文章：

当突变体获得新能力时：来自突变体p53领域的消息

When mutants gain new powers: news from the mutant p53 field

原文发布日期：2009-08-20

DOI: 10.1038/nrc2693

类型: Review Article

开放获取: 否

要点：

1. The tumour suppressor p53 (encoded by TP53 in humans) functions primarily as a transcription factor, which, upon cellular stress signals, regulates a plethora of genes that promote cell cycle arrest, senescence, apoptosis, differentiation, DNA repair and other processes.
2. TP53 is somatically mutated in the majority of sporadic human cancers, and mutations in TP53 are also associated with Li–Fraumeni Syndrome, a familial cancer predisposition syndrome.
3. The majority of cancer-associated mutations in TP53 are missense mutations in its DNA-binding domain. These mutations usually lead to the formation of a full-length mutant protein (mutant p53) incapable of activating p53 target genes and suppressing tumorigenesis. Besides losing their wild-type activities, many p53 mutants also function as dominant-negative proteins that inactivate wild-type p53 expressed from the remaining wild-type allele. Moreover, some mutant p53 forms also acquire new oncogenic properties that are independent of wild-type p53, known as 'gain-of-function' properties.
4. In the past three decades ample data were collected in support of the importance of mutant p53 gain-of-function properties for tumorigenesis. These data include cell culture studies that demonstrated the capability of mutant p53 to impinge on pivotal cellular regulatory networks, mouse models that established the ability of mutant p53 to increase tumour aggressiveness and metastatic potential, as well as clinical studies that revealed associations between TP53 mutations and poor clinical outcome in a variety of malignancies.
5. This Review describes recent advances in the research field of mutant p53, with an emphasis on the transcriptional effects of mutant p53, the expression signatures associated with TP53 mutations in vitro and in vivo and the diagnostic, prognostic and predictive value of TP53 mutations in human cancer.

要点翻译：

1. 肿瘤抑制因子p53（人类由TP53基因编码）主要作为转录因子发挥作用，在细胞应激信号传导时调控大量基因，这些基因促进细胞周期停滞、衰老、凋亡、分化、DNA修复及其他过程。
2. TP53在大多数散发性人类癌症中存在体细胞突变，且该基因突变也与李-弗劳梅尼综合征相关——一种家族性癌症易感综合征。
3. 大多数与癌症相关的TP53突变是其DNA结合结构域中的错义突变。这些突变通常导致形成全长突变蛋白（突变型p53），无法激活p53靶基因并抑制肿瘤发生。除了丧失野生型活性外，许多p53突变体还发挥显性负性作用，使来自剩余野生型等位基因表达的野生型p53失活。此外，部分突变型p53还获得独立于野生型p53的新致癌特性，即"功能获得性"特性。
4. 过去三十年间积累的大量数据支持了突变型p53功能获得性特性对肿瘤发生的重要性。这些数据包括：证明突变型p53能够影响关键细胞调控网络的细胞培养研究；证实突变型p53可增强肿瘤侵袭性和转移潜能的小鼠模型；以及揭示多种恶性肿瘤中TP53突变与不良临床结局相关性的临床研究。
5. 本综述阐述突变型p53研究领域的最新进展，重点探讨突变型p53的转录效应、体外和体内与TP53突变相关的表达特征，以及TP53突变在人类癌症中的诊断、预后和预测价值。

英文摘要：

Ample data indicate that mutant p53 proteins not only lose their tumour suppressive functions, but also gain new abilities that promote tumorigenesis. Moreover, recent studies have modified our view of mutant p53 proteins, portraying them not as inert mutants, but rather as regulated proteins that influence the cancer cell transcriptome and phenotype. This influence is clinically manifested as association of TP53 mutations with poor prognosis and drug resistance in a growing array of malignancies. Here, we review recent studies on mutant p53 regulation, gain-of-function mechanisms, transcriptional effects and prognostic association, with a focus on the clinical implications of these findings.

摘要翻译： 

大量数据表明，突变型p53蛋白不仅失去了抑瘤功能，还获得了促进肿瘤发生的新能力。此外，近期研究改变了我们对突变型p53蛋白的看法，它们并非“惰性”突变体，而是受调控的蛋白，能够影响癌细胞的转录组和表型。这种影响在临床上表现为TP53突变与越来越多恶性肿瘤的不良预后及耐药相关。本文综述了突变型p53调控、功能获得机制、转录效应及预后关联的最新研究，重点讨论这些发现的临床意义。

原文链接：

When mutants gain new powers: news from the mutant p53 field