p53-independent functions of MDM2.

The tumor suppressor p53 is inactivated by overexpression of MDM2 in about 10% of human tumors. However, p53 is inactivated by other mechanisms in the majority of tumors, raising the possibility that MDM2 may be irrelevant to transformation in most cases. However, MDM2 has been reported to have p53-independent functions, in cell cycle control, differentiation, cell fate determination, DNA repair, basal transcription, and other processes. Furthermore, MDM2 appears to contribute to the transformed phenotype in the absence of wild-type p53. Nevertheless, the number of studies is still limited, and the evidence in some cases does not unequivocally show that the functions are p53 independent. We will discuss the circuits of regulation involving MDM2 that do not directly concern p53. Hopefully, future work will consolidate our understanding of the p53-independent pathological functions of MDM2 and will lead to useful therapeutic interventions that target the majority of tumors.