In good times and bad
In good times and bad
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DOI：
10.4161/cc.7.12.6148
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发表时间：
2008-06-15
期刊：
影响因子：
4.3
通讯作者：
Stiewe, Thorsten
中科院分区：
文献类型：
--
作者：
Oswald, Claudia;Stiewe, Thorsten
在癌症生物学中广泛接受的是，p53具有肿瘤抑制活性，其在肿瘤发生期间最常见地由于p53基因中的突变而丧失。p73作为p53的第一个同源物的发现立即引起了对p53样肿瘤抑制活性的期望。虽然肿瘤显示p73表达水平的变化和p73亚型表达模式的差异，但通常观察不到突变，因此难以推断p73在肿瘤发生中的作用。人类细胞转化的实验模型密切模仿了在癌症患者中观察到的表达变化，并为p73在恶性转化道路上的各个步骤中的调节和功能提供了新的见解。p73的p53样亚型（TAp73）在转化过程的早期响应于RB途径改变而上调，并阻断向完全转化状态的进展。TAp73的拮抗剂如显性负性p73蛋白Delta Np73克服了这种阻断并为完全转化铺平了道路。在这里，我们回顾这些发现的背景下，患者的数据和最近的进展p73功能的分子方面，并讨论p73作为癌症治疗的目标的影响。
It is widely accepted in cancer biology that p53 has a tumor suppressive activity, which is lost during tumorigenesis most frequently by mutations in the p53 gene. The discovery of p73 as the first homologue of p53 raised immediate expectations about p53-like tumor suppressor activities. Although tumors show changes in the expression level of p73 and differences in the expression pattern of p73 isoforms, mutations are not commonly observed making it difficult to infer p73's role in tumorigenesis. An experimental model of human cell transformation closely mimics the expression changes observed in cancer patients and provides novel insights into the regulation and function of p73 in the various steps on the road to malignant transformation. p53-like isoforms of p73 (TAp73) are upregulated early during the transformation process in response to RB pathway alterations and block progression to the fully transformed state. Antagonists of TAp73 such as the dominant-negative p73 protein Delta Np73 overcome this block and pave the way to full transformation. Here we review these findings in the context of patient data and recent advances on molecular aspects of p73 function and discuss the implications for p73 as a target for cancer therapy.