文章：

p73：肿瘤发生的朋友或敌人

p73: Friend or foe in tumorigenesis

原文发布日期：2002-08-01

DOI: 10.1038/nrc861

类型: Review Article

开放获取: 否

要点：

1. The TP73 gene maps to a region (1p36.33) that is frequently deleted in neuroblastoma, indicating that loss of p73 function might have a role in the development of this tumour. However, mutations of TP73 are rare in human cancer.
2. p73 protein levels increase after DNA damage due to protein stabilization via a c-ABL-dependent pathway.
3. p53 seems to require p63 and p73 to induce apoptosis, indicating a very tight relationship between the three members of the same family.
4. The TP73 gene encodes two different proteins that are expressed under the control of two independent promoters, and that have opposite activities: the transcriptionally active full-length TAp73, and the amino-terminally truncated dominant-negative ΔNp73.
5. TAp73 induces cell-cycle arrest and apoptosis. Antithetically, ΔNp73 inhibits both TAp73- and p53-induced apoptosis. Furthermore, ΔNp73 is induced by TAp73 and p53, creating a dominant-negative feedback loop that regulates p53 and p73 function.
6. In keeping with its anti-apoptotic and potentially oncogenic role, ΔNp73 is an adverse prognostic marker for neuroblastoma patients. It would, therefore, seem that fine-tuning of TAp73 and ΔNp73 ratios within the individual cellular context dictates the functional outcome, and it comes as no surprise that enhanced expression of the ΔNp73 forms, rather than inactivating mutations within p73, is associated with cancer development.

要点翻译：

1. TP73基因定位的区域（1p36.33）在神经母细胞瘤中经常发生缺失，表明p73功能丧失可能在该肿瘤的发展中起作用。然而，TP73基因突变在人类癌症中较为罕见。
2. DNA损伤后，通过c-ABL依赖途径的蛋白质稳定性调节，p73蛋白水平会升高。
3. p53似乎需要p63和p73来诱导细胞凋亡，这表明同一家族的三个成员之间存在非常紧密的联系。
4. TP73基因编码两种不同的蛋白质，它们分别在两个独立启动子的控制下表达，且具有相反活性：具有转录活性的全长TAp73和氨基末端截短的显性负性ΔNp73。
5. TAp73诱导细胞周期停滞和凋亡。相反，ΔNp73抑制TAp73和p53诱导的凋亡。此外，ΔNp73受TAp73和p53诱导表达，形成显性负反馈环路来调节p53和p73功能。
6. 与其抗凋亡和潜在致癌作用一致，ΔNp73是神经母细胞瘤患者的不良预后标志物。因此，在特定细胞环境中TAp73与ΔNp73比例的微调决定了功能输出，这也解释了为何ΔNp73形式表达增强（而非p73失活突变）与癌症发展相关。

英文摘要：

As p53 and its homologue p73 have significant sequence and functional similarities, p73 might also be expected to act as a tumour suppressor. However, p73 is activated after DNA damage in a way that is distinct from that of p53. The existence of ΔNp73 — an isoform of p73 that is encoded by a distinct promoter and that lacks the transactivation domain — further complicates matters. It seems to function as an oncogene by inhibiting both p73- and p53-induced apoptosis. So how can these opposing functions be reconciled in human tumours?

摘要翻译： 

由于p53及其同源物p73在序列和功能上具有显著相似性，p73也可能被视为一种肿瘤抑制因子。然而，p73在DNA损伤后的激活方式与p53不同。p73的一种亚型ΔNp73由独立启动子编码，缺乏转激活结构域，使情况更加复杂。它似乎通过抑制p73和p53诱导的细胞凋亡而发挥癌基因的作用。那么，在人类肿瘤中，这些相反的功能如何得以协调？

原文链接：

p73: Friend or foe in tumorigenesis