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FLASH GENE

Symbol

MDM4

contributors: mct/ - updated : 24-05-2023

HGNC name	Mdm4 p53 binding protein homolog (mouse)
HGNC id	6974

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	110.62 kb     11 Exon(s)

Genomic sequence alignment details
10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
text structure	a TP53-responsive promoter in its first intron that drives the expression of mRNA transcripts with quantitatively and qualitatively different translation potential, which participate in an autoregulatory feedback loop to control the abundance and activity of TP53 in cancer cells

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

text	is regulated at the posttranscriptional level by alternative splicing (PMID: 24127580)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_002393 11 - 10090 NP_002384 54 490 highly in thymus 2012 2401879 MDM4-FL or HDMX MDMX-L - - - - 508 - 2012 2401879 transcribed from the HDMX-P2 promoter in response to TP53-activating signals. an additional 18 AAs at its N terminus retains the ability to cooperate with MDM2 in the ubiquitination of TP53 but has reduced capacity to inhibit TP53 activity and TP53-induced antiproliferative responses NM_001204171 10 - 9940 NP_001191100 - 440 - 2012 2401879 MDM4-A or HDMX-A NM_001278516 10 - 100022 NP_001265445 - 127 transformed cell lines 2012 2401879 MDM4-S, HDMX-S, or HDMX-E, product of exon 6 skipping truncated form, potent TP53 repressor lacks the central and C-terminal regions, but containing the NTD and 17 additional amino acids is likely to play a key role in the regulation of cell proliferation and apoptosis in a way distinct from MDM4 NM_001278518 7 - 9611 NP_001265447 - 116 - 2012 2401879 MDM4-ALT1, XALT1, or HDMX-ALT1 NM_001278519 5 - 9421 NP_001265448 - 267 - 2012 2401879 MDM4-ALT2, XALT2, or HDMX-ALT2 NM_001278517 8 - 9796 NP_001265446 - 392 - 2012 2401879 MDM4-G or HDMX-G NM_001204172 3 - 9112 NP_001191101 - 164 - 2012 2401879 DM4-211 or HDMX211

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Lymphoid/Immune lymph node       highly   spleen       highly   thymus       highly Reproductive male system testis     highly Visual eye retina       Homo sapiens Fetal

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Lymphoid

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal pocket, globular SWIB-like domain (NTD) that binds to the primary transactivation domain of TP53 , binds tightly to the N-terminal domain of TP53 and inhibits it
	a RANBP2-type zinc finger and a RING-type zinc finger
	a regulatory element (the “WWW element”), AAs 190–210 in that intrinsically disordered region constitute an inhibitory module that binds to its own N-terminal domain and prevents MDM4 from binding to TP53
	its N-terminus transactivation domain engages TP53 and its C-terminus RING domain binds to MDM2

HOMOLOGY

interspecies	homolog to murine Mdm4 (84.4pc)
	homolog to rattus Mdm4 (84.6pc)

intraspecies

homolog to to TP53-binding protein MDM2

Homologene

FAMILY

MDM2/MDM4 family

CATEGORY

regulatory

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,nucleus

basic FUNCTION	ubiquitin E3 ligase, involved in the apoptosis
	may act as a negative regulator of TP53 levels and activity
	can effectively function to promote cellular MDM2 E3 ubiquitin ligase activity when cellular MDM2 concentrations are limiting
	different roles of MDM2 and MDM4 in the regulation of TP53 activities
	mitochondrial MDM4 binds to BCL2, facilitates the mitochondrial localization of TP53Ser46(P) and promotes binding between BCL2 and p53Ser46(P), release of cytochrome C and apoptosis
	inhibits TP73-mediated cell cycle arrest and apoptosis
	inhibits degradation of MDM2
	having a TP53-independent role in suppressing oncogenic cell transformation, proliferation, and tumorigenesis by promoting centrosome clustering and bipolar mitosis
	structurally related TP53-binding proteins that function as critical negative regulators of TP53 activity in embryonic and adult tissue
	regulates TP53 abundance by modulating the levels and activity of MDM2
	with MDM4, bind TP53 and inhibit its function by distinct nonredundant mechanisms
	cooperated with MDM2 to control TP53 activity
	key modulator of TP53 activity in differentiating embryonic stem cells
	can suppress TP53, which is through transcriptional activation of TP53 principal negative regulator, MDM2
	is an important regulator of TP53 during embryonic development and malignant transformation
	is one of these key mRNAs that senses the defects in the spliceosomal machinery and transduces the signal to activate the TP53 response
	having TP53- and MDM2-independent oncogenic function providing new
	insight into the many cancers that overexpress MDM4
	MDM4/MDM2-TP53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury
	critical role played by the MDM2/MDM4-TP53 nexus on nephrogenesis
	MDM4 is a vital regulator of the tumor suppressor TP53
	in analogy to previously reported activities of MDM2, MDM4 enables unperturbed DNA replication through the avoidance of R-loops

CELLULAR PROCESS	cell life, cell death/apoptosis

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component	MDM2 and MDM4 can form a heterodimer through their Ring domains, and this may regulate MDM2-mediated degradation of TP53
	most oncogenic form of these proteins is the MDM2–MDM4 heterodimer

INTERACTION

DNA

RNA

small molecule

protein	TP53 binding and repressor
	binding to BCL2 in mitochondria
	binding to TP73 and MDM2
	YWHAG binds to the MDM4 domain adjacent to CDKN1A binding suggesting that YWHAG may affect MDM4-mediated CDKN1A proteasomal turnover
	critical role for noncoding 5S rRNA in modulating the TP53-MDM4-MDM2 axis
	CSNK1A1 stably associates with MDM4, stimulates MDM4-TP53 binding, and cooperates with MDM4 to inactivate TP53
	intricate interplay between MDM2 and MDM4 in TP53 regulation
	CNSK1A1 is an important functional partner of MDM 4
	RPL37, RPS15 and RPS20 regulate the MDM2-TP53-MDM4 network
	may contribute to the regulation of TP53 independently of MDM2
	JMJD6 antagonizes TP53 acetylation, promotes the association of TP53 with its negative regulator MDM4, and represses transcriptional activity of TP53
	MDM4 is a nutrient-sensor able to inhibit MTOR and highlight its metabolism-related tumor-suppressing function
	PRPF19 downregulation inhibits MDM4-mediated TP53 inactivation, resulting in induction of cellular senescence 7)
	FAM193A interacts with MDM4, and FAM193A depletion stabilizes MDM4 and inhibits the TP53 transcriptional program

cell & other

REGULATION

Phosphorylated by

AMPK, that phosphorylates and inactivates MDM4, resulting in TP53 stabilization and activation

Other	can be deubiquitinated by USP2 (Allende-Vega 2010)
	regulated through its subcellular localization (in many proliferating cells is primarily cytoplasmic)

ASSOCIATED DISORDERS

corresponding disease(s)

BMFS6

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral   amplification     strongly selected for during tumour progression as a mechanism to suppress the TP53 response in RB1-deficient retinal cells tumoral     --over   in malignant glioma escaping TP53 dependent growth control tumoral     --low   downregulation of MDM4 expression associates with cisplatin resistance in ovarian cancers constitutional   deletion     induces multipolar mitotic spindle formation and the loss of chromosomes from hyperploid TP53-null cells tumoral   amplification     in breast carcinomas, colon carcinomas, lung carcinomas, and a smaller percentage of gliomas constitutional     --over   in fibroblast-like synoviocyte, may contribute to the hyperplasia phenotype of rheumatoid arthritis synovial tissues tumoral     --over   in retinoblastoma constitutional germinal mutation       in a family with features suggestive of dyskeratosis congenita, e.g., bone marrow hypocellularity, short telomeres, tongue squamous cell carcinoma, and acute myeloid leukemia

Susceptibility

Variant & Polymorphism

Candidate gene
Marker	MDM4 is a novel biomarker for hematologic malignancies
	MDM4 expression is a factor conferring poor prognosis in patients with Gastric cancer with low expression of TP53 and may confer drug resistance
Therapy target
	System Type Disorder Pubmed cancer eye   specific chemotherapeutic target for treating retinoblastoma cancer eye   MDM4 inhibitor, SJ-172550, and can efficiently kill MDM4-amplified retinoblastoma cells cancer skin   is a promising target for antimelanoma combination therapy cancer hemopathy   therapeutic target for hematologic malignancies

ANIMAL & CELL MODELS