MDM2 (transformed mouse 3T3 cell double minute 2, p53 binding protein)

2006-12-01   Wenrui Duan , Miguel A Villalona-Calero 

Comprehensive Cancer Center, 1230 JCHRI, 300 West 10th Ave, Columbus, Ohio 43210, USA

Identity

HGNC
LOCATION
12q15
LOCUSID
ALIAS
ACTFS,HDMX,LSKB,hdm2
FUSION GENES

DNA/RNA

Description

The gene encompasses 33 kb of DNA; 12 exons.

Transcription

2.3 kb nucleotides mRNA. 1476 b open reading frame.

Proteins

Description

491 amino acids; 90 kDa protein.

Expression

Expression of MDM2 during embryogenesis was studied in mice. During 14.5 to 18.5 days of prenatal development, the nasal respiratory epithelium expresses high levels of MDM2 RNA and protein in both wild type and p53 null embryos. MDM2 expression during development is tissue-specific and is independent of p53. The mdm2 basal mRNA expression appears relatively moderate in most organs in adult mice.
MDM2 gene was overexpressed in some types of leukemias and lymphomas. Overexpression was significantly more frequent in the low-grade type of B-cell non-Hodgkins lymphoma (B-NHL) than in the intermediate/high grade types of lymphoma and the overexpression was also significantly more frequent in the advanced rather than the earlier stages of B-cell chronic lymphocytic leukemia (B-CLL).

Localisation

MDM2 protein was found in nucleus and cytoplasm.

Function

MDM2 was originally cloned from transformed Balb/c3T3 cell line called 3T3DM and was identified as an amplified oncogene in murine cell lines. MDM2 was shown to be amplified in approximately 30% of osteosarcomas and soft tissue tumors and was subsequently found to act as an ubiquitin ligase promoting proteasome dependent degradation of p53. MDM2 is also a transcriptional target of p53 such that p53 activity controls the expression and protein level of its own negative regulator, providing for an elegant feedback loop. MDM2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein. The MDM2-p53 complex also inhibits p53 mediated transactivation.
MDM2 knockout mouse embryos died during development and deletion of the p53 gene rescues MDM2 null embryos. These studies suggested that p53 is lethal in the absence of MDM2 during mouse development and MDM2 is a critical regulator to control p53 activity.
In addition, MDM2 involves nuclear export of p53 protein. Interaction between the p53 and MDM2 is not sufficient to mediate p53 degradation. The p53 MDM2 complex must be shuttled from the nucleus to the cytoplasm in order for p53 degradation.
Besides, the MDM2 protein also promotes RB (retinoblastoma) protein degradation in a proteasome-dependent manner in human tumor cell lines. MDM2 overexpression contributes to cancer development in part by destabilizing RB.
Interaction between MDM2 and the tumor suppressor genes p53 and Rb lead to deregulate cell proliferation and apoptosis. MDM2 is a key factor in human tumorigenesis.
Both MDM2 and Pirh2 (RCHY1) proteins are p53 ubiquitin-protein E3 ligases promoting for degradation of p53 protein. However, MDM2 operates in a distinct manner from Pirh2 in response to DNA damage in cancer cells. MDM2 protein is reduced or absent in the p53 null cells compared to the p53 positive cells, Whereas, Pirh2 expression is not affected by the status of p53.
A single nucleotide polymorphism (SNP309) found in the MDM2 promoter is shown to increase the affinity of the transcriptional activator Sp1, resulting in higher levels of MDM2 RNA and protein and the subsequent attenuation of the p53 pathway. In humans, SNP309 is shown to associate with accelerated tumor formation in both hereditary and sporadic cancers.

Homology

The MDM2 gene has been identified in various organisms including mammals, amphibians and fishes. It belongs to the ring finger ubiquitin protein E3 ligase family, containing Conserved RING-finger Domain.

Mutations

Note

MDM2 mutations are uncommon. Point mutations were reported in human cancers.

Implicated in

Entity name
Soft tissue tumors and osteosarcomas.
Disease
A set of data of MDM2 amplification based on 3889 samples from tumors or xenografts from 28 tumor types from previously published sources was collected. The overall frequency of MDM2 amplification in these human tumors was 7%. Gene amplification was observed in 19 tumor types, with the highest frequency observed in soft tissue tumors (20%), osteosarcomas (16%) and esophageal carcinomas (13%).
Oncogenesis
MDM2 is amplified in many cancers. Because the MDM2 is an ubiquitin-protein ligase that promotes p53 protein degradation, the increased MDM2 protein could play an important role in tumorigenesis, especially in the development of soft tissue tumors, osteosarcomas and esophageal carcinomas.

Bibliography

Pubmed IDLast YearTitleAuthors
84402371993mdm2 expression is induced by wild type p53 activity.Barak Y et al
155502422004A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans.Bond GL et al
34747841987Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3T3 cell line.Cahilly-Snyder L et al
81461751994Interactions between p53 and MDM2 in a mammalian cell cycle checkpoint pathway.Chen CY et al
86283121996mdm-2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein.Chen J et al
169348002006Differential response between the p53 ubiquitin-protein ligases Pirh2 and MdM2 following DNA damage in human cancer cells.Duan W et al
20261491991Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line.Fakharzadeh SS et al
98194151998Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6.Freedman DA et al
91533951997Mdm2 promotes the rapid degradation of p53.Haupt Y et al
94505431997Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53.Honda R et al
74773271995Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53.Jones SN et al
91533961997Regulation of p53 stability by Mdm2.Kubbutat MH et al
96515261998MDM2 expression during mouse embryogenesis and the requirement of p53.Léveillard T et al
96718041998The MDM2 gene amplification database.Momand J et al
15355571992The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation.Momand J et al
74773261995Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53.Montes de Oca Luna R et al
16145371992Amplification of a gene encoding a p53-associated protein in human sarcomas.Oliner JD et al
84795251993Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53.Oliner JD et al
82655991993The mdm-2 gene is induced in response to UV light in a p53-dependent manner.Perry ME et al
92273421997Point mutations and nucleotide insertions in the MDM2 zinc finger structure of human tumours.Schlott T et al
163375942005MDM2 promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma protein.Sdek P et al
103598171999P19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2.Tao W et al
91728031996Overexpression of the MDM2 oncogene in leukemia and lymphoma.Watanabe T et al

Other Information

Locus ID:

NCBI: 4193
MIM: 164785
HGNC: 6973
Ensembl: ENSG00000135679

Variants:

dbSNP: 4193
ClinVar: 4193
TCGA: ENSG00000135679
COSMIC: MDM2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000135679ENST00000258148G3XA89
ENSG00000135679ENST00000258149Q00987
ENSG00000135679ENST00000299252Q00987
ENSG00000135679ENST00000311420J3QST1
ENSG00000135679ENST00000348801A0A0C4DFR5
ENSG00000135679ENST00000350057J3KN53
ENSG00000135679ENST00000360430Q00987
ENSG00000135679ENST00000393410Q9H4C5
ENSG00000135679ENST00000393412Q9H4C5
ENSG00000135679ENST00000393413Q00987
ENSG00000135679ENST00000393415A7UKX8
ENSG00000135679ENST00000393416E7EPE2
ENSG00000135679ENST00000393417F6UXB6
ENSG00000135679ENST00000428863Q8TE47
ENSG00000135679ENST00000478070E5RHE2
ENSG00000135679ENST00000481186E5RJQ0
ENSG00000135679ENST00000496959Q96DS5
ENSG00000135679ENST00000517852Q9H4C3
ENSG00000135679ENST00000523991E7EMW5
ENSG00000135679ENST00000536089F5H1M7
ENSG00000135679ENST00000537182F5H1M7
ENSG00000135679ENST00000539479Q00987
ENSG00000135679ENST00000540352F5H4Q8
ENSG00000135679ENST00000542502F5GZC3
ENSG00000135679ENST00000543323A0A1B0GXJ6
ENSG00000135679ENST00000544561F5GWH7
ENSG00000135679ENST00000545204F5GZB0
ENSG00000135679ENST00000546048F5H1M7
ENSG00000135679ENST00000665020A0A0A8KB88
ENSG00000135679ENST00000666617A0A0A8K986
ENSG00000135679ENST00000671567A0A0A8KBA1

Expression (GTEx)

0
5
10
15
20
25
30
35

Pathways

PathwaySourceExternal ID
Cell cycleKEGGko04110
p53 signaling pathwayKEGGko04115
Ubiquitin mediated proteolysisKEGGko04120
GliomaKEGGko05214
Prostate cancerKEGGko05215
MelanomaKEGGko05218
Bladder cancerKEGGko05219
Chronic myeloid leukemiaKEGGko05220
Cell cycleKEGGhsa04110
p53 signaling pathwayKEGGhsa04115
Ubiquitin mediated proteolysisKEGGhsa04120
Pathways in cancerKEGGhsa05200
GliomaKEGGhsa05214
Prostate cancerKEGGhsa05215
MelanomaKEGGhsa05218
Bladder cancerKEGGhsa05219
Chronic myeloid leukemiaKEGGhsa05220
EndocytosisKEGGko04144
EndocytosisKEGGhsa04144
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
FoxO signaling pathwayKEGGhsa04068
Thyroid hormone signaling pathwayKEGGhsa04919
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
SUMOylationREACTOMER-HSA-2990846
SUMO E3 ligases SUMOylate target proteinsREACTOMER-HSA-3108232
Neuronal SystemREACTOMER-HSA-112316
Transmission across Chemical SynapsesREACTOMER-HSA-112315
Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic CellREACTOMER-HSA-112314
Glutamate Binding, Activation of AMPA Receptors and Synaptic PlasticityREACTOMER-HSA-399721
Trafficking of AMPA receptorsREACTOMER-HSA-399719
DiseaseREACTOMER-HSA-1643685
Diseases of signal transductionREACTOMER-HSA-5663202
PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
Constitutive Signaling by AKT1 E17K in CancerREACTOMER-HSA-5674400
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
AKT phosphorylates targets in the cytosolREACTOMER-HSA-198323
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GAB1 signalosomeREACTOMER-HSA-180292
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by SCF-KITREACTOMER-HSA-1433557
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Cell CycleREACTOMER-HSA-1640170
Cell Cycle CheckpointsREACTOMER-HSA-69620
G1/S DNA Damage CheckpointsREACTOMER-HSA-69615
p53-Dependent G1/S DNA damage checkpointREACTOMER-HSA-69580
p53-Dependent G1 DNA Damage ResponseREACTOMER-HSA-69563
Stabilization of p53REACTOMER-HSA-69541
Cellular responses to stressREACTOMER-HSA-2262752
Cellular SenescenceREACTOMER-HSA-2559583
Oncogene Induced SenescenceREACTOMER-HSA-2559585
Oxidative Stress Induced SenescenceREACTOMER-HSA-2559580
SUMOylation of transcription factorsREACTOMER-HSA-3232118
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Expression and DegradationREACTOMER-HSA-6806003
Regulation of TP53 DegradationREACTOMER-HSA-6804757
Regulation of TP53 Activity through PhosphorylationREACTOMER-HSA-6804756
Regulation of TP53 Activity through MethylationREACTOMER-HSA-6804760
Platinum drug resistanceKEGGko01524
Endocrine resistanceKEGGko01522
Platinum drug resistanceKEGGhsa01524
Endocrine resistanceKEGGhsa01522
DeubiquitinationREACTOMER-HSA-5688426
Ub-specific processing proteasesREACTOMER-HSA-5689880

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA164713176Platinum compoundsChemicalClinicalAnnotationassociatedPD29662106
PA165290931nutlin-3ChemicalMultilinkAnnotationassociated14704432
PA36679TP53GeneMultilinkAnnotationassociated14704432
PA443622Carcinoma, Non-Small-Cell LungDiseaseClinicalAnnotationassociatedPD29662106
PA445062NeoplasmsDiseaseMultilinkAnnotationassociated14704432

References

Pubmed IDYearTitleCitations
155502422004A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans.413
146713062003Mono- versus polyubiquitination: differential control of p53 fate by Mdm2.280
182044392008ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation.267
146124272003Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway.233
153086432004Inhibition of MDM2-mediated p53 ubiquitination and degradation by ribosomal protein L5.224
153141732004Ribosomal protein L23 activates p53 by inhibiting MDM2 function in response to ribosomal perturbation but not to translation inhibition.219
125075562003The p53-Mdm2 module and the ubiquitin system.200
201727292010The p53 orchestra: Mdm2 and Mdmx set the tone.195
124263952002MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation.186
209519462010Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development.182

Citation

Wenrui Duan ; Miguel A Villalona-Calero

MDM2 (transformed mouse 3T3 cell double minute 2, p53 binding protein)

Atlas Genet Cytogenet Oncol Haematol. 2006-12-01

Online version: http://atlasgeneticsoncology.org/gene/115/mdm2