The mouse double minute 2 (MDM2) protein is an E3-ubiquitin ligase recognized for its role as a negative regulator of the tumor suppressor protein p53 [1]. Genetic studies showing that embryonic lethality of mice lacking MDM2 could only be rescued by the concomitant deletion of Tp53 suggested that the main physiological role of MDM2 is to inhibit p53. Furthermore, MDM2/p53 double knock-out (KO) mice displayed a cancer incidence similar to that observed in Tp53 KO animals, supporting the notion that the major role of MDM2 is to interfere with p53 activities [2, 3]. However, several reports have challenged this notion and convincingly showed that MDM2 functions extend beyond p53 regulation both in normal and cancer cells.

A first hint came from the analysis of transgenic mice overexpressing MDM2 in the absence of functional p53. These mice displayed higher incidence of sarcomas compared to p53-null animals, indicating a role for MDM2 in tumorigenesis independent of p53 [4]. This notion was further supported by the ability of MDM2 to transform p53-null cells in vitro [5] and by the identification of several MDM2 splice variants that are unable to bind p53 in certain tumor types [6]. Moreover, although rare, some soft tissue tumors exhibit both overexpression of MDM2 and mutations of Tp53, a feature that correlates with a higher tumor grade and a poorer prognosis compared to cancer patients harboring only one of these genetic alterations [7].

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