以任何方法剪接:Mdm2位于肿瘤监视的十字路口

Any Way You Splice It:Mdm2 at the Crossroads of Tumor Surveillance

鼠双微基因2(Mdm2)是p53最重要的调节基因,同时也是对各种类型细胞应激(包DNA损害和致癌损伤)的主要应答者。尽管已有文章描述了Mdm2基因的替代产物的异常拼接产物,但是关于该变异体的起源、功能和影响,现在尚不清楚。最近发现了一种新的mdm2基因的剪接形式。在该剪接体中,108bp的基因内序列合并到成熟的Mdm2 mRNA中。编码框内终止密码子的额外序列可使Mdm2蛋白明显缩短。最有趣的现象是,阿霉素和放线菌素D能诱导产生一种交替剪接形式,即成熟的Mdm2+108,而其他的DNA损伤剂没有这种诱导作用。Mdm2+108基因可诱导p53的大量快速聚集,证明该交替剪接事件的作用是形成p53的肿瘤监视途径,同时抑制细胞的增殖(该细胞为被有效的遗传毒性化合物所破坏的细胞)。

Mdm2 is the most important regulator of p53, the chief responder of various modes of cellular stress, including DNA damage and oncogenic insult. Many alternative and aberrant splice products of the Mdm2 gene product have been described, but relatively little is known about the origin, function, or consequence of these variants. Recently, a novel splice form of mdm2 was discovered which incorporates 108bp of intronic sequence into the mature Mdm2 mRNA. The additional sequence encodes inframe stop codons, resulting in severely truncated mdm2 protein. Most intriguingly, this alternative splice form, termed Mdm2^＋108, is acutely induced by the chemotherapeutic agents Adriamycin and Actinomycin D, but not other DNA damaging agents. The effect of Mdm2^ ＋108 induction is a rapid and robust accumulation of p53, arguing that the function of this alternative splice event is to engage the p53 tumor surveillance pathway and restrain proliferation of cells damaged with these potently genotoxic compounds.