”，相应地，包括通过 p53 稳定蛋白 ARF 对致癌信号作出反应。与预期相反，最近的小鼠遗传证据表明 p53 对 DNA 损伤的反应对癌症保护作用很小或没有影响。相反，ARF 依赖性 p53 激活对于 p53 介导的肿瘤抑制至关重要。在这里，我们讨论这些观察结果的机制意义及其与癌症治疗的相关性。
The process of malignant transformation universally entails genetic damage and oncogenic signaling, two stresses that are signaled to p53 through different genetic pathways. Based on this, it is possible to distinguish two jobs for p53: "guardian of the genome" that consists in sensing and reacting to DNA damage through the ATM/ATR and Chk1/Chk2 kinases, and "policeman of the oncogenes" that, correspondingly, consists in responding to oncogenic signaling through the p53-stabilizing protein ARF. Contrary to expectation, recent genetic evidence in mice indicates that the response of p53 to DNA damage has little or no impact on cancer protection. In contrast, ARF-dependent activation of p53 is critical for p53-mediated tumor suppression. Here, we discuss the mechanistic implications of these observations and their relevance for cancer therapy.