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

Identity

Other names	HDMX
	hdm2
Hugo	MDM2
Location	12q15

DNA/RNA

Description	The gene encompasses 33 kb of DNA; 12 exons.
Transcription	2.3 kb nucleotides mRNA. 1476 b open reading frame.

Protein

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-Hodgkin's 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 p53­MDM2 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	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.

External links

	Nomenclature
Hugo	MDM2
GDB	MDM2
Entrez_Gene	MDM2  4193  Mdm2, transformed 3T3 cell double minute 2, p53 binding protein (mouse)
	Cards
Atlas	MDM2ID115ch12q15
GeneCards	MDM2
Ensembl	MDM2 [Search_View]   ENSG00000135679 [Gene_View]
Genatlas	MDM2
GeneLynx	MDM2
eGenome	MDM2
euGene	4193
	Genomic and cartography
GoldenPath	MDM2  -  12q15   chr12:67488247-67520481 +  12q14.3-q15   [Description]    (hg18-Mar_2006)
Ensembl	MDM2 - 12q14.3-q15 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	MDM2
	Gene and transcription
Genbank	AF092843 [ ENTREZ ]
Genbank	AF092844 [ ENTREZ ]
Genbank	AF092845 [ ENTREZ ]
Genbank	AF201370 [ ENTREZ ]
Genbank	AF201371 [ ENTREZ ]
RefSeq	NM_002392 [ SRS ]    NM_002392 [ ENTREZ ]
RefSeq	NM_006878 [ SRS ]    NM_006878 [ ENTREZ ]
RefSeq	NM_006879 [ SRS ]    NM_006879 [ ENTREZ ]
RefSeq	NM_006881 [ SRS ]    NM_006881 [ ENTREZ ]
RefSeq	NM_006882 [ SRS ]    NM_006882 [ ENTREZ ]
RefSeq	AC_000055 [ SRS ]    AC_000055 [ ENTREZ ]
RefSeq	NC_000012 [ SRS ]    NC_000012 [ ENTREZ ]
RefSeq	NT_029419 [ SRS ]    NT_029419 [ ENTREZ ]
RefSeq	NW_925395 [ SRS ]    NW_925395 [ ENTREZ ]
AceView	MDM2 AceView - NCBI
Unigene	Hs.567303 [ SRS ]    Hs.567303 [ NCBI ]     HS567303 [ spliceNest ]
Fast-db	10348 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	Q00987 [ SRS]    Q00987 [ EXPASY ]     Q00987 [ INTERPRO ]
Prosite	PS01358 ZF_RANBP2_1 [ SRS ]    PS01358 ZF_RANBP2_1 [ Expasy ]
Prosite	PS50199 ZF_RANBP2_2 [ SRS ]    PS50199 ZF_RANBP2_2 [ Expasy ]
Prosite	PS00518 ZF_RING_1 [ SRS ]    PS00518 ZF_RING_1 [ Expasy ]
Prosite	PS50089 ZF_RING_2 [ SRS ]    PS50089 ZF_RING_2 [ Expasy ]
Interpro	IPR003121 SWIB_MDM2 [ SRS ]    IPR003121 SWIB_MDM2 [ EBI ]
Interpro	IPR001876 Znf_RanBP2 [ SRS ]    IPR001876 Znf_RanBP2 [ EBI ]
Interpro	IPR001841 Znf_RING [ SRS ]    IPR001841 Znf_RING [ EBI ]
CluSTr	Q00987
Pfam	PF02201 SWIB [ SRS ]    PF02201 SWIB [ Sanger ]    pfam02201 [ NCBI-CDD ]
Pfam	PF00641 zf-RanBP [ SRS ]    PF00641 zf-RanBP [ Sanger ]    pfam00641 [ NCBI-CDD ]
Smart	SM00184 RING [EMBL]
Blocks	Q00987
PDB	1RV1 [ SRS ]    1RV1 [ PdbSum ],   1RV1 [ IMB ]   1RV1 [ RSDB ]
PDB	1T4E [ SRS ]    1T4E [ PdbSum ],   1T4E [ IMB ]   1T4E [ RSDB ]
PDB	1T4F [ SRS ]    1T4F [ PdbSum ],   1T4F [ IMB ]   1T4F [ RSDB ]
PDB	1YCR [ SRS ]    1YCR [ PdbSum ],   1YCR [ IMB ]   1YCR [ RSDB ]
PDB	1Z1M [ SRS ]    1Z1M [ PdbSum ],   1Z1M [ IMB ]   1Z1M [ RSDB ]
PDB	2AXI [ SRS ]    2AXI [ PdbSum ],   2AXI [ IMB ]   2AXI [ RSDB ]
PDB	2C6A [ SRS ]    2C6A [ PdbSum ],   2C6A [ IMB ]   2C6A [ RSDB ]
PDB	2C6B [ SRS ]    2C6B [ PdbSum ],   2C6B [ IMB ]   2C6B [ RSDB ]
PDB	2F1Y [ SRS ]    2F1Y [ PdbSum ],   2F1Y [ IMB ]   2F1Y [ RSDB ]
PDB	2FOP [ SRS ]    2FOP [ PdbSum ],   2FOP [ IMB ]   2FOP [ RSDB ]
PDB	2GV2 [ SRS ]    2GV2 [ PdbSum ],   2GV2 [ IMB ]   2GV2 [ RSDB ]
PDB	2HDP [ SRS ]    2HDP [ PdbSum ],   2HDP [ IMB ]   2HDP [ RSDB ]
HPRD	01272
	Protein Interaction databases
DIP	Q00987
IntAct	Q00987
	Polymorphism : SNP, mutations, diseases
OMIM	164785    [ map ]
GENECLINICS	164785
SNP	MDM2 [dbSNP-NCBI]
SNP	NM_002392 [SNP-NCI]
SNP	NM_006878 [SNP-NCI]
SNP	NM_006879 [SNP-NCI]
SNP	NM_006881 [SNP-NCI]
SNP	NM_006882 [SNP-NCI]
SNP	MDM2 [GeneSNPs - Utah]  MDM2] [HGBASE - SRS]
HAPMAP	MDM2 [HAPMAP]
COSMIC	MDM2 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	MDM2
	General knowledge
Family Browser	MDM2 [UCSC Family Browser]
SOURCE	NM_002392
SOURCE	NM_006878
SOURCE	NM_006879
SOURCE	NM_006881
SOURCE	NM_006882
SMD	Hs.567303
SAGE	Hs.567303
Enzyme	6.3.2.- [ Enzyme-SRS ]   6.3.2.- [ Brenda-SRS ]   6.3.2.- [ KEGG ]   6.3.2.- [ WIT ]
GO	negative regulation of transcription from RNA polymerase II promoter [Amigo]  negative regulation of transcription from RNA polymerase II promoter
GO	negative regulation of transcription from RNA polymerase II promoter [Amigo]  negative regulation of transcription from RNA polymerase II promoter
GO	ubiquitin-protein ligase activity [Amigo]  ubiquitin-protein ligase activity
GO	protein binding [Amigo]  protein binding
GO	intracellular [Amigo]  intracellular
GO	insoluble fraction [Amigo]  insoluble fraction
GO	nucleus [Amigo]  nucleus
GO	nucleoplasm [Amigo]  nucleoplasm
GO	nucleolus [Amigo]  nucleolus
GO	cytoplasm [Amigo]  cytoplasm
GO	protein complex assembly [Amigo]  protein complex assembly
GO	zinc ion binding [Amigo]  zinc ion binding
GO	zinc ion binding [Amigo]  zinc ion binding
GO	negative regulation of cell proliferation [Amigo]  negative regulation of cell proliferation
GO	protein ubiquitination [Amigo]  protein ubiquitination
GO	ligase activity [Amigo]  ligase activity
GO	negative regulator of basal transcription activity [Amigo]  negative regulator of basal transcription activity
GO	negative regulator of basal transcription activity [Amigo]  negative regulator of basal transcription activity
GO	enzyme binding [Amigo]  enzyme binding
GO	regulation of protein catabolic process [Amigo]  regulation of protein catabolic process
GO	metal ion binding [Amigo]  metal ion binding
BIOCARTA	HIV-I Nef: negative effector of Fas and TNF    [Genes]
BIOCARTA	Tumor Suppressor Arf Inhibits Ribosomal Biogenesis    [Genes]
BIOCARTA	ATM Signaling Pathway    [Genes]
BIOCARTA	CTCF: First Multivalent Nuclear Factor    [Genes]
BIOCARTA	Cell Cycle: G2/M Checkpoint    [Genes]
BIOCARTA	p53 Signaling Pathway    [Genes]
BIOCARTA	Hypoxia and p53 in the Cardiovascular system    [Genes]
BIOCARTA	Sumoylation by RanBP2 Regulates Transcriptional Repression    [Genes]
KEGG	Cell cycle
PubGene	MDM2
TreeFam	MDM2
CTD	4193 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	MDM2 Related clones (RZPD - Berlin)
	PubMed
PubMed	344 Pubmed reference(s) in LocusLink

Bibliography

Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3T3 cell line.

Cahilly-Snyder L, Yang-Feng T, Francke U, George DL

Somatic cell and molecular genetics. 1987 ; 13 (3) : 235-244.

PMID 3474784

Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line.

Fakharzadeh SS, Trusko SP, George DL

The EMBO journal. 1991 ; 10 (6) : 1565-1569.

PMID 2026149

The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation.

Momand J, Zambetti GP, Olson DC, George D, Levine AJ

Cell. 1992 ; 69 (7) : 1237-1245.

PMID 1535557

Amplification of a gene encoding a p53-associated protein in human sarcomas.

Oliner JD, Kinzler KW, Meltzer PS, George DL, Vogelstein B

Nature. 1992 ; 358 (6381) : 80-83.

PMID 1614537

mdm2 expression is induced by wild type p53 activity.

Barak Y, Juven T, Haffner R, Oren M

The EMBO journal. 1993 ; 12 (2) : 461-468.

PMID 8440237

Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53.

Oliner JD, Pietenpol JA, Thiagalingam S, Gyuris J, Kinzler KW, Vogelstein B

Nature. 1993 ; 362 (6423) : 857-860.

PMID 8479525

The mdm-2 gene is induced in response to UV light in a p53-dependent manner.

Perry ME, Piette J, Zawadzki JA, Harvey D, Levine AJ

Proceedings of the National Academy of Sciences of the United States of America. 1993 ; 90 (24) : 11623-11627.

PMID 8265599

Interactions between p53 and MDM2 in a mammalian cell cycle checkpoint pathway.

Chen CY, Oliner JD, Zhan Q, Fornace AJ Jr, Vogelstein B, Kastan MB

Proceedings of the National Academy of Sciences of the United States of America. 1994 ; 91 (7) : 2684-2688.

PMID 8146175

Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53.

Jones SN, Roe AE, Donehower LA, Bradley A

Nature. 1995 ; 378 (6553) : 206-208.

PMID 7477327

Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53.

Montes de Oca Luna R, Wagner DS, Lozano G

Nature. 1995 ; 378 (6553) : 203-206.

PMID 7477326

mdm-2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein.

Chen J, Wu X, Lin J, Levine AJ

Molecular and cellular biology. 1996 ; 16 (5) : 2445-2452.

PMID 8628312

Overexpression of the MDM2 oncogene in leukemia and lymphoma.

Watanabe T, Ichikawa A, Saito H, Hotta T

Leukemia & lymphoma. 1996 ; 21 (5-6) : 391-397.

PMID 9172803

Mdm2 promotes the rapid degradation of p53.

Haupt Y, Maya R, Kazaz A, Oren M

Nature. 1997 ; 387 (6630) : 296-299.

PMID 9153395

Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53.

Honda R, Tanaka H, Yasuda H

FEBS letters. 1997 ; 420 (1) : 25-27.

PMID 9450543

Regulation of p53 stability by Mdm2.

Kubbutat MH, Jones SN, Vousden KH

Nature. 1997 ; 387 (6630) : 299-303.

PMID 9153396

Point mutations and nucleotide insertions in the MDM2 zinc finger structure of human tumours.

Schlott T, Reimer S, Jahns A, Ohlenbusch A, Ruschenburg I, Nagel H, Droese M

The Journal of pathology. 1997 ; 182 (1) : 54-61.

PMID 9227342

Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6.

Freedman DA, Levine AJ

Molecular and cellular biology. 1998 ; 18 (12) : 7288-7293.

PMID 9819415

MDM2 expression during mouse embryogenesis and the requirement of p53.

Lˆ©veillard T, Gorry P, Niederreither K, Wasylyk B

Mechanisms of development. 1998 ; 74 (1-2) : 189-193.

PMID 9651526

The MDM2 gene amplification database.

Momand J, Jung D, Wilczynski S, Niland J

Nucleic acids research. 1998 ; 26 (15) : 3453-3459.

PMID 9671804

P19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2.

Tao W, Levine AJ

Proceedings of the National Academy of Sciences of the United States of America. 1999 ; 96 (12) : 6937-6941.

PMID 10359817

A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans.

Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC, Bargonetti J, Bartel F, Taubert H, Wuerl P, Onel K, Yip L, Hwang SJ, Strong LC, Lozano G, Levine AJ

Cell. 2004 ; 119 (5) : 591-602.

PMID 15550242

MDM2 promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma protein.

Sdek P, Ying H, Chang DL, Qiu W, Zheng H, Touitou R, Allday MJ, Xiao ZX

Molecular cell. 2005 ; 20 (5) : 699-708.

PMID 16337594

Differential response between the p53 ubiquitin-protein ligases Pirh2 and MdM2 following DNA damage in human cancer cells.

Duan W, Gao L, Wu X, Zhang Y, Otterson GA, Villalona-Calero MA

Experimental cell research. 2006 ; 312 (17) : 3370-3378.

PMID 16934800

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

Search in all EBI   NCBI

Contributor(s)

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

Citation

This paper should be referenced as such :

Duan W, Villalona-Calero MA . MDM2 (transformed mouse 3T3 cell double minute 2, p53 binding protein). Atlas Genet Cytogenet Oncol Haematol. December 2006 . URL : http://AtlasGeneticsOncology.org/Genes/MDM2ID115ch12q15.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Wed Jul 2 08:24:52 2008