Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

O15151 (MDM4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 148. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Protein Mdm4
Alternative name(s):
Double minute 4 protein
Mdm2-like p53-binding protein
Protein Mdmx
p53-binding protein Mdm4
Gene names
Name:MDM4
Synonyms:MDMX
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length490 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions. Ref.9 Ref.10

Subunit structure

Interacts with MDM2, TP53, TP73 and USP2. Found in a trimeric complex with UPB2, MDM2 and MDM4. Interacts (phosphorylated) with YWHAG; negatively regulates MDM4 activity toward TP53. Ref.9 Ref.10 Ref.11

Subcellular location

Nucleus.

Tissue specificity

Expressed in all tissues tested with high levels in thymus.

Induction

Down-regulated by cisplatin (at protein level). Ref.11

Domain

Region I is sufficient for binding TP53 and inhibiting its G1 arrest and apoptosis functions. It also binds TP73. Region II contains most of a central acidic region and a putative C4-type zinc finger. The RING finger domain which coordinates two molecules of zinc mediates the heterooligomerization with MDM2.

Post-translational modification

Phosphorylated. Phosphorylation at Ser-367 promotes interaction with YWHAG and subsequent ubiquitination and degradation. Phosphorylation at Ser-342 also induces ubiquitination and degradation but to a lower extent. Ref.9 Ref.10

Ubiquitinated and degraded by MDM2. Deubiquitination by USP2 on the other hand stabilizes the MDM4 protein. Ref.9 Ref.11

Sequence similarities

Belongs to the MDM2/MDM4 family.

Contains 1 RanBP2-type zinc finger.

Contains 1 RING-type zinc finger.

Contains 1 SWIB domain.

Mass spectrometry

Molecular mass is 54863.3 Da from positions 1 - 490. Determined by MALDI. Ref.12

Ontologies

Keywords
   Cellular componentNucleus
   Coding sequence diversityAlternative splicing
Polymorphism
   DomainZinc-finger
   LigandMetal-binding
Zinc
   PTMPhosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processDNA damage response, signal transduction by p53 class mediator

Inferred from expression pattern PubMed 14660608. Source: UniProtKB

G0 to G1 transition

Inferred from expression pattern PubMed 12101245. Source: UniProtKB

cell proliferation

Inferred from expression pattern PubMed 12101245. Source: UniProtKB

cellular response to hypoxia

Inferred from expression pattern PubMed 20810912. Source: UniProtKB

negative regulation of apoptotic process

Inferred from electronic annotation. Source: InterPro

negative regulation of cell cycle arrest

Inferred from electronic annotation. Source: InterPro

negative regulation of cell proliferation

Traceable author statement Ref.1. Source: ProtInc

negative regulation of protein catabolic process

Inferred from mutant phenotype Ref.8. Source: UniProtKB

negative regulation of transcription from RNA polymerase II promoter

Inferred from direct assay Ref.1. Source: UniProtKB

positive regulation of cell proliferation

Inferred from electronic annotation. Source: Ensembl

protein complex assembly

Inferred from direct assay Ref.8. Source: UniProtKB

protein stabilization

Inferred from expression pattern Ref.8. Source: UniProtKB

   Cellular_componentnucleus

Non-traceable author statement Ref.1. Source: UniProtKB

   Molecular_functionenzyme binding

Inferred from physical interaction Ref.11. Source: UniProtKB

zinc ion binding

Traceable author statement Ref.8. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 5 isoforms produced by alternative splicing. [Align] [Select]

Note: Additional isoforms seem to exist.
Isoform 1 (identifier: O15151-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: O15151-2)

Also known as: MDMX-S;

The sequence of this isoform differs from the canonical sequence as follows:
     109-490: LATATTDAAQ...IQLVIKVFIA → SASNNTARCNRILQSQKKN
Note: No experimental confirmation available.
Isoform 3 (identifier: O15151-3)

Also known as: MDMX;

The sequence of this isoform differs from the canonical sequence as follows:
     109-490: LATATTDAAQ...IQLVIKVFIA → SASNNTDAAQTLALAQDHT
Note: No experimental confirmation available.
Isoform HDMX211 (identifier: O15151-4)

The sequence of this isoform differs from the canonical sequence as follows:
     27-352: Missing.
Note: Cancer-specific isoform, may counteract MDM2/MDM4-mediated p53 degradation.
Isoform 5 (identifier: O15151-5)

The sequence of this isoform differs from the canonical sequence as follows:
     225-274: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 490490Protein Mdm4
PRO_0000157336

Regions

Domain26 – 10681SWIB
Zinc finger300 – 32930RanBP2-type
Zinc finger437 – 47842RING-type
Region246 – 33287Region II
Region393 – 49098Necessary for interaction with UBP2
Motif442 – 4454Nuclear localization signal Potential
Compositional bias243 – 30866Asp/Glu-rich (acidic)

Amino acid modifications

Modified residue3421Phosphoserine; by CHEK2 Ref.9
Modified residue3671Phosphoserine; by CHEK1 and CHEK2 Ref.9 Ref.10

Natural variations

Alternative sequence27 – 352326Missing in isoform HDMX211.
VSP_042563
Alternative sequence109 – 490382LATAT…KVFIA → SASNNTARCNRILQSQKKN in isoform 2.
VSP_035669
Alternative sequence109 – 490382LATAT…KVFIA → SASNNTDAAQTLALAQDHT in isoform 3.
VSP_035670
Alternative sequence225 – 27450Missing in isoform 5.
VSP_043145
Natural variant1751I → T. Ref.4
Corresponds to variant rs4252716 [ dbSNP | Ensembl ].
VAR_017106
Natural variant4061T → I. Ref.4
Corresponds to variant rs4252741 [ dbSNP | Ensembl ].
VAR_017107

Experimental info

Mutagenesis4371C → G: Fails to interact with MDM2. Ref.8
Sequence conflict941D → N in AAB62928. Ref.1

Secondary structure

................................... 490
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified September 27, 2005. Version 2.
Checksum: 415E6FA5A0C69857

FASTA49054,864
        10         20         30         40         50         60 
MTSFSTSAQC STSDSACRIS PGQINQVRPK LPLLKILHAA GAQGEMFTVK EVMHYLGQYI 

        70         80         90        100        110        120 
MVKQLYDQQE QHMVYCGGDL LGELLGRQSF SVKDPSPLYD MLRKNLVTLA TATTDAAQTL 

       130        140        150        160        170        180 
ALAQDHSMDI PSQDQLKQSA EESSTSRKRT TEDDIPTLPT SEHKCIHSRE DEDLIENLAQ 

       190        200        210        220        230        240 
DETSRLDLGF EEWDVAGLPW WFLGNLRSNY TPRSNGSTDL QTNQDVGTAI VSDTTDDLWF 

       250        260        270        280        290        300 
LNESVSEQLG VGIKVEAADT EQTSEEVGKV SDKKVIEVGK NDDLEDSKSL SDDTDVEVTS 

       310        320        330        340        350        360 
EDEWQCTECK KFNSPSKRYC FRCWALRKDW YSDCSKLTHS LSTSDITAIP EKENEGNDVP 

       370        380        390        400        410        420 
DCRRTISAPV VRPKDAYIKK ENSKLFDPCN SVEFLDLAHS SESQETISSM GEQLDNLSEQ 

       430        440        450        460        470        480 
RTDTENMEDC QNLLKPCSLC EKRPRDGNII HGRTGHLVTC FHCARRLKKA GASCPICKKE 

       490 
IQLVIKVFIA 

« Hide

Isoform 2 (MDMX-S) [UniParc].

Checksum: 59649D26B113EFB4
Show »

FASTA12714,185
Isoform 3 (MDMX) [UniParc].

Checksum: 0A00E52B32331543
Show »

FASTA12713,981
Isoform HDMX211 [UniParc].

Checksum: 1C39025CBD527C11
Show »

FASTA16418,195
Isoform 5 [UniParc].

Checksum: BB377C938A8C3D1C
Show »

FASTA44049,541

References

« Hide 'large scale' references
[1]"Isolation and identification of the human homolog of a new p53-binding protein, Mdmx."
Shvarts A., Bazuine M., Dekker P., Ramos Y.F.M., Steegenga W.T., Merckx G., van Ham R.C.A., van der Houven van Oordt W., van der Eb A.J., Jochemsen A.G.
Genomics 43:34-42(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Colon tumor.
[2]"Identification of an aberrantly spliced form of HDMX in human tumors: a new mechanism for HDM2 stabilization."
Giglio S., Mancini F., Gentiletti F., Sparaco G., Felicioni L., Barassi F., Martella C., Prodosmo A., Iacovelli S., Buttitta F., Farsetti A., Soddu S., Marchetti A., Sacchi A., Pontecorvi A., Moretti F.
Cancer Res. 65:9687-9694(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM HDMX211).
[3]Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.
Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Gastric mucosa.
[4]NIEHS SNPs program
Submitted (DEC-2002) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS THR-175 AND ILE-406.
[5]"The DNA sequence and biological annotation of human chromosome 1."
Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. expand/collapse author list , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.
Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 5).
Tissue: Brain and Testis.
[7]"Identification of a domain within MDMX-S that is responsible for its high affinity interaction with p53 and high-level expression in mammalian cells."
Rallapalli R., Strachan G., Tuan R.S., Hall D.J.
J. Cell. Biochem. 89:563-575(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: ALTERNATIVE SPLICING (ISOFORMS 2 AND 3).
[8]"Stabilization of the MDM2 oncoprotein by interaction with the structurally related MDMX protein."
Sharp D.A., Kratowicz S.A., Sank M.J., George D.L.
J. Biol. Chem. 274:38189-38196(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF CYS-437.
[9]"ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage."
Chen L., Gilkes D.M., Pan Y., Lane W.S., Chen J.
EMBO J. 24:3411-3422(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN TP53 ACTIVATION, PHOSPHORYLATION AT SER-342 AND SER-367 BY CHEK2, UBIQUITINATION, INTERACTION WITH MDM2.
[10]"14-3-3gamma binds to MDMX that is phosphorylated by UV-activated Chk1, resulting in p53 activation."
Jin Y., Dai M.S., Lu S.Z., Xu Y., Luo Z., Zhao Y., Lu H.
EMBO J. 25:1207-1218(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN TP53 ACTIVATION, PHOSPHORYLATION AT SER-367 BY CHEK1, INTERACTION WITH YWHAG.
[11]"MdmX is a substrate for the deubiquitinating enzyme USP2a."
Allende-Vega N., Sparks A., Lane D.P., Saville M.K.
Oncogene 29:432-441(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH USP2 AND MDM2, INDUCTION, UBIQUITINATION, DEUBIQUITINATION BY USP2.
[12]"Cluster analysis of an extensive human breast cancer cell line protein expression map database."
Harris R.A., Yang A., Stein R.C., Lucy K., Brusten L., Herath A., Parekh R., Waterfield M.D., O'Hare M.J., Neville M.A., Page M.J., Zvelebil M.J.
Proteomics 2:212-223(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: MASS SPECTROMETRY.
Tissue: Mammary cancer.
[13]"Solution structure of the ZF-RANBP domain of p53-binding protein MDM4."
RIKEN structural genomics initiative (RSGI)
Submitted (NOV-2005) to the PDB data bank
Cited for: STRUCTURE BY NMR OF 300-340.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF007111 mRNA. Translation: AAB62928.1.
AY923176 mRNA. Translation: AAY22054.1.
AK223228 mRNA. Translation: BAD96948.1.
AY207458 Genomic DNA. Translation: AAO13494.1.
AL512306 Genomic DNA. Translation: CAI14100.1.
BC067299 mRNA. Translation: AAH67299.1.
BC105106 mRNA. Translation: AAI05107.1.
RefSeqNP_001191100.1. NM_001204171.1.
NP_001191101.1. NM_001204172.1.
NP_001265445.1. NM_001278516.1.
NP_001265446.1. NM_001278517.1.
NP_001265447.1. NM_001278518.1.
NP_001265448.1. NM_001278519.1.
NP_002384.2. NM_002393.4.
UniGeneHs.497492.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2CR8NMR-A300-339[»]
2VJEX-ray2.20B/D428-490[»]
2VJFX-ray2.30B/D428-490[»]
2VYRX-ray2.00A/B/C/D16-116[»]
3DABX-ray1.90A/C/E/G23-111[»]
3EQYX-ray1.63A/B24-108[»]
3FDOX-ray1.40A23-111[»]
3FE7X-ray1.35A14-111[»]
3FEAX-ray1.33A14-111[»]
3JZOX-ray1.80A23-111[»]
3JZPX-ray1.74A23-111[»]
3JZQX-ray1.80A/B23-111[»]
3LBJX-ray1.50E23-111[»]
3U15X-ray1.80A/B/C/D14-111[»]
ProteinModelPortalO15151.
SMRO15151. Positions 26-108, 301-344, 429-490.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid110359. 49 interactions.
DIPDIP-24199N.
IntActO15151. 29 interactions.
MINTMINT-113852.
STRING9606.ENSP00000356150.

Chemistry

BindingDBO15151.
ChEMBLCHEMBL2221344.

PTM databases

PhosphoSiteO15151.

Proteomic databases

PaxDbO15151.
PRIDEO15151.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000367182; ENSP00000356150; ENSG00000198625. [O15151-1]
ENST00000367183; ENSP00000356151; ENSG00000198625. [O15151-4]
ENST00000454264; ENSP00000396840; ENSG00000198625. [O15151-5]
GeneID4194.
KEGGhsa:4194.
UCSCuc001hay.2. human. [O15151-5]
uc001hba.3. human. [O15151-1]
uc021phx.1. human. [O15151-4]

Organism-specific databases

CTD4194.
GeneCardsGC01P204486.
HGNCHGNC:6974. MDM4.
HPAHPA018919.
MIM602704. gene.
neXtProtNX_O15151.
PharmGKBPA30719.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG46328.
HOGENOMHOG000293341.
HOVERGENHBG013472.
InParanoidO15151.
KOK10127.
OMALKPCSLC.
OrthoDBEOG7RRF7T.
PhylomeDBO15151.
TreeFamTF105306.

Gene expression databases

ArrayExpressO15151.
BgeeO15151.
CleanExHS_MDM4.
GenevestigatorO15151.

Family and domain databases

Gene3D1.10.245.10. 1 hit.
3.30.40.10. 1 hit.
InterProIPR015458. MDM4.
IPR016495. p53_neg-reg_MDM_2/4.
IPR003121. SWIB_MDM2_domain.
IPR001876. Znf_RanBP2.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
[Graphical view]
PANTHERPTHR10360:SF10. PTHR10360:SF10. 1 hit.
PfamPF02201. SWIB. 1 hit.
PF00641. zf-RanBP. 1 hit.
[Graphical view]
PIRSFPIRSF500699. MDM4. 1 hit.
PIRSF006748. p53_MDM_2/4. 1 hit.
SMARTSM00184. RING. 1 hit.
SM00547. ZnF_RBZ. 1 hit.
[Graphical view]
SUPFAMSSF47592. SSF47592. 1 hit.
PROSITEPS01358. ZF_RANBP2_1. 1 hit.
PS50199. ZF_RANBP2_2. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSMDM4. human.
EvolutionaryTraceO15151.
GeneWikiMDM4.
GenomeRNAi4194.
NextBio16538.
PMAP-CutDBO15151.
PROO15151.
SOURCESearch...

Entry information

Entry nameMDM4_HUMAN
AccessionPrimary (citable) accession number: O15151
Secondary accession number(s): Q2M2Y2 expand/collapse secondary AC list , Q32SL2, Q6GS18, Q8IV83
Entry history
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: September 27, 2005
Last modified: April 16, 2014
This is version 148 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 1

Human chromosome 1: entries, gene names and cross-references to MIM