p53家族新成员Trp73新功能

　　

来自加拿大多伦多玛格丽特王子医院的科学家近期发现破解p53家族新成员TAp73蛋白的功能。相关成果发布在《Genes & Development》（9月18日）上。

 

Trp73基因是抑癌基因Trp53家族新成员，其可表达两种相互独立而又密切相关的同源蛋白TAp73和△Np73。因此，基因功能上存在两面性的特点。TAp73的功能类似于p53，诱导细胞凋亡和抑制肿瘤发生；而△Np73反过来抑制TAp73表达，缩小凋亡反应，促进肿瘤生长。

 

为了深入研究这两个蛋白的功能，Tak W. Mak带领的研究小组通过遗传技术对小鼠进行改造，改造后的小鼠编码TAp73的外显子被剔除，因此改造小鼠是TAp73缺陷表型（TAp-/-）。研究发现，TAp73缺陷型小鼠的肿瘤发生率和不育发生率以及老化的程度都处于Trp73缺陷型和Trp53缺陷型之间。TAp73缺陷型小鼠海马发育异常。从TAp73缺陷型小鼠体内抽取细胞进行实验，结果发现基因组不稳定更容易趋向于非整倍体，这些结果表明，除了诱导细胞凋亡和抑制肿瘤，促进发育以外，TAp73还具有稳定基因组的功能。

 

原文摘要：TAp73 knockout shows genomic instability with infertility and tumor suppressor functions

 

【Abstract】

The Trp53 gene family member Trp73 encodes two major groups of protein isoforms, TAp73 and Np73, with opposing pro- and anti-apoptotic functions; consequently, their relative ratio regulates cell fate. However, the precise roles of p73 isoforms in cellular events such as tumor initiation, embryonic development, and cell death remain unclear. To determine which aspects of p73 function are attributable to the TAp73 isoforms, we generated and characterized mice in which exons encoding the TAp73 isoforms were specifically deleted to create a TAp73-deficient (TAp73–/–) mouse. Here we show that mice specifically lacking in TAp73 isoforms develop a phenotype intermediate between the phenotypes of Trp73–/– and Trp53–/– mice with respect to incidence of spontaneous and carcinogen-induced tumors, infertility, and aging, as well as hippocampal dysgenesis. In addition, cells from TAp73–/– mice exhibit genomic instability associated with enhanced aneuploidy, which may account for the increased incidence of spontaneous tumors observed in these mutants. Hence, TAp73 isoforms exert tumor-suppressive functions and indicate an emerging role for Trp73 in the maintenance of genomic stability.

 

附

P53基因是迄今发现与人类肿瘤相关性最高的基因.在短短的十多年里，人们对 P53基因的认识经历了癌蛋白抗原，癌基因到抑癌基因的三个认识转变，现已认识到，引起肿瘤形成或细胞转化的P53蛋白是P53基因突变的产物，是一种肿瘤促进因 子，它可以消除正常P53的功能，而野生型P53基因是一种抑癌基因，它的失活对肿瘤 形成起重要作用。

 

（生物通 张欢）