MDM2 controls gene expression independently of p53 in both normal and cancer cells

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.