Mdm2 in growth signaling and cancer

Abstract

Genetic and biochemical evidence have demonstrated a direct link between Mdm2 and cancer development. Elevated expression of Mdm2 is observed in a significant proportion of different types of cancer. The major contribution of Mdm2 to the development of cancer is through a tight inhibition of the activities and stability of the tumor suppressor p53. However, extensive studies over the past few years have identified p53-independent functions of Mdm2, in the regulation of several important cellular processes and multiple signaling pathways. The promotion of cell cycle progression by Mdm2 is mediated via p53 inhibition, and by regulating the pRb/E2F complex. Mdm2 is an important mediator of growth and survival signaling in the PI3K/Akt pathway, an activator of certain steroid hormone receptors, and an inhibitor of the TGF-beta growth restrictive pathway. Thus, the impact on these pathways by deregulated Mdm2, as often observed in cancer, can be oncogenic in a permissible environment. This renders Mdm2 as an important target for the development of anti-cancer drugs.