Oliner J D, Kinzler K W, Meltzer P S, George D L, Vogelstein B
Department of Pediatrics, University of Michigan Cancer Center, Ann Arbor 48109.
Nature. 1992 Jul 2;358(6381):80-3. doi: 10.1038/358080a0.
Despite extensive data linking mutations in the p53 gene to human tumorigenesis, 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 and the MDM2 protein subsequently shown to bind to p53 in rat cells transfected with p53 genes. 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, 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, in which viral oncogene products bind to and functionally inactivate p53.
尽管有大量数据表明p53基因突变与人类肿瘤发生有关，但对于p53功能的细胞调节因子和介质却知之甚少。MDM2是这类细胞蛋白的有力候选者；MDM2基因最初是因其在小鼠BALB/c细胞的自发转化衍生物中扩增而被鉴定出来的，随后在转染了p53基因的大鼠细胞中发现MDM2蛋白可与p53结合。为了确定MDM2是否在人类癌症中起作用，我们克隆了人类MDM2基因。在此我们表明，重组衍生的人类MDM2蛋白在体外可与人p53结合，并且我们使用MDM2克隆将人类MDM2基因定位到染色体12q13 - 14。由于这个染色体位置在许多肉瘤中似乎发生了改变，我们在这类癌症中寻找人类MDM2的变化。在47个肉瘤中的三分之一以上发现该基因发生了扩增，包括常见的骨和软组织肉瘤。这些结果与以下假设一致，即MDM2与p53结合，并且肉瘤中MDM2的扩增导致逃避p53调节的生长控制。这种肿瘤发生机制与病毒诱导的肿瘤相似，在病毒诱导的肿瘤中，病毒癌基因产物与p53结合并使其功能失活。
