E3 ubiquitin-protein ligase Mdm2

Function

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. 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. 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.

Classification

Family (Pfam)

PF02201 SWIB, PF13920 zf-C3HC4_3, PF00641 Zn_ribbon_RanBP

InterPro

Mdm2, MDM2_mRING-HC-C2H2C4, p53_neg-reg_MDM_2/4, SWIB_MDM2_dom_sf, SWIB_MDM2_domain, Znf_RanBP2, Znf_RanBP2_sf, Znf_RING, Znf_RING/FYVE/PHD

Functional cluster

Zinc-Finger & Chromatin Regulatory Proteins

Experimental structures · PDB · 147

• 1RV1 X-ray 2.30A
• 1T4E X-ray 2.60A
• 1T4F X-ray 1.90A
• 1YCR X-ray 2.60A
• 1Z1M NMR
• 2AXI X-ray 1.40A
• 2C6A NMR
• 2C6B NMR
• 2F1Y X-ray 1.70A
• 2FOP X-ray 2.10A
• 2GV2 X-ray 1.80A
• 2HDP NMR
• … and 135 more

A predicted model is available from AlphaFold.

Gene Ontology · 82

• GO:0005737 cytoplasm
• GO:0005829 cytosol
• GO:0030666 endocytic vesicle membrane
• GO:0098978 glutamatergic synapse
• GO:0005730 nucleolus
• GO:0005654 nucleoplasm
• GO:0005634 nucleus
• GO:0005886 plasma membrane
• GO:0014069 postsynaptic density
• GO:0032991 protein-containing complex
• GO:0008097 5S rRNA binding
• GO:0097718 disordered domain specific binding
• GO:0019899 enzyme binding
• GO:0042802 identical protein binding
• GO:0016874 ligase activity
• GO:0061663 NEDD8 ligase activity
• GO:0002039 p53 binding
• GO:0042975 peroxisome proliferator activated receptor binding
• GO:0019904 protein domain specific binding
• GO:0033612 receptor serine/threonine kinase binding
• GO:0043021 ribonucleoprotein complex binding
• GO:0019789 SUMO transferase activity
• GO:0043130 ubiquitin binding
• GO:0061630 ubiquitin protein ligase activity
• GO:0031625 ubiquitin protein ligase binding
• GO:0004842 ubiquitin-protein transferase activity
• GO:0008270 zinc ion binding
• GO:1990000 amyloid fibril formation
• GO:0006915 apoptotic process
• GO:0071312 cellular response to alkaloid
• GO:0071236 cellular response to antibiotic
• GO:0071391 cellular response to estrogen stimulus
• GO:0071480 cellular response to gamma radiation
• GO:0071363 cellular response to growth factor stimulus
• GO:0070301 cellular response to hydrogen peroxide
• GO:0071456 cellular response to hypoxia
• GO:0071375 cellular response to peptide hormone stimulus
• GO:0071494 cellular response to UV-C
• GO:0071301 cellular response to vitamin B1
• GO:0030330 DNA damage response, signal transduction by p53 class mediator
• GO:0045184 establishment of protein localization
• GO:0072537 fibroblast activation
• GO:0043066 negative regulation of apoptotic process
• GO:0043518 negative regulation of DNA damage response, signal transduction by p53 class mediator
• GO:0045892 negative regulation of DNA-templated transcription
• GO:1902254 negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator
• GO:0010977 negative regulation of neuron projection development
• GO:0010955 negative regulation of protein processing
• GO:1901797 negative regulation of signal transduction by p53 class mediator
• GO:0000122 negative regulation of transcription by RNA polymerase II
• GO:0008284 positive regulation of cell population proliferation
• GO:0010628 positive regulation of gene expression
• GO:0045931 positive regulation of mitotic cell cycle
• GO:0051149 positive regulation of muscle cell differentiation
• GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process
• GO:0046827 positive regulation of protein export from nucleus
• GO:1904754 positive regulation of vascular associated smooth muscle cell migration
• GO:1904707 positive regulation of vascular associated smooth muscle cell proliferation
• GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process
• GO:0051865 protein autoubiquitination
• GO:0031648 protein destabilization
• GO:0034504 protein localization to nucleus
• GO:0000209 protein polyubiquitination
• GO:0016925 protein sumoylation
• GO:0016567 protein ubiquitination
• GO:0065003 protein-containing complex assembly
• GO:0051603 proteolysis involved in protein catabolic process
• GO:0051726 regulation of cell cycle
• GO:0099149 regulation of postsynaptic neurotransmitter receptor internalization
• GO:0042176 regulation of protein catabolic process
• GO:0099576 regulation of protein catabolic process at postsynapse, modulating synaptic transmission
• GO:0046677 response to antibiotic
• GO:0042220 response to cocaine
• GO:0045472 response to ether
• GO:1904404 response to formaldehyde
• GO:0010039 response to iron ion
• GO:0032026 response to magnesium ion
• GO:0048545 response to steroid hormone
• GO:0009636 response to toxic substance
• GO:1990785 response to water-immersion restraint stress
• GO:0009410 response to xenobiotic stimulus
• GO:0006511 ubiquitin-dependent protein catabolic process

Disease associations

• obsolete accelerated tumor formation, susceptibility to MONDO:0013733
• lessel-kubisch syndrome MONDO:0032868

Drugs targeting this protein · 4

• IDASANUTLIN inhibitor
• NAVTEMADLIN inhibitor
• SIREMADLIN inhibitor
• ALRIZOMADLIN inhibitor

Related proteins · sequence + function similarity

• E3 ubiquitin-protein ligase Mdm2 0.99
• E3 ubiquitin-protein ligase Mdm2 0.99
• E3 ubiquitin-protein ligase Mdm2 0.99
• E3 ubiquitin-protein ligase Mdm2 0.97
• E3 ubiquitin-protein ligase Mdm2 0.95
• E3 ubiquitin-protein ligase Mdm2 0.94
• E3 ubiquitin-protein ligase Mdm2 0.88
• Protein Mdm4 0.86
• Protein Mdm4 0.86
• Protein Mdm4 0.85
• Protein Mdm4 0.83
• Protein Mdm4 0.81

Co-cited proteins · studied together in the literature

• Pyrin and HIN domain-containing protein 1 1 shared papers
• Protein Mdm4 4 shared papers
• E3 ubiquitin-protein ligase Mdm2 1 shared papers
• Viral IRF4-like protein 1 shared papers
• Ubiquitin carboxyl-terminal hydrolase 2 2 shared papers
• E3 ubiquitin-protein ligase Mdm2 4 shared papers
• E3 ubiquitin-protein ligase Mdm2 1 shared papers
• Mdm2-binding protein 1 shared papers
• Cellular tumor antigen p53 12 shared papers
• CDKN2A-interacting protein 1 shared papers
• Bis(5'-adenosyl)-triphosphatase 1 shared papers
• RING1 and YY1-binding protein 1 shared papers

Literature · 70 cited papers

• Structure of nascent 5S RNPs at the crossroad between ribosome assembly and MDM2-p53 pathways. Nat. Struct. Mol. Biol. · 2023
• FAM193A is a positive regulator of p53 activity. Cell Rep. · 2023
• MDM2 Integrates Cellular Respiration and Apoptotic Signaling through NDUFS1 and the Mitochondrial Network. Mol. Cell · 2019
• A Designed Peptide Targets Two Types of Modifications of p53 with Anti-cancer Activity. Cell Chem. Biol. · 2018
• Dysfunction of the MDM2/p53 axis is linked to premature aging. J. Clin. Invest. · 2017
• Nucleolar GTP-binding protein-1 (NGP-1) promotes G1 to S phase transition by activating cyclin-dependent kinase inhibitor p21 Cip1/Waf1. J. Biol. Chem. · 2015
• F-box protein FBXO31 directs degradation of MDM2 to facilitate p53-mediated growth arrest following genotoxic stress. Proc. Natl. Acad. Sci. U.S.A. · 2015
• Rad54B serves as a scaffold in the DNA damage response that limits checkpoint strength. Nat. Commun. · 2014
• The 5S RNP couples p53 homeostasis to ribosome biogenesis and nucleolar stress. Cell Rep. · 2013
• Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
• PDCD5 interacts with p53 and functions as a positive regulator in the p53 pathway. Apoptosis · 2012
• BMK1 is involved in the regulation of p53 through disrupting the PML-MDM2 interaction. Oncogene · 2013
• … and 58 more in the literature graph