p53-Independent Roles of MDM2 in NF-κB Signaling: Implications for Cancer Therapy, Wound Healing, and Autoimmune Diseases

Abstract

Murine double minute-2 (MDM2) is an intracellular molecule with multiple biologic functions. It serves as a negative regulator of p53 and thereby limits cell cycle arrest and apoptosis. Because MDM2 blockade suppresses tumor cell growth in vitro and in vivo, respective MDM2 inhibition is currently evaluated as anti-cancer therapy in clinical trials. However, the anti-proliferative effects of MDM2 inhibition also impair regenerative cell growth upon tissue injury. This was so far documented for tubular repair upon postischemic acute kidney injury and might apply to wound healing responses in general. Furthermore, MDM2 has numerous p53-independent effects. As a new entry, MDM2 was identified to act as a co-transcription factor for nuclear factor-kappa-light-enhancer of activated B cells (NF-κB) at cytokine promoters. This explains the potent anti-inflammatory effects of MDM2 inhibitors in vitro and in vivo. For example, the NF-κB-antagonistic and p53-agonistic activities of MDM2 inhibitors elicit potent therapeutic effects on experimental lymphoproliferative autoimmune disorders such as systemic lupus erythematosus. In this review, we discuss the classic p53-dependent, the recently discovered p53-independent, and the NF-κB-agonistic biologic functions of MDM2. We describe its complex regulatory role on p53 and NF-κB signaling and name areas of research that may help to foresee previously unexpected effects or potential alternative indications of therapeutic MDM2 blockade.

The Double Role of p53 in Cancer and Autoimmunity and Its Potential as Therapeutic Target

“…The role of p53 in inflammation has been extensively in experimental animal models especially in reference to non-organ specific autoimmune diseases [36,43,67,68,69]. Systemic p53-deficient mice develop more rapidly collagen-induced arthritis and antigen-induced arthritis [70,71].…”

Combination of chrysin and cisplatin promotes the apoptosis of Hep G2 cells by up-regulating p53

“…Therefore, we speculate that the change of p53 protein is caused by post-translation modification of the protein. We analyzed the oncoprotein MDM2, a p53-binding protein that promotes p53 degradation [7,33]. Nevertheless, no significant changes of MDM2 and phosphorylated MDM2 were observed at the early stage of chrysin treatment (Fig.…”

Murine Double Minute-2 Prevents p53-Overactivation-Related Cell Death (Podoptosis) of Podocytes

“…The E3 ubiquitin ligase murine double minute-2 (MDM2) regulates proteasomal degradation of the tumor suppressor gene and cell cycle regulator p53 but also, facilitates NF-kB signaling. 5,6 MDM2 overexpression promotes tumor growth, whereas MDM2 antagonists are effective in cancer. 7,8 We have previously shown that MDM2 drives NF-kB signaling-related inflammation in acute tubular injury, whereas its proregenerative effect in the healing phase was exclusively p53-dependent.…”