MDM2 gene

The MDM2 gene (MDM2 stands for Mouse Double Minute 2 or MDM2 protooncogene) is a protein-coding gene located on chromosome 12q15.

The MDM2 gene encodes a nuclear localized E3 ubiquitin ligase (Note: Ligases are enzymes that catalyze the joining of two molecules with simultaneous hydrolysis of the diphosphate bond in ATP or a similar triphosphate. They belong to the enzyme class E.C. 6, which also includes synthases and carboxylases). There is a pseudogene for this gene on chromosome 2. Alternative splicing results in numerous transcript variants, many of which can only be expressed in tumor cells. An important paralog of this gene is MDM4.

The encoded protein can promote tumor formation by marking tumor suppressor proteins such as p53 for proteasomal degradation. This NDM2 gene itself is transcriptionally regulated by p53. Overexpression or amplification of this locus is found in a variety of different tumor entities.

The nuclear localized E3 ubiquitin ligase (Mdm2), encoded by the MDM2 gene, mediates its own ubiquitination and the ubiquitination of p53/TP53, leading to its degradation by the proteasome (Liang L et al. 2018) . E3 ubiquitin ligase thus inhibits cell cycle arrest mediated by p53/TP53 and p73/TP73 as well as apoptosis by binding to its transcriptional activation domain (Stevenson LF et al. (2007). The E3 ubiquitin ligase also acts as ubiquitin ligase E3 for ARRB1.

It enables the nuclear export of p53/TP53. Promotes proteasome-dependent, ubiquitin-independent degradation of the retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. The E3 ubiquitin ligase is a component of the TRIM28/KAP1-MDM2-p53/TP53 complex, which is involved in the stabilization of p53/TP53. It is also a component of the TRIM28/KAP1-ERBB4-MDM2 complex, which links the growth factor and DNA damage response pathways, and mediates the ubiquitination and subsequent proteasome degradation of DYRK2 in the nucleus. Ubiquitinates IGF1R as well as the SNAI1 protein and promotes their proteasomal degradation (Girnita L et al. 2003; Stevenson LF et al. 2007; Taira N et al. 2010).

The Mdm2 ubiquitin ligase ubiquitinates the DCX protein, leading to DCX degradation and a reduction in the dendritic spine density of the olfactory bulb granule cells (see DCX gene below). The ligase ubiquitinates DLG4, leading to proteasomal degradation of DLG4, which is required for endocytosis of the AMPA receptor . Negatively regulates NDUFS1, leading to reduced mitochondrial function, pronounced oxidative stress and binding to the mitochondrial apoptosis pathway (Elkholi R et al. 2019). Binds NDUFS1, leading to its cytosolic retention rather than mitochondrial localization, which in turn leads to decreased supercomplex formation (interactions between complex I and complex III), decreased complex I activity, decreased ROS production and apoptosis.

Diseases associated with MDM2 include:

• Lessel-Kubisch syndrome and
• accelerated tumor formation(hyperprogression).

1. Elkholi R et al. (2019) MDM2 Integrates Cellular Respiration and Apoptotic Signaling through NDUFS1 and the Mitochondrial Network. Mol Cell 74:452-465.
2. Girnita L et al. (2003) Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor. Proc Natl Acad Sci U S A 100:8247-8252.
3. Liang L et al. (2018) A Designed Peptide Targets Two Types of Modifications of p53 with Anti-cancer Activity. Cell Chem Biol 25:761-774.
4. Stevenson LF et al. (2007) The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. EMBO J 26:976-86.
5. Taira N et al. (2010) ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage. J Biol Chem 285:4909-4919.