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

Abstract

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.

Twenty years of p53 research: structural and functional aspects of the p53 protein

“…), or with the cellular protein MDM-2. This protein has been identi®ed as the product of mdm-2 oncogene, which is ampli®ed in some types of tumour Oliner et al, 1992). This is an alternative mechanism of p53 inactivation which is common in many tumour types (including soft tissue sarcomas, neural tumours, bladder, cervical and breast carcinomas as well as leukaemias).…”

“…For instance the product of the mdm2 oncogene, which binds and is believed to mask the activation domain of p53, is overexpressed in certain tumours, resulting in the abrogation of p53 function, accompanied by the proteolytic degradation of p53, mediated by the ubiquitin pathway Oliner et al, 1992Oliner et al, , 1993Midgley and Lane, 1997). Additional data showed that p53 may down-regulate the expression from a number of other promoters including those of the c-fos, c-jun, c-myc, b-actin, hsc-70, IL-6 genes (Ginsberg et al, 1991;Lechner et al, 1992;Ko and Prives, 1996).…”

The carboxy terminus of p53 mimics the polylysine effect of protein kinase CK2-catalyzed MDM2 phosphorylation

“…Overexpression of the mdm2 gene in BALB/c 3T3 cells confers tumorigenicity in nude mice (Fakharzadeh et al, 1991). Later also the corresponding human mdm2 gene was identi®ed (Oliner et al, 1992). The mdm2 gene encodes a 490 amino acid protein which binds to the p53 protein and is thought to function as a regulator of p53.…”

“…The mdm2 gene encodes a 490 amino acid protein which binds to the p53 protein and is thought to function as a regulator of p53. The MDM2 protein binds to a region in the N-terminus of p53 representing the transcription activation domain of p53 Oliner et al, 1992). Overexpression of MDM2 protein inhibits both the transcriptional activation and the repression activities of p53 (Chen et al, 1995;Momand et al, 1992).…”

Roles for negative cell regulator 14-3-3σ in control of MDM2 activities

“…Importantly, MDM2 is amplified and overexpressed in several types of human malignancy, including sarcomas, breast carcinomas and brain tumors (Oliner et al, 1992;Momand et al, 1998). MDM2 is regulated by negative regulators including ADP-ribosylation factor, promyelocytic leukemia and ribosomal proteins L5, L11, L23, but positively regulated by Gankyrin, YY1 and kinase associated phosphatase 1 (reviewed in Lee and Lozano, 2006).…”