| A prominent phenotype observed in many malignancies is a dramatic over-expression of MDM2, however the cellular impact and consequences of this phenotype remain largely elusive. Since the identification of MDM2, the majority of the literature has focused on the role of MDM2 as a negative regulator of the p53 tumor suppressor, despite many lines of evidence to suggest that MDM2 has unique and independent functions. The p53-independent cellular functions of MDM2 remain poorly described. This work investigates the impact of exogenous MDM2 over-expression on cellular signaling, stress, and survival pathways. Exogenous expression of MDM2 induces a cell stress and cell death response that is p53-independent. This cell death response engages the mitochondrial pathway of apoptosis and is caspase-dependent. The pro-apoptotic BCL-2 proteins BIM and BAX are essential for this phenotype, which is also be regulated by the anti-apoptotic proteins BCL-2 and BCL-xL. In addition, treatment with with the BCL-2 inhibitor ABT-737 sensitizes cells to MDM2-induced death, further indicating a regulatory role for the BCL-2 family of proteins in this process.;This work identifies a pro-apoptotic domain at the N-terminus of MDM2 that is both necessary and sufficient for MDM2-induced stress and cell death. Expression of this pro-apoptotic domain results in massive induction of oxidative stress, DNA damage accumulation, chromosomal instability, and eventually cell death. Data presented here suggest that cells expressing high levels of MDM2 are particularly sensitive to chemotherapeutic DNA damaging agents and eventually succumb to death. This novel pro-apoptotic domain of MDM2 that has been uncovered has the potential to serve as the basis for the creation of small peptide with potential therapeutic implications.;Many MDM2-p53 inhibitors are beginning to enter clinical trials for the treatment of tumors that harbor MDM2 amplifications with concurrent wild-type p53 expression. This work suggests that these inhibitors may have potential therapeutic benefit in tumors that lack p53 or harbor p53 mutations by stabilizing the N-terminus of MDM2 and exploiting its pro-apoptotic functions. By identifying novel signaling pathways targeted by MDM2, we can potentially categorize tumors with MDM2 amplification as potential responders or non-responders to an MDM2 peptide, as well as determine the optimal combination therapies to maximize sensitivity. This work has substantiated that pharmacologically targeting the MDM2 network to either switch on MDM2-mediated tumor suppression or switch off the oncogenic functions of MDM2 have the potential to provide cancer patients with enhanced chemotherapeutic strategies. |
