文章：

生存或死亡：细胞对p53的反应

Live or let die: the cell's response to p53

原文发布日期：2002-08-01

DOI: 10.1038/nrc864

类型: Review Article

开放获取: 否

要点：

1. p53 is a tumour-suppressor protein that induces apoptotic cell death in response to oncogenic stress. Malignant progression is dependent on loss of p53 function, either through mutation in the TP53 gene (which encodes p53) itself or by defects in the signalling pathways that are upstream or downstream of p53.
2. Mutations in TP53 occur in about half of all human cancers, almost always resulting in the expression of a mutant p53 protein that has acquired transforming activity.
3. p53-induced apoptosis depends on the ability of p53 to activate gene expression, although transcriptionally independent activities of p53 can also contribute to the apoptotic response.
4. The apoptotic and cell-cycle arrest activities of p53 can be separated, and apoptotic cofactors that play a specific role in allowing p53-induced death are being identified.
5. Regulation of the apoptotic function of p53 is associated with selective activation of apoptotic target genes. Cofactors that specifically contribute to p53-mediated activation of apoptotic target genes include JMY, ASPP and the other p53-family members p63 and p73.
6. Phosphorylation of p53 regulates its ability to activate the expression of apoptotic target genes, and other post-translational modifications such as acetylation might also have a role.
7. In tumours that retain wild-type p53, the apoptotic response might be hindered by defects in the apoptotic cofactors. These, therefore, represent additional targets for the design of therapeutics that are aimed at reactivating p53-mediated apoptosis in cancer cells.

要点翻译：

1. p53是一种肿瘤抑制蛋白，它能响应致癌应激诱导凋亡性细胞死亡。恶性肿瘤的进展依赖于p53功能的丧失，这种丧失既可能源于TP53基因（编码p53）本身的突变，也可能由于p53上游或下游信号通路存在缺陷。
2. 约半数人类癌症存在TP53基因突变，这些突变几乎总是导致具有转化活性的突变型p53蛋白表达。
3. p53诱导的凋亡取决于其激活基因表达的能力，但p53的非转录活性功能也可能参与凋亡应答。
4. p53的凋亡诱导功能与细胞周期阻滞功能可相互分离，目前正在鉴定那些特异性参与p53诱导死亡过程的凋亡辅助因子。
5. p53凋亡功能的调控与其选择性激活凋亡靶基因相关，特异性参与p53介导的凋亡靶基因激活的辅助因子包括JMY、ASPP以及p53家族其他成员p63和p73。
6. p53的磷酸化修饰调控其激活凋亡靶基因表达的能力，其他翻译后修饰（如乙酰化）也可能发挥作用。
7. 在保留野生型p53的肿瘤中，凋亡应答可能因凋亡辅助因子缺陷而受阻。因此，这些辅助因子为设计旨在重新激活癌细胞中p53介导凋亡的治疗方案提供了新的靶点。

英文摘要：

Compared with many normal tissues, cancer cells are highly sensitized to apoptotic signals, and survive only because they have acquired lesions — such as loss of p53 — that prevent or impede cell death. We are now beginning to understand the complex mechanisms that regulate whether or not a cell dies in response to p53 — insights that will ultimately contribute to the development of therapeutic strategies to repair the apoptotic p53 response in cancers.

摘要翻译： 

与许多正常组织相比，癌细胞对凋亡信号高度敏感，其存活仅因它们获得了如p53缺失等损伤，这些损伤阻止或阻碍了细胞死亡。我们正开始理解调控细胞是否响应p53而死亡的复杂机制——这些洞见最终将有助于开发修复癌症中凋亡性p53反应的治疗策略。

原文链接：

Live or let die: the cell's response to p53