MDM2 — master regulator of the p53 tumor suppressor protein

Abstract

MDM2 is an oncogene that mainly functions to modulate p53 tumor suppressor activity. In normal cells the MDM2 protein binds to the p53 protein and maintains p53 at low levels by increasing its susceptibility to proteolysis by the 26S proteosome. Immediately after the application of cellular stress, the ability of MDM2 to bind to p53 is blocked or altered in a fashion that prevents MDM2-mediated degradation. As a result, p53 levels rise, causing cell cycle arrest or apoptosis. In this review, we present evidence for the existence of three highly conserved regions (CRs) shared by MDM2 proteins and MDMX proteins of different species. These highly conserved regions encompass residues 42–94 (CR1), 301–329 (CR2), and 444–483 (CR3) on human MDM2. These three domains are respectively important for binding p53, for binding the retinoblastoma protein, and for transferring ubiquitin to p53. This review discusses the major milestones uncovered in MDM2 research during the past 12 years and potential uses of this knowledge in the fight against cancer.

Introduction

Murine Double Minute Clone 2 (MDM2) was originally cloned from purified acentric chromosomes harbored within a spontaneously transformed Balb/c3T3 cell line called 3T3DM (Cahilly-Snyder et al., 1987). The rationale for cloning genes from these abnormal chromosomes, also known as double minutes, is that they often contain amplified genes that contribute to cellular proliferation and tumorigenesis. MDM2 was the second of two tandem genes cloned together from these amplified sequences. When a genomic clone of MDM2 was amplified in rodent cells, it conferred high tumorigenic potential in nude mice (Fakharzadeh et al., 1991). This observation gave the first suggestion that MDM2 is an oncogene. Independently, researchers in another laboratory were isolating proteins bound to the p53 tumor suppressor protein with the rationale that such proteins might regulate p53 activity (Momand et al., 1992). In a cultured transformed rat fibroblast line that overexpresses a temperature-sensitive mutant p53, a 90 kDa phosphoprotein was observed to co-immunoprecipitate with p53 at the permissive temperature. The p90 kDa protein turned out to be the product of the MDM2 gene. It was subsequently found that overexpression of the MDM2 gene blocked p53-mediated transactivation of a reporter gene bearing a p53-responsive element. Thus, a potential mechanism of MDM2-mediated oncogenicity was established-inactivation of the p53 tumor suppressor gene. In a third laboratory, the human homologue of MDM2 was mapped to chromosome 12q13–14 and was shown to be amplified in approximately 30% of osteosarcomas and soft tissue tumors (Oliner et al., 1992). Therefore, within a span of 2 years a new oncogene was discovered, a mechanism of its action was proposed, and its involvement in human cancers was established.

Since 1992, researchers have uncovered a clearer picture of how MDM2 modulates p53 activity and of the prevalence of MDM2 abnormalities in human cancers. Several reviews have covered MDM2 (Freedman et al., 1999, Haines, 1997, Juven-Gershon and Oren, 1999, Lane and Hall, 1997, Momand and Zambetti, 1997, Piette et al., 1997, Prives, 1998); however, the research pace has quickened and some major discoveries have been made quite recently. The purpose of this review is to point out fundamental milestones reached during the course of research into this interesting gene and to present an in-depth analysis of more recent progress in our understanding of MDM2's varied functions. Finally, we will chart potential areas of future research that will likely be important in furthering our understanding of this critical growth-control molecule. At the outset, we wish to apologize to the authors of those studies that could not be cited owing to space constraints.