AMPLIFICATION OF A GENE ENCODING A P53-ASSOCIATED PROTEIN IN HUMAN SARCOMAS
AMPLIFICATION OF A GENE ENCODING A P53-ASSOCIATED PROTEIN IN HUMAN SARCOMAS
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DOI：
10.1038/358080a0
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发表时间：
1992-07-02
期刊：
影响因子：
64.8
通讯作者：
VOGELSTEIN, B
中科院分区：
文献类型：
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作者：
OLINER, JD;KINZLER, KW;VOGELSTEIN, B
尽管有大量的数据将p53基因突变与人类肿瘤发生联系起来，但对p53功能的细胞调节因子和介导因子知之甚少。MDM 2是一种这样的细胞蛋白的强有力的候选者; MDM 2基因最初是通过其在小鼠BALB/c细胞的自发转化衍生物中的扩增而鉴定的2，并且MDM 2蛋白随后显示在用p53基因转染的大鼠细胞中与p53结合3，4。 为了确定MDM 2是否在人类癌症中起作用，我们克隆了人类MDM 2基因。在这里，我们表明，重组衍生的人MDM 2蛋白结合人p53在体外，我们使用MDM 2克隆定位的人MDM 2基因的染色体12 q13 -14。因为这种染色体位置在许多肉瘤中似乎发生了改变5-7，我们在这些癌症中寻找人MDM 2的变化。该基因在47个肉瘤中的三分之一以上扩增，包括常见的骨和软组织形式。这些结果与MDM 2与p53结合的假设一致，并且肉瘤中MDM 2的扩增导致逃离p53调节的生长控制。这种肿瘤发生的机制与病毒诱导的肿瘤相似8，9，其中病毒致癌基因产物与p53结合并在功能上抑制p53。
DESPITE extensive data linking mutations in the p53 gene to human tumorigenesis 1, little is known about the cellular regulators and mediators of p53 function. MDM2 is a strong candidate for one such cellular protein; the MDM2 gene was originally identified by virtue of its amplification in a spontaneously transformed derivative of mouse BALB/c cells 2 and the MDM2 protein subsequently shown to bind to p53 in rat cells transfected with p53 genes 3,4. To determine whether MDM2 plays a role in human cancer, we have cloned the human MDM2 gene. Here we show that recombinant-derived human MDM2 protein binds human p53 in vitro, and we use MDM2 clones to localize the human MDM2 gene to chromosome 12q13-14. Because this chromosomal position appears to be altered in many sarcomas 5-7, we looked for changes in human MDM2 in such cancers. The gene was amplified in over a third of 47 sarcomas, including common bone and soft tissue forms. These results are consistent with the hypothesis that MDM2 binds to p53, and that amplification of MDM2 in sarcomas leads to escape from p53-regulated growth control. This mechanism of tumorigenesis parallels that for virally-induced tumours 8,9, in which viral oncogene products bind to and functionally inactivate p53.