BACKGROUND The p14(ARF)/MDM2/p53 pathway plays an important role in modulation of DNA damage and oxidative stress responses. The aim of this study was to determine whether genetic variants in MDM2 and p14(ARF) are associated with risk of salivary gland carcinoma (SGC). METHODS Four single nucleotide polymorphisms (SNPs) in MDM2 and p14(ARF) (MDM2-rs2279744, MDM2-rs937283, p14(ARF)-rs3731217, ...

Drugs targeting MDM2's hydrophobic pocket activate p53. However, these agents act allosterically and have agonist effects on MDM2's protein interaction landscape. Dominant p53-independent MDM2-drug responsive-binding proteins have not been stratified. We used as a variable the differential expression of MDM2 protein as a function of cell density to identify Nutlin-3 responsive MDM2-binding prot...

p53 plays a central role in tumor suppression. It does so by inducing anti-proliferative processes as a response to various tumor-promoting stresses. p53 is regulated by the ubiquitin ligase Mdm2. The optimal function of Mdm2 requires Daxx, which stabilizes Mdm2 through the deubiquitinase Hausp/USP7 and also directly promotes Mdm2's ubiquitin ligase activity towards p53. The Daxx-Mdm2 interacti...

PURPOSE Reactivation of p53 tumor suppressor activity in diseases such as soft-tissue sarcoma is considered an attractive means of targeted therapy. By systematically assessing alterations affecting the p53 pathway, we aimed to (a) classify sarcoma subtypes, (b) define a potential role in malignancy, and (c) identify potential patient biomarkers in this heterogeneous disease. EXPERIMENTAL DES...

MDM2 is a substrate of caspase-3 in p53-mediated apoptosis. In addition, MDM2 mediates its own ubiquitination in a RING finger-dependent manner. Thus, we investigated whether MDM2 is degraded through a ubiquitin-dependent proteasome pathway in the absence of p53. When HL-60 cells, p53 null, were treated with etoposide, MDM2 was markedly decreased prior to caspase-3-dependent retinoblastoma tumo...

Oncoprotein MDM2 inhibits p53-dependent cell cycle arrest and apoptosis. MDM2-overexpressing human cancer cell lines (n = 3) were found to be resistant to growth inhibition after infection by p53-expressing adenovirus (AdPS3), as compared to low MDM2-expressing tumors (n 3), in vitro. The growth of MDM2-overexpressing tumors, however, was inhibited by p21-expressing adenovirus (Ad-p21) infectio...

It is believed that Mdm2 suppresses p53 in two ways: transcriptional inhibition by direct binding, and degradation via its E3 ligase activity. To study these functions physiologically, we generated mice bearing a single-residue substitution (C462A) abolishing the E3 function without affecting p53 binding. Unexpectedly, homozygous mutant mice died before E7.5, and deletion of p53 rescued the let...

The RING domain of MDM2 that is essential for its E3 ligase activity mediates binding to itself and its structural homologue MDMX. Whereas it has been reported that RING domain interactions are critical, it is not well understood how they affect the E3 ligase activity of MDM2. We report that the E3 ligase activity requires the RING domain-dependent complex formation. In vivo, MDM2 and MDMX hete...

INTRODUCTION The presence of a variety of MDM2 splice variants has been reported in a range of different tumor types and is associated with poor patient prognosis. Furthermore, several MDM2 variants have been shown to have oncogenic properties. Despite this, MDM2 splice variants have not been comprehensively characterized in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS MDM2 spli...

MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2, found in many human tumors, effectively impairs p53 function. Inhibition of MDM2-p53 interaction can stabilize p53 and may offer a novel strategy for cancer therapy. Here, we identify potent and selective small-molecule antagonists of MDM2 a...