MDM2

GeneName

MDM2

Summary

MDM2, also known as Hdm2 or mdm-2, is a 55kDa E3 ubiquitin ligase that primarily functions in the regulation of the p53 tumour suppressor protein. It is expressed in various tissues, including the nucleus and cytoplasm, and plays a critical role in modulating cellular responses to stress, DNA damage, and apoptosis. MDM2 binds to p53, promoting its ubiquitination and subsequent degradation, thus regulating the cell cycle and preventing excessive apoptosis. Additionally, MDM2 is involved in various cellular processes such as protein localization, signal transduction, and the response to various stimuli, including growth factors and hypoxia.

Importance

MDM2 is relevant to: - Cancer research due to its role in regulating p53, a key player in tumour suppression and cell cycle control. - Understanding mechanisms of drug resistance, as MDM2 overexpression can lead to decreased p53 activity and resistance to chemotherapy. - Cardiovascular development and pathology, given its involvement in cardiac septum morphogenesis and blood vessel development. - Neurobiology, as it plays a role in synaptic transmission and neuronal development through its regulation of protein ubiquitination and degradation.

Top Products

For researchers investigating MDM2, we recommend two excellent primary antibodies that cater to a variety of applications. The first is the highly regarded Anti-MDM2 antibody [2A10] (ab16895), which has garnered 129 citations, reflecting its strong reputation in the field. This antibody is versatile, suitable for Western blotting (WB), immunohistochemistry (IHC), immunocytochemistry (ICC), and flow cytometry (FC). Additionally, we offer the recombinant antibody, Anti-MDM2 antibody [EPR22256-98] (ab259265). This product has been validated for use in WB, ICC, and immunoprecipitation (IP), making it a reliable choice for researchers seeking consistency in their experiments. With 29 citations, it is also gaining traction among scientists studying MDM2. Together, these antibodies provide robust options for effective MDM2 detection and analysis.

Abcam Product Citation Summary

The data indicates that MDM2 is frequently studied in the context of human cancer, particularly in breast cancer and various human cell lines, with a focus on its interactions with the p53 pathway and the regulation of its expression. Additionally, MDM2 is also investigated in mouse liver tissue, highlighting its relevance in studies of AKT activation.

Abcam Product Citation Table

Domain

Region I is sufficient for binding p53 and inhibiting its G1 arrest and apoptosis functions. It also binds p73 and E2F1. Region II contains most of a central acidic region required for interaction with ribosomal protein L5 and a putative C4-type zinc finger. The RING finger domain which coordinates two molecules of zinc interacts specifically with RNA whether or not zinc is present and mediates the heterooligomerization with MDM4. It is also essential for its ubiquitin ligase E3 activity toward p53 and itself.

Function

E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome (PubMed:29681526). 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).

Involvement in disease

Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.

Lessel-Kubisch syndrome

LSKB

An autosomal recessive progeroid syndrome characterized by short stature, pinched facial features, prematurely gray hair, scleroderma-like skin changes, small kidneys and consecutive kidney failure, followed by severe arterial hypertension.

None

The disease may be caused by variants affecting the gene represented in this entry.

Post-translational modifications

Phosphorylation on Ser-166 by SGK1 activates ubiquitination of p53/TP53 (PubMed:19756449). Phosphorylated at multiple sites near the RING domain by ATM upon DNA damage; this promotes its ubiquitination and degradation, preventing p53/TP53 degradation (PubMed:10611322, PubMed:12167711, PubMed:18382127, PubMed:19816404, PubMed:26124108).

Autoubiquitination leads to proteasomal degradation; resulting in p53/TP53 activation it may be regulated by SFN (PubMed:18382127, PubMed:30879903). Also ubiquitinated by TRIM13 (PubMed:21333377). ATM-phosphorylated MDM2 is ubiquitinated by the SCF(FBXO31) complex in response to genotoxic stress, promoting its degradation and p53/TP53-mediated DNA damage response (PubMed:26124108). Deubiquitinated by USP2 leads to its accumulation and increases deubiquitination and degradation of p53/TP53 (PubMed:17290220). Deubiquitinated by USP7 leading to its stabilization (PubMed:15053880).

Sequence Similarities

Belongs to the MDM2/MDM4 family.

Tissue Specificity

Ubiquitous. Isoform Mdm2-A, isoform Mdm2-B, isoform Mdm2-C, isoform Mdm2-D, isoform Mdm2-E, isoform Mdm2-F and isoform Mdm2-G are observed in a range of cancers but absent in normal tissues.

Cellular localization

• Nucleus
• Nucleoplasm
• Cytoplasm
• Nucleus
• Nucleolus
• Nucleus
• Expressed predominantly in the nucleoplasm. Interaction with ARF(P14) results in the localization of both proteins to the nucleolus. The nucleolar localization signals in both ARF(P14) and MDM2 may be necessary to allow efficient nucleolar localization of both proteins. Colocalizes with RASSF1 isoform A in the nucleus.

Alternative names

E3 ubiquitin-protein ligase Mdm2, Double minute 2 protein, Oncoprotein Mdm2, RING-type E3 ubiquitin transferase Mdm2, p53-binding protein Mdm2, Hdm2, MDM2

Database links

swissprot:Q00987 omim:164785 entrezGene:4193

Other research areas

• Epigenetics