Target Name: MDM2
NCBI ID: G4193
Other Name(s): MGC5370 | Mdm2, transformed 3T3 cell double minute 2, p53 binding protein | MGC71221 | OTTHUMP00000183488 | Hdm2 | E3 ubiquitin-protein ligase Mdm2 | Ubiquitin-protein ligase E3 Mdm2 | Mdm2, p53 E3 ubiquitin protein ligase homolog | OTTHUMP00000183496 | OTTHUMP00000240290 | OTTHUMP00000240285 | oncoprotein Mdm2 | ACTFS | OTTHUMP00000183489 | MDM2 proto-oncogene, transcript variant 1 | p53-binding protein Mdm2 | MDM2 variant 3 | E3 ubiquitin-protein ligase Mdm2 (isoform g) | MDM2 variant 1 | MDM2 variant FB28 | double minute 2, human homolog of; p53-binding protein | E3 ubiquitin-protein ligase Mdm2 (isoform a) | OTTHUMP00000183495 | MDM2 oncogene, E3 ubiquitin protein ligase | LSKB | OTTHUMP00000240280 | Double minute 2, human homolog of; p53-binding protein | MDM2 proto-oncogene | RING-type E3 ubiquitin transferase Mdm2 | p53-Binding protein MDM2 | MDM2_HUMAN | MDM2 proto-oncogene, transcript variant 3 | HDMX | MDM2 proto-oncogene, E3 ubiquitin protein ligase | Oncoprotein Mdm2 | MDM2 variant FB30 | hdm2 | Double minute 2 protein

Drug Target and Biomarker: MDM2

MDM2 is involved in the repair of DNA double-strand breaks caused by chemotherapy. Chemotherapy-induced double-strand breaks activate kinases that dissociate MDM2 from the MRN complex, leading to MDM2 degradation and facilitating DNA repair through homologous recombination. This process contributes to the acquisition of chemoresistance.

In the absence of stress, MDM2 binds to p53 and promotes its degradation, keeping its levels low. However, under stress conditions such as DNA damage, hypoxia, or oncogene activation, the MDM2/p53 complex is disrupted, leading to p53 stabilization and activation. Mutations in the MDM2 gene can inhibit p53 stabilization under stress and increase susceptibility to oncogenesis.

The balance between MDM2 and p53 expression is disrupted in hepatocellular carcinoma (HCC) cells, with increased MDM2 expression and decreased p53 expression. This imbalance can be achieved through the dysregulation of specific proteins and pathways. Elevated rRNA synthesis in HCC cells can inhibit p53 through decreased availability of ribosomal proteins for MDM2 binding.

MDM2 regulation under DNA damage involves various mechanisms, including expression control, stabilization, modification, and cellular localization. Different splice variants of MDM2 can disrupt the interaction between MDM2 and p53, leading to increased p53 activity. The T/G SNP309 single nucleotide polymorphism can increase MDM2 expression and inhibit p53. Post-translational modifications and interactions with other proteins also influence MDM2 stability and function.

Sirtuins, particularly SIRT1, have been shown to interact with MDM2 and regulate its acetylation status. SIRT1, SIRT6, and SIRT7 can interact with MDM2, and SIRT1 is the major deacetylase that physiologically regulates MDM2 acetylation. Depletion of SIRT1 leads to an accumulation of acetylated MDM2 and a decrease in MDM2 ubiquitination.

Overall, MDM2 plays a crucial role in various cellular processes, including DNA repair, cell cycle regulation, oncogenesis, and the interaction with p53. Dysregulation of the MDM2-p53 pathway can contribute to chemoresistance and the development of cancer, particularly in HCC. The acetylation status of MDM2 is regulated by SIRT1, which has implications for MDM2 stability and activity.

MDM2 is involved in ErbB2 signaling and HSF1 activation, which leads to the upregulation of Hsp90 clients, including mutp53. Inhibition of ErbB2 by lapatinib can lead to the degradation of mutp53 and MDM2.

Under normal conditions, MDM2, along with other factors, maintains p53 at a low level. However, under ribosomal stress, RPs (including S25) can interact with MDM2, inhibiting its E3 ligase activity and leading to the stabilization and activation of p53.

In the context of HIV-1 infection, Tat can have a dual effect on IRF-1 activity. Initially, Tat can stimulate IRF-1 transcriptionally, but later, it can nullify the function of IRF-1 and accelerate its degradation by recruiting the HDM2 E3 ligase.

Nutlin-3 treatment can disrupt the mitochondrial proteome and lead to the dissociation of dihydrolipoamide dehydrogenase from MDM2, potentially affecting p53 protein activation.

The expression level of pre-45s rRNA is positively correlated with tumor size and is associated with poor survival outcome in colorectal cancer patients. The high level of pre-45s rRNA can promote G1/S cell-cycle transition by reducing inhibitory factors on MDM2, leading to decreased p53 levels and contributing to colon tumorigenesis.

Protein Name: MDM2 Proto-oncogene

Functions: E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as a ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also a component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal degradation (PubMed:12821780, PubMed:15053880, PubMed:15195100, PubMed:15632057, PubMed:16337594, PubMed:17290220, PubMed:19098711, PubMed:19219073, PubMed:19837670, PubMed:19965871, PubMed:20173098, PubMed:20385133, PubMed:20858735, PubMed:22128911). Ubiquitinates DCX, leading to DCX degradation and reduction of the dendritic spine density of olfactory bulb granule cells (By similarity). Ubiquitinates DLG4, leading to proteasomal degradation of DLG4 which is required for AMPA receptor endocytosis (By similarity). Negatively regulates NDUFS1, leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis (PubMed:30879903). Binds NDUFS1 leading to its cytosolic retention rather than mitochondrial localization resulting in decreased supercomplex assembly (interactions between complex I and complex III), decreased complex I activity, ROS production, and apoptosis (PubMed:30879903)

More Common Targets

MDM4 | MDN1 | MDS2 | ME1 | ME2 | ME3 | MEA1 | MEAF6 | MEAF6P1 | MEAK7 | Mechanoelectrical transducer (MET) channel | Mechanosensitive Ion Channel | MECOM | MECOM-AS1 | MeCP1 histone deacetylase (HDAC) complex | MECP2 | MECR | MED1 | MED10 | MED11 | MED12 | MED12L | MED13 | MED13L | MED14 | MED14P1 | MED15 | MED15P8 | MED16 | MED17 | MED18 | MED19 | MED20 | MED21 | MED22 | MED23 | MED24 | MED25 | MED26 | MED27 | MED28 | MED29 | MED30 | MED31 | MED4 | MED4-AS1 | MED6 | MED7 | MED8 | MED9 | MEDAG | Mediator Complex | Mediator of RNA Polymerase II Transcription | MEF2A | MEF2B | MEF2C | MEF2C-AS1 | MEF2C-AS2 | MEF2D | MEFV | MEG3 | MEG8 | MEG9 | MEGF10 | MEGF11 | MEGF6 | MEGF8 | MEGF9 | MEI1 | MEI4 | MEIG1 | MEIKIN | MEIOB | MEIOC | MEIOSIN | MEIS1 | MEIS1-AS2 | MEIS1-AS3 | MEIS2 | MEIS3 | MEIS3P1 | MEIS3P2 | Melanin | Melanin-concentrating hormone (MCH) receptor | Melanocortin receptor | Melanoma-Associated Antigen | Melatonin receptor | MELK | MELTF | MELTF-AS1 | Membrane-Bound Protein Tyrosine Phosphatases (rPTPs) | Membrane-spanning 4-domains subfamily A member 4A | MEMO1 | MEMO1P1 | MEMO1P4 | MEMO1P5 | MEN1 | MEOX1 | MEOX2 | MEP1A