文章：

抑制p53-MDM2相互作用：癌症治疗的重要靶点

Inhibiting the p53–MDM2 interaction: an important target for cancer therapy

原文发布日期：2003-02-01

DOI: 10.1038/nrc991

类型: Review Article

开放获取: 否

要点：

1. The tumour suppressor p53 induces cell death by apoptosis in response to various stress conditions, such as oncogene activation or DNA damage.
2. The loss of p53 tumour-suppressor activity — either by mutation/deletion of the TP53 gene or by inhibition of the p53 protein — favours the development of cancer.
3. The MDM2 protein is a negative regulator of p53. After binding to p53, it inhibits its transcriptional activity, favours its nuclear export and stimulates its degradation.
4. The overexpression of MDM2 in various tumours inhibits p53, therefore favouring uncontrolled cell proliferation.
5. The inhibition of the p53–MDM2 interaction is an attractive strategy to activate p53-mediated apoptosis in tumours with overexpressed MDM2, but wild-type p53.
6. Several low-molecular-weight compounds and peptides that inhibit the p53–MDM2 interaction have been obtained. The peptidic inhibitors show an antiproliferative effect in tumour cells overexpressing MDM2.

要点翻译：

1. 肿瘤抑制因子p53在响应各种应激条件（如癌基因激活或DNA损伤）时，通过细胞凋亡途径诱导细胞死亡。
2. p53肿瘤抑制活性的丧失——无论是由于TP53基因突变/缺失，还是p53蛋白被抑制——都会促进癌症的发生发展。  
3. MDM2蛋白是p53的负调控因子。它与p53结合后，会抑制其转录活性，促进其核输出并刺激其降解。
4. MDM2在多种肿瘤中的过度表达会抑制p53功能，从而促进不受控的细胞增殖。  
5. 抑制p53-MDM2相互作用是一种具有吸引力的治疗策略，可在MDM2过度表达但p53仍为野生型的肿瘤中激活p53介导的细胞凋亡。
6. 目前已有多种抑制p53-MDM2相互作用的低分子量化合物和多肽被研发出来，其中多肽抑制剂在过度表达MDM2的肿瘤细胞中显示出抗增殖效应。

英文摘要：

p53 is an attractive therapeutic target in oncology because its tumour-suppressor activity can be stimulated to eradicate tumour cells. Inhibiting the p53–MDM2 interaction is a promising approach for activating p53, because this association is well characterized at the structural and biological levels. MDM2 inhibits p53 transcriptional activity, favours its nuclear export and stimulates its degradation, so inhibiting the p53–MDM2 interaction with synthetic molecules should lead to p53-mediated cell-cycle arrest or apoptosis in p53-positive stressed cells.

摘要翻译： 

p53是肿瘤学中极具吸引力的治疗靶点，因为其抑瘤活性可被激活以清除肿瘤细胞。抑制p53–MDM2相互作用是激活p53的一条有前景的途径，因为该相互作用在结构和生物学层面已被充分阐明。MDM2可抑制p53的转录活性，促进其核输出并加速其降解；因此，用合成小分子阻断p53–MDM2相互作用，应在p53阳性的应激细胞中引发p53介导的细胞周期停滞或凋亡。

原文链接：

Inhibiting the p53–MDM2 interaction: an important target for cancer therapy