文章：

p53在肿瘤发生中的翻译后修饰

Post-translational modification of p53 in tumorigenesis

原文发布日期：2004-10-01

DOI: 10.1038/nrc1455

类型: Review Article

开放获取: 否

要点：

1. When a cell is confronted by stress, p53 is stabilized in the nucleus, where it initiates cellular responses through transcriptional activation or repression of distinct target genes that primarily function to prevent proliferation of damaged cells.
2. The function of p53 is tightly controlled by its interaction with negative regulators including MDM2, which induces p53 degradation and prevents its accumulation in normal cells. This interaction can be disrupted when the cell detects DNA damage or other stresses, resulting in stabilization and activation of p53.
3. Active p53 is subject to a diverse array of covalent post-translational modifications, which markedly influence the expression of p53 target genes.
4. Phosphorylation and acetylation of p53 generally result in its stabilization and accumulation in the nucleus, followed by activation. Significant redundancies are observed in that the same p53 site is phosphorylated by several different protein kinases and distinct protein kinases also phosphorylate several sites on p53.
5. Mutant p53 proteins generally show intense phosphorylation and acetylation at sites that are well known to stabilize wild-type p53, and so could facilitate accumulation of dysfunctional mutant p53 in the nucleus, where it can act as an oncogene.
6. Overexpression of MDM2 E3 ubiquitin ligase is observed in many tumour types and results in the aberrant deactivation of p53.
7. In normal cells, p53 post-translational modification is induced by numerous carcinogens. Evidence indicates that normal cells and cancer cells show a markedly different response to ultraviolet-light exposure.
8. Dietary-derived chemopreventive agents induce phosphorylation of p53, resulting in cell-cycle arrest or apoptosis. These agents might have a preventive function in future anticancer therapies.

要点翻译：

1. 当细胞面临应激时，p53在细胞核内趋于稳定，通过转录激活或抑制特定靶基因启动细胞应答反应，这些靶基因主要功能是阻止受损细胞增殖。
2. p53的功能受到其与MDM2等负调控因子相互作用的严格调控，MDM2可诱导p53降解并阻止其在正常细胞中积累。当细胞检测到DNA损伤或其他应激时，这种相互作用会被破坏，导致p53稳定化和激活。
3. 活性p53会受到多种共价翻译后修饰的影响，这些修饰显著调控p53靶基因的表达。
4. p53的磷酸化和乙酰化通常导致其稳定并在细胞核内积累，继而激活。研究发现该过程存在显著冗余性：同一p53位点可被多种不同蛋白激酶磷酸化，而不同蛋白激酶也能磷酸化p53的多个位点。
5. 突变型p53蛋白通常在已知能稳定野生型p53的位点发生强烈磷酸化和乙酰化，这可能促进功能异常的突变型p53在细胞核内积累，使其发挥癌基因作用。
6. MDM2 E3泛素连接酶的过表达见于多种肿瘤类型，会导致p53异常失活。
7. 在正常细胞中，多种致癌物可诱导p53翻译后修饰。证据表明正常细胞与癌细胞对紫外线照射的反应存在显著差异。
8. 膳食来源的化学预防剂可诱导p53磷酸化，导致细胞周期阻滞或凋亡。这些制剂可能在未来的抗癌治疗中发挥预防作用。

英文摘要：

Interest in the tumour suppressor p53 has generated much information regarding the complexity of its function and regulation in carcinogenesis. However, gaps still exist in our knowledge regarding the role of p53 post-translational modifications in carcinogenesis and cancer prevention. A thorough understanding of p53 will be extremely useful in the development of new strategies for treating and preventing cancer, including restoration of p53 function and selective killing of tumours with mutant TP53.

摘要翻译： 

对肿瘤抑制因子p53的关注已使人们在癌症发生过程中对其功能和调控的复杂性有了大量了解。然而，关于p53翻译后修饰在癌症发生和预防中的作用，我们的认识仍存在空白。深入理解p53将极有助于开发新的癌症治疗和预防策略，包括恢复p53功能以及选择性杀灭携带TP53突变的肿瘤。

原文链接：

Post-translational modification of p53 in tumorigenesis