The Role of MDM2 in Promoting Genome Stability versus Instability

Abstract

In cancer, the mouse double minute 2 (MDM2) is an oncoprotein that contributes to the promotion of cell growth, survival, invasion, and therapeutic resistance. The impact of MDM2 on cell survival versus cell death is complex and dependent on levels of MDM2 isoforms, p53 status, and cellular context. Extensive investigations have demonstrated that MDM2 protein-protein interactions with p53 and other p53 family members (p63 and p73) block their ability to function as transcription factors that regulate cell growth and survival. Upon genotoxic insults, a dynamic and intricately regulated DNA damage response circuitry is activated leading to release of p53 from MDM2 and activation of cell cycle arrest. What ensues following DNA damage, depends on the extent of DNA damage and if the cell has sufficient DNA repair capacity. The well-known auto-regulatory loop between p53-MDM2 provides an additional layer of control as the cell either repairs DNA damage and survives (i.e., MDM2 re-engages with p53), or undergoes cell death (i.e., MDM2 does not re-engage p53). Furthermore, the decision to live or die is also influenced by chromatin-localized MDM2 which directly interacts with the Mre11-Rad50-Nbs1 complex and inhibits DNA damage-sensing giving rise to the potential for increased genome instability and cellular transformation.

Keywords: DNA damage; MDM2; genome instability; p53.

Figure 1

Illustrative Representation of MDM2-FL and MDM2 Isoforms (MDM2-A, MDM2-B, and MDM2-C). Adapted and modified from Huun et al. [5]. NES = nuclear export signal, NoLS = nucleolar localization signal, and NLS = nuclear localization signal.

Figure 2

Regulation of p53 by MDM2 and MDMX following DNA damage. (A) In the absence of DNA damage, p53 levels and activation are tightly controlled by the MDM2-MDMX complex, and (B) upstream kinases act as sensors of DNA damage to regulate MDM2, MDMX, and p53; (C) Upon resolution of DNA damage, the p53/MDM2 feedback loop controls p53 levels. Ub = ubiquitin, P = phosphorylation site (purple arrow = phosphorylation by ATM; red arrow = phosphorylation by c-Abl; black = phosphorylation by CHK2); S = serine, and T = tyrosine.

Figure 3

Regulation of the MDM2-signaling network by the pro-survival kinase AKT. AKT-mediated phosphorylation of Mdm2 promotes Mdm2 entry into the nucleus and enhances its ubiquitination-promoting function which leads to p53 inactivation, inhibition of apoptosis, and increased survival. Phosphorylation of MDMX by AKT stabilizes MDM2 E3-ligase activity.

Figure 4

Model of inhibition of DNA break repair by Mdm2. Double-strand break induced by irradiation is detected by the M/R/N complex. ATM is recruited to the DNA-strand break and activated by auto-phosphorylation. In turn, activated ATM phosphorylates Nbs1, histone H2AX, p53, and Mdm2. MDM2 delays the early phosphorylation process, which is necessary for DNA double-strand break repair, causing inefficient DNA break repair and if not repaired could lead to genomic instability and tumorigenesis (Modified from Bouska and Eischen [56,84,93]). Inhibition = Activation = .