Targeted expression of MDM2 uncouples S phase from mitosis and inhibits mammary gland development independent of p53.

Abstract

MDM2 is a cellular protein that binds to and inactivates the p53 tumor suppressor protein. Although mdm2has been shown to function as an oncogene in vitro, all studies to date have assessed MDM2 activities in the presence of p53, implicating p53 inactivation in MDM2-directed transformation. To determine the role of MDM2 in the cell cycle and in tumorigenesis and whether or not this role is dependent on p53, an MDM2 minigene was expressed during gestation and lactation in the mammary gland of both wild-type p53 (p53+/+) and p53 knockout (p53-/-) mice using the bovine 3-lactoglobulin promoter. In six different transgenic mouse lines, deregulated expression of MDM2 inhibited normal development and morphogenesis of the mammary gland, and caused cellular hypertrophy and nuclear abnormalities. These abnormalities included both multinucleated cells and enlarged cells with giant nuclei. Although there were fewer epithelial cells present in the transgenic mammary gland, no apoptosis was observed. Instead, BrdU incorporation and PCNA staining showed that 12%-27% of the transgenic mammary epithelial cells were in S phase at a time when normal cells were terminally differentiated. Analysis of DNA content showed that 30%-45% of the cells were polyploid, with DNA contents up to 16N, indicating that overexpression of MDM2 caused mammary epithelial cells to undergo multiple rounds of S phase without cell division. This phenotype was similar in the p53+/+ and p53-/-background, demonstrating a role for MDM2 in the regulation of DNA synthesis that is independent of the ability of MDM2 to inhibit p53 activity. Additionally, multiple lines of BLGMDM2 transgenic mice developed mammary tumors, confirming that overproduction of MDM2 contributes to tumorigenesis in epithelial cells in vivo.

Elevated Mdm2 expression induces chromosomal instability and confers a survival and growth advantage to B cells

“…In support of this idea, loss of one allele of Mdm2 in ARF-null mouse embryo fibroblasts, which are predisposed to transformation, resulted in increased chromosomal stability with fewer breaks, fusions and exchanges and a decreased transformation ability (Wang et al, 2006). Moreover, Mdm2 overexpression in breast epithelial cell-specific Mdm2 transgenic mice in the presence or absence of p53, led to multinucleated polyploid epithelial cells (Lundgren et al, 1997). We have observed similar findings to these in fibroblast cells (TL and CME, unpublished data), but rarely have we seen multinucleated hematopoietic cells from overexpressing Mdm2.…”

Mdm2: keeping p53 under control

“…Targetted overexpression of an Mdm2 minigene in the mammary gland led to uncontrolled entry into Sphase, polyploidy and tumor formation both in p53 wild type and p53 null mice (Lundgren et al, 1997). In conclusion, Mdm2 appears to be involved in cellular proliferation and transformation, not only through its ability to modulate p53's transcriptional activity, but also through additional functions which may be provided by both its N-terminal and C-terminal domains.…”

A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans

“…Consistent with its role as a negative regulator of an important tumor suppressor, altering MDM2 levels has been shown in many mouse models to affect p53-dependent tumor suppression (Poyurovsky and Prives, 2006). For example, the overexpression of MDM2 in either the whole mouse (Jones et al, 1998), the mammary epithelium (Lundgren et al, 1997) or the adult dorsal skin (Ganguli et al, 2000) leads to significantly increased tumor formation. In contrast, even a modest reduction of MDM2 levels in mice enhances tumor resistance (Alt et al, 2003;Mendrysa et al, 2006).…”