MDM4 Mdm4 p53 binding protein homolog (mouse) [Homo sapiens (human)] - Gene

Summary

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Official Symbol: MDM4provided by HGNC
Official Full Name: Mdm4 p53 binding protein homolog (mouse)provided by HGNC
Primary source: HGNC:6974
Locus tag: RP11-430C7.1
See related: Ensembl:ENSG00000198625; HPRD:04082; MIM:602704; Vega:OTTHUMG00000035877
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: HDMX; MDMX; MRP1
Summary: This gene encodes a nuclear protein that contains a p53 binding domain at the N-terminus and a RING finger domain at the C-terminus, and shows structural similarity to p53-binding protein MDM2. Both proteins bind the p53 tumor suppressor protein and inhibit its activity, and have been shown to be overexpressed in a variety of human cancers. However, unlike MDM2 which degrades p53, this protein inhibits p53 by binding its transcriptional activation domain. This protein also interacts with MDM2 protein via the RING finger domain, and inhibits the latter's degradation. So this protein can reverse MDM2-targeted degradation of p53, while maintaining suppression of p53 transactivation and apoptotic functions. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Feb 2011]

Genomic context

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Location :: 1q32

Sequence :: Chromosome: 1; NC_000001.10 (204485507..204527248)

See MDM4 in Epigenomics, MapViewer

Chromosome 1 - NC_000001.10 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Genomic Sequence

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Go to reference sequence details

Bibliography

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GeneRIFs: Gene References Into Functions What's a GeneRIF?

quantify the expression of MDM4 and MDM2 mRNA and protein in human fetal retinae, primary retinoblastomas, retinoblastoma cell lines and several independent orthotopic retinoblastoma xenografts
Title: Analysis of MDM2 and MDM4 single nucleotide polymorphisms, mRNA splicing and protein expression in retinoblastoma.
FULL length-MDM4 and a splicing variant of MDM4 overexpression are indicators of p53 aberrations in chronic lymphocytic leukemia patients, suggesting that those patients have a poor prognosis.
Title: S-MDM4 mRNA overexpression indicates a poor prognosis and marks a potential therapeutic target in chronic lymphocytic leukemia.
MicroRNA-34a modulates MDM4 expression via a target site in the open reading frame.
Title: MicroRNA-34a modulates MDM4 expression via a target site in the open reading frame.
The results of this study showed that strong association between MDM4 gene alternation and high-grade oligodendroglial tumors.
Title: Identification of a novel population in high-grade oligodendroglial tumors not deleted on 1p/19q using array CGH.
DNA damage activates p53 in part by disrupting CK1a-MDMX interaction and reducing MDMX-p53 binding affinity.
Title: Casein kinase 1α regulates an MDMX intramolecular interaction to stimulate p53 binding.
The length of the C-terminal regions of MdmX proteins has been conserved in evolution, because it can influence their activity toward tumor suppressor p53.
Title: Mutational analysis of Mdm2 C-terminal tail suggests an evolutionarily conserved role of its length in Mdm2 activity toward p53 and indicates structural differences between Mdm2 homodimers and Mdm2/MdmX heterodimers.
MDM2 protein & mRNA expression levels did not correlate with lack of TP53 genetic changes or expression. There was an inverse relationship between detectable TP53 protein expression & MDM4 copy number gains & mRNA expression.
Title: TP53 pathway analysis in paediatric Burkitt lymphoma reveals increased MDM4 expression as the only TP53 pathway abnormality detected in a subset of cases.
MDM4 is significantly higher in chronic lymphocytic leukemia patients with P53 deletion or mutation.
Title: [mRNA levels detected by real-time quantitative RT-PCR in chronic lymphocytic leukemia and their clinical significance].
These compounds effectively inhibit the E3 ligase activity of the Mdm2-MdmX hetero-complex.
Title: Discovery of Mdm2-MdmX E3 ligase inhibitors using a cell-based ubiquitination assay.
Loss of ARF during tumor development not only prevents p53 stabilization by proliferative stress but also causes accumulation of MDMX compromising p53 activity
Title: Abnormal MDMX degradation in tumor cells due to ARF deficiency.

Submit: New GeneRIF Correction See all (96)

Phenotypes

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Review eQTL and phenotype association data in this region using PheGenI

NHGRI GWAS Catalog

A genome-wide study of common SNPs and CNVs in cognitive performance in the CANTAB.

Interactions

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Products	Interactant	Other Gene	Source	Pubs	Description
NP_002384.1	NP_001777.1	CDK1	BIND	PubMed	CDC2 interacts with MDM4 (MDMX). This interaction was modeled on a demonstrated interaction between human CDC2, and MDM4 from an unspecified species.
NP_002384.1	NP_005216.1	E2F1	BIND	PubMed	E2F-1 interacts with MDMX. This interaction was modeled on a demonstrated interaction between human E2F-1 and mouse MDMX.
NP_002384.1	NP_002383.1	MDM2	BIND	PubMed	Mdm2 interacts with Hdmx.
NP_002384.1	NP_002383.1	MDM2	BIND	PubMed	MDM2 interacts with MDM4 (MDMX).
NP_002384.1	NP_000312.1	RB1	BIND	PubMed	pRb interacts with MDMX. This interaction was modeled on a demonstrated interaction between mouse MDMX and human pRb.
NP_002384.1	NP_003461.1	USP7	BIND	PubMed	Hdmx interacts with HAUSP.
O15151	P31749	AKT1	HPRD	PubMed
O15151	P84077	ARF1	HPRD	PubMed
O15151	Q13315	ATM	HPRD	PubMed
O15151	P42574	CASP3	HPRD	PubMed
O15151	P06493	CDK1	HPRD	PubMed
O15151	O14757	CHEK1	HPRD	PubMed
O15151	O96017	CHEK2	HPRD	PubMed
O15151	P48729	CSNK1A1	HPRD	PubMed
O15151	Q01094	E2F1	HPRD	PubMed
O15151	Q09472	EP300	HPRD	PubMed
O15151	Q00987	MDM2	HPRD	PubMed
O15151	P06400	RB1	HPRD	PubMed
O15151	P31947	SFN	HPRD	PubMed
O15151	P84022	SMAD3	HPRD	PubMed
O15151	P04637	TP53	HPRD	PubMed
O15151	O15350	TP73	HPRD	PubMed
O15151	P51668	UBE2D1	HPRD	PubMed
O15151	Q93009	USP7	HPRD	PubMed
O15151	P31946	YWHAB	HPRD	PubMed
O15151	P62258	YWHAE	HPRD	PubMed
O15151	P61981	YWHAG	HPRD	PubMed
O15151	Q04917	YWHAH	HPRD	PubMed
O15151	P27348	YWHAQ	HPRD	PubMed
O15151	P63104	YWHAZ	HPRD	PubMed
BioGRID:110359	BioGRID:106543	ABL1	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110359	BioGRID:106848	APP	BioGRID	PubMed	Reconstituted Complex
BioGRID:110359	BioGRID:107068	BCL2	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110359	BioGRID:107460	CDKN1A	BioGRID	PubMed	Affinity Capture-Western; Co-fractionation; Reconstituted Complex
BioGRID:110359	BioGRID:107463	CDKN2A	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110359	BioGRID:107536	CHEK1	BioGRID	PubMed	Biochemical Activity
BioGRID:110359	BioGRID:116369	CHEK2	BioGRID	PubMed	Biochemical Activity
BioGRID:110359	BioGRID:107836	CSNK1A1	BioGRID	PubMed	Affinity Capture-MS; Affinity Capture-Western; Reconstituted Complex
BioGRID:110359	BioGRID:108201	E2F1	BioGRID	PubMed	Reconstituted Complex; Two-hybrid
BioGRID:110359	BioGRID:108347	EP300	BioGRID	PubMed	Reconstituted Complex
BioGRID:110359	BioGRID:109552	HSP90AA1	BioGRID	PubMed	Affinity Capture-Luminescence
BioGRID:110359	BioGRID:124754	LRSAM1	BioGRID	PubMed	Two-hybrid
BioGRID:110359	BioGRID:110358	MDM2	BioGRID	PubMed	Affinity Capture-Western; Biochemical Activity; Co-crystal Structure; Co-localization; PCA; Reconstituted Complex; Two-hybrid
BioGRID:110359	BioGRID:110359	MDM4	BioGRID	PubMed	Biochemical Activity
BioGRID:110359	BioGRID:113479	MKRN3	BioGRID	PubMed	Two-hybrid
BioGRID:110359	BioGRID:110474	MNAT1	BioGRID	PubMed	Two-hybrid
BioGRID:110359	BioGRID:111493	PPP1CA	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110359	BioGRID:111494	PPP1CB	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110359	BioGRID:111495	PPP1CC	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110359	BioGRID:111678	PSMC5	BioGRID	PubMed	Co-fractionation
BioGRID:110359	BioGRID:111681	PSMD2	BioGRID	PubMed	Affinity Capture-Western; Co-fractionation; Reconstituted Complex
BioGRID:110359	BioGRID:111860	RB1	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110359	BioGRID:117406	RCHY1	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110359	BioGRID:122136	RFWD2	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110359	BioGRID:111955	RN5S1@	BioGRID	PubMed	Affinity Capture-RNA; Affinity Capture-Western; Protein-RNA
BioGRID:110359	BioGRID:109072	SFN	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110359	BioGRID:110263	SMAD3	BioGRID	PubMed	Reconstituted Complex
BioGRID:110359	BioGRID:110264	SMAD4	BioGRID	PubMed	Reconstituted Complex
BioGRID:110359	BioGRID:113188	SUMO1	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110359	BioGRID:113010	TP53	BioGRID	PubMed	Affinity Capture-Western; Biochemical Activity; Co-crystal Structure; Co-localization; PCA; Protein-peptide; Reconstituted Complex
BioGRID:110359	BioGRID:114181	TP63	BioGRID	PubMed	Reconstituted Complex
BioGRID:110359	BioGRID:113014	TP73	BioGRID	PubMed	Affinity Capture-Western; Reconstituted Complex
BioGRID:110359	BioGRID:123129	TRIM46	BioGRID	PubMed	Two-hybrid
BioGRID:110359	BioGRID:124194	TRIM55	BioGRID	PubMed	Two-hybrid
BioGRID:110359	BioGRID:113164	UBC	BioGRID	PubMed	Affinity Capture-Western; Reconstituted Complex
BioGRID:110359	BioGRID:113169	UBE2D1	BioGRID	PubMed	Reconstituted Complex
BioGRID:110359	BioGRID:113170	UBE2D2	BioGRID	PubMed	Reconstituted Complex
BioGRID:110359	BioGRID:113171	UBE2D3	BioGRID	PubMed	Reconstituted Complex
BioGRID:110359	BioGRID:114553	USP2	BioGRID	PubMed	Affinity Capture-Western; Reconstituted Complex
BioGRID:110359	BioGRID:113622	USP7	BioGRID	PubMed	Co-crystal Structure; Protein-peptide; Reconstituted Complex
BioGRID:110359	BioGRID:113361	YWHAB	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110359	BioGRID:113363	YWHAE	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110359	BioGRID:113364	YWHAG	BioGRID	PubMed	Affinity Capture-Western; Reconstituted Complex
BioGRID:110359	BioGRID:113365	YWHAH	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110359	BioGRID:116168	YWHAQ	BioGRID	PubMed	Affinity Capture-MS; Affinity Capture-Western
BioGRID:110359	BioGRID:113366	YWHAZ	BioGRID	PubMed	Affinity Capture-Western

Pathways from BioSystems

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Signaling Pathways in Glioblastoma, organism-specific biosystem (from WikiPathways)
Signaling Pathways in Glioblastoma, organism-specific biosystemThe most frequently altered genes in glioblastoma. This pathway originally accompanied the 2008 Nature publication on the comprehensive genomic characterization of human glioblastoma genes and core p...
p53 pathway, organism-specific biosystem (from Pathway Interaction Database)
p53 pathway, organism-specific biosystem
p53 pathway
p53 signaling pathway, organism-specific biosystem (from KEGG)
p53 signaling pathway, organism-specific biosystemp53 activation is induced by a number of stress signals, including DNA damage, oxidative stress and activated oncogenes. The p53 protein is employed as a transcriptional activator of p53-regulated ge...
p53 signaling pathway, conserved biosystem (from KEGG)
p53 signaling pathway, conserved biosystemp53 activation is induced by a number of stress signals, including DNA damage, oxidative stress and activated oncogenes. The p53 protein is employed as a transcriptional activator of p53-regulated ge...

General gene information

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Markers

SHGC-76197 (e-PCR)
- UniSTS:43281

D11S2560 (e-PCR)
- UniSTS:37928

PMC156606P1 (e-PCR)
- UniSTS:271408

D8S2279 (e-PCR)
- UniSTS:473907

D13S116 (e-PCR)
- UniSTS:147007

SHGC-76181 (e-PCR)
- UniSTS:13135

NoName (e-PCR)
- UniSTS:485483

RH79802 (e-PCR)
- UniSTS:88688

D15S1477 (e-PCR)
- UniSTS:474482

D1S1423 (e-PCR)
- UniSTS:149619

D1S1425 (e-PCR)
- UniSTS:149621

D1S2250 (e-PCR)
- UniSTS:74361

SHGC-67307 (e-PCR)
- UniSTS:89991

D1S3601 (e-PCR)
- UniSTS:3244

L18441 (e-PCR)
- UniSTS:71348

RH80388 (e-PCR)
- UniSTS:89563

Homology

Homologs of the MDM4 gene: The MDM4 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, and zebrafish.
Map Viewer (Mouse, Rat)
OrthoDB: The Hierarchical Catalog of Eukaryotic Orthologs

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enzyme binding	IPI Inferred from Physical Interaction more info	PubMed
protein binding	IPI Inferred from Physical Interaction more info	PubMed
zinc ion binding	TAS Traceable Author Statement more info	PubMed

Process	Evidence Code	Pubs
DNA damage response, signal transduction by p53 class mediator	IEP Inferred from Expression Pattern more info	PubMed
G0 to G1 transition	IEP Inferred from Expression Pattern more info	PubMed
cell proliferation	IEP Inferred from Expression Pattern more info	PubMed
cellular response to hypoxia	IEP Inferred from Expression Pattern more info
negative regulation of apoptotic process	IEA Inferred from Electronic Annotation more info
negative regulation of cell cycle arrest	IEA Inferred from Electronic Annotation more info
negative regulation of cell proliferation	TAS Traceable Author Statement more info	PubMed
negative regulation of protein catabolic process	IMP Inferred from Mutant Phenotype more info	PubMed
negative regulation of transcription from RNA polymerase II promoter	IDA Inferred from Direct Assay more info	PubMed
positive regulation of cell proliferation	IEA Inferred from Electronic Annotation more info
protein complex assembly	IDA Inferred from Direct Assay more info	PubMed
protein stabilization	IEP Inferred from Expression Pattern more info	PubMed

Component	Evidence Code	Pubs
nucleus	NAS Non-traceable Author Statement more info	PubMed

General protein information

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Preferred Names: protein Mdm4

Names: protein Mdm4; protein Mdmx; MDM4-related protein 1; mdm2-like p53-binding protein; double minute 4, human homolog of; p53-binding protein; Mdm4, transformed 3T3 cell double minute 4, p53 binding protein

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_029367.1 RefSeqGene

Range

5001..46742

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001204171.1 → NP_001191100.1 protein Mdm4 isoform 2

Status: REVIEWED

Description

Transcript Variant: This variant (2) lacks an in-frame coding exon compared to variant 1, resulting in a shorter isoform (2) missing an internal protein segment in the 3' coding region compared to isoform 1.

Source sequence(s)

AB209383, AK097188, AL512306, BC105106, BP247507, BP334671, BX108199

Consensus CDS

CCDS55674.1

UniProtKB/Swiss-Prot

O15151

UniProtKB/TrEMBL

Q59FS6

Conserved Domains (4) summary

pfam02201
Location:26 – 101
Blast Score: 163

SWIB; SWIB/MDM2 domain

pfam00641
Location:254 – 279
Blast Score: 98

zf-RanBP; Zn-finger in Ran binding protein and others

pfam13920
Location:387 – 432
Blast Score: 100

zf-C3HC4_3; Zinc finger, C3HC4 type (RING finger)

pfam13923
Location:387 – 429
Blast Score: 80

zf-C3HC4_2; Zinc finger, C3HC4 type (RING finger)
NM_001204172.1 → NP_001191101.1 protein Mdm4 isoform 3

Status: REVIEWED

Description

Transcript Variant: This variant (3) is missing 8 consecutive coding exons, and uses an alternate acceptor splice site at the 3' terminal exon compared to variant 1. However, it maintains the reading frame, and encodes a very short isoform (3, also known as HDMX211) that lacks the N-terminal p53 binding domain, but retains the ring finger domain at the C-terminus. This isoform has been shown to bind and stabilize oncoprotein HDM2, and also indirectly stabilize p53 protein by counteracting its degradation by HDM2. Screening of lung cancer biopsies shows the presence of this isoform in samples that overexpress HDM2 protein, supporting a pathologic role for this protein (PMID:16266988).

Source sequence(s)

AB209383, AK097188, AL512306, AY923176, BP247507, BP334671, BX108199

Consensus CDS

CCDS55675.1

UniProtKB/Swiss-Prot

O15151

UniProtKB/TrEMBL

Q59FS6

Conserved Domains (1) summary

pfam13920
Location:111 – 156
Blast Score: 87

zf-C3HC4_3; Zinc finger, C3HC4 type (RING finger)
NM_002393.4 → NP_002384.2 protein Mdm4 isoform 1

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the predominant transcript, and encodes the longest isoform (1, also known as HDMX).

Source sequence(s)

AB209383, AK097188, AL512306, BC067299, BP247507, BP334671, BX108199

Consensus CDS

CCDS1447.1

UniProtKB/Swiss-Prot

O15151

UniProtKB/TrEMBL

Q59FS6

Related

ENSP00000356150, OTTHUMP00000034072, ENST00000367182, OTTHUMT00000087415

Conserved Domains (4) summary

pfam02201
Location:26 – 101
Blast Score: 165

SWIB; SWIB/MDM2 domain

pfam00641
Location:304 – 329
Blast Score: 100

zf-RanBP; Zn-finger in Ran binding protein and others

pfam13920
Location:437 – 482
Blast Score: 104

zf-C3HC4_3; Zinc finger, C3HC4 type (RING finger)

pfam13923
Location:437 – 479
Blast Score: 84

zf-C3HC4_2; Zinc finger, C3HC4 type (RING finger)

RNA

NR_024171.2 RNA Sequence

Status: REVIEWED

Description

Transcript Variant: This variant (4) lacks an internal exon compared to variant 1. This causes a frame-shift, and premature translation termination, rendering this transcript a candidate for nonsense-mediated decay (NMD).

Source sequence(s)

AB209383, AK097188, AL512306, BC143431, BP247507, BP334671, BX108199

RefSeqs of Annotated Genomes: Homo sapiens Annotation Release 104

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh37.p10 Primary Assembly

Genomic

NC_000001.10 Reference GRCh37.p10 Primary Assembly

Range

204485507..204527248

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate HuRef

Genomic

AC_000133.1 Alternate HuRef

Range

175650570..175692491

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate CHM1_1.0

Genomic

NC_018912.1 Alternate CHM1_1.0

Range

211023163..211064908

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Nucleotide		Protein
Heading	Accession and Version	Protein
genomic	ABBA01027439.1 (116006..118778)	None
genomic	ABBA01027440.1	None
genomic	ABBA01027441.1	None
genomic	ABBA01027442.1 (17090..23796)	None
genomic	AL512306.16 (88986..130727)	None
genomic	AMYH01001663.1 (104131..145876)	None
genomic	AY207458.1	AAO13494.1
genomic	CH471067.1	EAW91515.1
		EAW91516.1
mRNA	AB209383.1	BAD92620.1
mRNA	AF007111.1	AAB62928.1
mRNA	AK097188.1	None
mRNA	AK223228.1	BAD96948.1
mRNA	AK303626.1	BAG64634.1
mRNA	AK304698.1	BAG65468.1
mRNA	AK310607.1	None
mRNA	AK310903.1	None
mRNA	AY923176.1	AAY22054.1
mRNA	AY949028.1	AAX51227.1
mRNA	BC025993.1	None
mRNA	BC067299.1	AAH67299.1
mRNA	BC105106.1	AAI05107.1
mRNA	BC143431.1	None
mRNA	BC143432.1	None
mRNA	BM475824.1	None
mRNA	BP247507.1	None
mRNA	BP334671.1	None
mRNA	BX108199.1	None
mRNA	BX640923.1	CAE45961.1
mRNA	CA395099.1	None
mRNA	CR749470.1	CAH18300.1