Amplification of a gene encoding a p53-associated protein in human sarcomas

DESPITE extensive data linking mutations in the p53 gene to human tumorigenesis1, 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 iden-tified by virtue of its amplification in a spontaneously transformed derivative of mouse BALB/c cells2 and the MDM2 protein subsequently shown to bind to p53 in rat cells transfected with pS3 genes3,4. 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 12ql3–14. Because this chromosomal position appears to be altered in many sarcomas5–7, 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 tumours8,9, in which viral oncogene products bind to and functionally inactivate p53.