Affinage

MDM4

Protein Mdm4 · UniProt O15151

Length
490 aa
Mass
54.9 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MDM4 (MDMX) is a critical non-redundant negative regulator of p53 that inhibits p53 transcriptional activity through direct binding and enhances MDM2-mediated p53 polyubiquitination and degradation via RING–RING heterodimerization. Genetically, MDM4 controls p53 transcriptional activity whereas MDM2 controls p53 protein stability, and these roles are non-interchangeable in vivo (PMID:16492744, PMID:16616333); mechanistically, MDM4 converts MDM2 from a p53 monoubiquitin ligase to a polyubiquitin ligase by recruiting the E2 enzyme UbcH5c through its C-terminal RING domain (PMID:21572037, PMID:33277368). MDM4 is tightly regulated by DNA damage–induced ATM/Chk2 phosphorylation at S403/S367/S342, which promotes 14-3-3–dependent nuclear import and MDM2-mediated proteasomal degradation, counterbalanced by stabilizing deubiquitinases HAUSP/USP7 and USP2a and an intramolecular autoinhibitory mechanism involving a p53-mimicking peptide (PMID:15788536, PMID:16943424, PMID:15916963, PMID:25825738). Beyond p53, MDM4 has p53-independent roles including promotion of cell-cycle progression through E2F1/E2F3/p73 maintenance, inhibition of DNA double-strand break repair via the MRN complex, and facilitation of ferroptosis through PPARα-mediated lipid remodeling (PMID:34716260, PMID:24608433, PMID:32079652).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 Medium

    The basis of MDM4–MDM2 cooperation was established: MDM4's RING finger domain hetero-oligomerizes with MDM2's RING finger, stabilizing both MDM2 and p53 by inhibiting MDM2 E3 ligase activity, while leaving MDM2-mediated transcriptional repression of p53 intact.

    Evidence RING domain deletion mutant analysis and protein stability assays in co-expression systems

    PMID:10827196

    Open questions at the time
    • Overexpression system without endogenous validation
    • Whether stabilization or activation of MDM2 is the physiological role was unresolved
    • No in vivo genetic confirmation
  2. 2001 Medium

    MDM4 was shown to be predominantly cytoplasmic and to require MDM2 for nuclear entry, where it inhibits MDM2-mediated p53 ubiquitination and nuclear export; ARF was identified as an additional regulator that sequesters MDM4 to the nucleolus to relieve p53 inhibition.

    Evidence Subcellular fractionation, immunofluorescence, ubiquitination assays, and Co-IP with ARF nucleolar localization studies

    PMID:11297540 PMID:11606419 PMID:11744695

    Open questions at the time
    • Endogenous protein dynamics not yet characterized
    • ARF–MDM4 nucleolar sequestration based on overexpression
    • Apparent contradiction between MDM4 inhibiting vs. stimulating MDM2 E3 activity was unresolved
  3. 2003 High

    Resolving the apparent paradox, reconstituted biochemistry demonstrated that MDM4 stimulates (not inhibits) MDM2-mediated p53 ubiquitination in vitro and that MDM2 reciprocally ubiquitinates and degrades MDM4 through its RING domain E3 ligase activity.

    Evidence In vitro ubiquitination assays with purified proteins; siRNA knockdown showing p53 accumulation upon MDM4 depletion; MDM2 RING mutant analysis

    PMID:12860999 PMID:14507994

    Open questions at the time
    • Whether MDM4 converts MDM2 from mono- to polyubiquitination was not yet distinguished
    • In vivo genetic epistasis not yet performed
  4. 2005 High

    The DNA damage–responsive degradation pathway for MDM4 was mapped: ATM phosphorylates MDM4 at S403, Chk2 at S367, and these phosphorylations (with S342) are required for efficient MDM2-mediated MDM4 ubiquitination and degradation; concurrently, CK1α phosphorylation at S289 was shown to enhance MDM4–p53 binding under basal conditions.

    Evidence Direct kinase assays identifying ATM (S403) and CK1α (S289); phospho-site mutagenesis; in vivo ubiquitination assays after ionizing radiation

    PMID:15788536 PMID:16024788

    Open questions at the time
    • The 14-3-3 binding and nuclear import mechanism downstream of phosphorylation was not yet elucidated
    • Phosphatase responsible for dephosphorylation unknown
  5. 2005 High

    HAUSP/USP7 was identified as a direct deubiquitinase stabilizing MDM4; DNA damage disrupts HAUSP–MDM4 interaction via ATM-dependent phosphorylation, providing a dual mechanism (increased ubiquitination plus decreased deubiquitination) for damage-induced MDM4 degradation.

    Evidence In vitro deubiquitination assay; reciprocal Co-IP; siRNA knockdown of HAUSP; ATM inhibitor experiments

    PMID:15916963 PMID:16082221

    Open questions at the time
    • Relative contribution of HAUSP loss vs. enhanced MDM2 E3 activity to MDM4 degradation kinetics unknown
    • Whether other DUBs compensate was not addressed
  6. 2006 High

    Chk2-mediated S367 phosphorylation was shown to create a 14-3-3 binding site that unmasks a cryptic NLS, driving MDM4 nuclear import—a prerequisite for MDM2-mediated degradation; independently, genetic epistasis in mice definitively established that MDM4 controls p53 transcriptional activity while MDM2 controls p53 protein stability in a non-redundant manner.

    Evidence Chk2 kinase assay; 14-3-3 Co-IP with phospho-mutants; nuclear import assays; conditional knockout mouse crosses with p53 knock-in alleles

    PMID:16492744 PMID:16511560 PMID:16616333 PMID:16943424

    Open questions at the time
    • Structural basis for 14-3-3–mediated NLS exposure not determined
    • Whether MDM4 has additional p53-independent roles in vivo was unexplored
  7. 2009 High

    Wip1 phosphatase was identified as the eraser that dephosphorylates MDM4 at S403, opposing ATM and restoring MDM4 stability; USP2a was identified as a second deubiquitinase stabilizing MDM4 independently of MDM2; a mitochondrial pool of MDM4 was found to promote p53-dependent apoptosis by facilitating p53(Ser46P)–BCL-2 interaction.

    Evidence In vitro dephosphorylation assay (Wip1 on S403); in vitro deubiquitination with USP2a catalytic mutant control; subcellular fractionation showing mitochondrial MDM4–p53–BCL-2 complexes

    PMID:19808970 PMID:19838211 PMID:19887911

    Open questions at the time
    • Mitochondrial MDM4 pro-apoptotic role from a single lab, limited independent replication
    • Relative physiological importance of USP2a vs. HAUSP unclear
    • How MDM4 targets to mitochondria mechanistically unknown
  8. 2011 High

    A critical biochemical distinction was established: native (non-GST-tagged) MDM2 alone catalyzes only p53 monoubiquitination, and MDM4 is required to convert MDM2 into a p53 polyubiquitination E3 ligase through RING–RING heterodimer formation.

    Evidence In vitro ubiquitination with native MDM2 ± MDM4; RING domain mutant analysis; siRNA knockdown with subcellular fractionation

    PMID:21572037

    Open questions at the time
    • The specific E2 enzyme recruited by MDM4 in the heterodimer was not yet identified
    • Whether this switch operates identically in all tissues unknown
  9. 2014 High

    Two new dimensions of MDM4 function emerged: ATM-phosphorylated MDM4 binds p53 mRNA via its RING domain as an IRES trans-acting factor to promote p53 translation after DNA damage; separately, MDM4 was shown to associate with NBS1 of the MRN complex and inhibit DNA break repair independently of p53.

    Evidence RNA–protein interaction assays with S403 mutagenesis and ATM inhibitors; Co-IP with NBS1 in chromatin fractions of p53-null cells with chromosomal break analysis

    PMID:24608433 PMID:24813712

    Open questions at the time
    • IRES-ITAF function not confirmed in vivo in animal models
    • MRN inhibition mechanism at the structural level unknown
    • Whether RNA-binding and E3-cofactor functions are mutually exclusive unclear
  10. 2015 High

    MDM4 was shown to possess an intramolecular autoinhibitory mechanism: a p53-mimicking hydrophobic peptide in the central disordered region binds the N-terminal p53-binding pocket, and its disruption enhances p53 binding; separately, SRSF3 was identified as the splicing factor driving cancer-specific exon 6 inclusion to produce full-length MDM4, while normal tissues produce a decay-targeted short isoform.

    Evidence NMR spectroscopy and PFR assay with tryptophan mutagenesis; SRSF3 siRNA/overexpression with ASO-mediated exon skipping in melanoma PDX models

    PMID:25825738 PMID:26595814

    Open questions at the time
    • Whether autoinhibition is relieved by specific signals or binding partners in vivo unknown
    • Tissue-specific splicing regulation beyond SRSF3 not characterized
  11. 2016 High

    A secondary mode of p53 inhibition was revealed: after canonical N-terminal binding, the MDM4 acidic domain and RING domain contact the p53 DNA-binding domain core, inhibiting sequence-specific DNA binding in a CK1α/S289-phosphorylation-dependent manner.

    Evidence PFR assay; EMSA for p53 DNA binding; CK1α siRNA knockdown

    PMID:27114532

    Open questions at the time
    • Structural model of the ternary MDM4–p53-DBD complex not available
    • Whether this secondary interaction affects all p53 target genes equally unknown
  12. 2020 High

    In vivo genetic models established that MDM4 recruits UbcH5c (E2 enzyme) through its C-terminal residues to enable MDM2 E3 ligase activity; additionally, MDM2–MDM4 was found to promote ferroptosis via PPARα-mediated lipid remodeling and FSP1/CoQ10 suppression, revealing a p53-independent metabolic function.

    Evidence Conditional MDM2/MDM4 knockout mice with inducible p53 and domain-swap mutants; lipidomics and FSP1/CoQ10 measurements in p53-null cells with MDM2/MDM4 inhibition

    PMID:32079652 PMID:33277368

    Open questions at the time
    • Structural basis of UbcH5c recruitment by MDM4 C-terminus not determined
    • Ferroptosis role not yet confirmed in vivo with genetic models
    • Whether UbcH5c is the sole E2 in all cellular contexts unclear
  13. 2021 Medium

    MDM2–MDM4 heterocomplexes were shown to promote cell-cycle progression independently of p53 by maintaining E2F1, E2F3, and p73 activity, expanding the p53-independent functional repertoire of MDM4.

    Evidence siRNA/shRNA knockdown in p53-null cell lines; E2F and p73 protein/mRNA measurement; E3 ligase activity inhibition

    PMID:34716260

    Open questions at the time
    • Direct substrates of the MDM2–MDM4 E3 complex in this context not identified
    • In vivo validation in p53-null genetic models not performed
    • Whether this function requires E3 ligase activity or a scaffolding role is unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the full-length MDM2–MDM4 heterodimer complex with p53, how MDM4's RNA-binding ITAF function coordinates with its E3-cofactor role after DNA damage, and the physiological significance of MDM4's p53-independent roles in DNA repair, ferroptosis, and cell-cycle control across normal tissues.
  • No full-length MDM2–MDM4–p53 structural model exists
  • In vivo validation of ITAF function lacking
  • Tissue-specific contribution of p53-independent functions not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0140110 transcription regulator activity 3 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 5 GO:0005829 cytosol 4 GO:0005739 mitochondrion 2 GO:0005730 nucleolus 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-8953854 Metabolism of RNA 2 R-HSA-1640170 Cell Cycle 1 R-HSA-73894 DNA Repair 1
Partners
CSNK1A1MDM2NBS1TOP2ATP53USP2AUSP7YWHAB
Complex memberships
MDM2–MDM4 RING heterodimer

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 HdmX (MDM4) stimulates Hdm2-mediated ubiquitination and degradation of p53 in vitro, rather than inhibiting it; HdmX also facilitates mutual ubiquitination between HdmX and Hdm2, and HdmX alone lacks appreciable E3 ubiquitin ligase activity. In vitro ubiquitination assay; siRNA knockdown in cells showing accumulation of p53 and Hdm2 upon HdmX depletion Proceedings of the National Academy of Sciences of the United States of America High 14507994
2003 MDM2 promotes MDMX ubiquitination and proteasomal degradation; this effect requires an intact MDM2 RING domain for both E3 ligase activity and MDMX binding, and is stimulated by ARF via its N-terminal domain. In vivo ubiquitination assay; inducible MDM2 expression; ARF adenovirus infection; proteasome inhibitor experiments Molecular and cellular biology High 12860999
2001 Hdmx stabilizes Mdm2 by inhibiting its auto-ubiquitylation, an activity requiring the RING finger of Hdmx (likely through RING–RING heterodimerization); Hdmx also blocks Hdm2-mediated nuclear export of p53 and inhibits Hdm2-mediated p53 ubiquitination when in the nucleus. Overexpression/co-expression studies; ubiquitylation assays; nuclear export assays; RING finger mutant analysis EMBO reports High 11606419
2000 Hdmx stabilizes both p53 and Mdm2; the RING finger domain of Hdmx is necessary and sufficient for this stabilization, likely through hetero-oligomerization with the Mdm2 RING finger inhibiting Mdm2 ubiquitin ligase activity; Hdmx does not relieve Mdm2-mediated inhibition of p53 transcription, suggesting a trimeric Hdmx–Mdm2–p53 complex. Co-expression studies; RING finger deletion mutant analysis; protein stability assays The Journal of biological chemistry Medium 10827196
2005 HAUSP (USP7) directly deubiquitinates and stabilizes Hdmx; DNA damage leads to reduced HAUSP–Hdmx interaction (via ATM-dependent phosphorylation), thereby contributing to damage-induced Hdmx degradation. Co-immunoprecipitation; in vitro deubiquitination assay; siRNA knockdown; DNA damage experiments Molecular cell High 15916963
2005 ATM directly phosphorylates Hdmx at S403 in response to DNA double-strand breaks; phosphorylation at S403, S367, and S342 is required for efficient Hdm2-mediated ubiquitination and subsequent degradation of Hdmx after DNA damage. Phospho-site mutagenesis; in vivo ubiquitination assays; ATM kinase assays; DNA damage (ionizing radiation) experiments Proceedings of the National Academy of Sciences of the United States of America High 15788536
2005 ATM-mediated phosphorylations of Hdmx and Mdm2 reduce their affinity for the deubiquitinating enzyme HAUSP, contributing to their destabilization after DNA damage and thus enabling p53 activation. Co-immunoprecipitation; phosphorylation-site mutant analysis; ATM inhibitor experiments Cell cycle (Georgetown, Tex.) Medium 16082221
2006 Chk2 phosphorylates Hdmx at S367, creating a 14-3-3 binding site that drives nuclear accumulation of Hdmx following DNA double-strand breaks; this nuclear translocation is an essential step toward Hdmx ubiquitination and degradation. S342 phosphorylation also contributes to 14-3-3 binding, whereas S403 (direct ATM site) does not. Phospho-site mutagenesis; Chk2 kinase assay; 14-3-3 co-immunoprecipitation; subcellular fractionation; fluorescence microscopy Molecular and cellular biology High 16943424
2006 Chk2-mediated phosphorylation of MDMX at S367 stimulates 14-3-3 binding and nuclear import of MDMX through a cryptic nuclear import signal; 14-3-3 expression further stimulates MDM2-mediated degradation of phosphorylated MDMX. Co-immunoprecipitation with 14-3-3; Chk2 kinase assay; MDMX S367A mutant analysis; nuclear import assays The EMBO journal High 16511560
2006 Genetic epistasis in mice shows that Mdm4 and Mdm2 are both required in a non-redundant manner to prevent p53 activity in the same cell type; Mdm2 controls p53 protein levels (stability), while Mdm4 regulates p53 transcriptional activity independently of Mdm2. Conditional p53 knock-in crossed to Mdm2-null and Mdm4-null alleles; Cre-mediated p53 reactivation in vivo and in vitro Proceedings of the National Academy of Sciences of the United States of America High 16492744
2006 A mouse p53 lacking the proline-rich domain (p53ΔP) rescued Mdm4-/- but not Mdm2-/- embryos; loss of Mdm4 increased p53ΔP transactivation without altering its levels, while loss of Mdm2 increased p53ΔP levels without changing transactivation, demonstrating that Mdm4 controls p53 activity and Mdm2 controls p53 stability. Knock-in mouse models; genetic rescue experiments; p53 transactivation assays; protein stability analysis Cancer cell High 16616333
2001 Hdmx is cytoplasmic when overexpressed, but Hdm2 recruits Hdmx into the nucleus; nuclear Hdmx then blocks Hdm2-mediated nuclear export of p53 and inhibits Hdm2 ubiquitin ligase activity toward p53. Subcellular fractionation; fluorescence microscopy; co-immunoprecipitation; ubiquitination assays The Journal of biological chemistry Medium 11744695
2002 MDMX is predominantly cytoplasmic; DNA damage promotes nuclear translocation of MDMX through p53-dependent (via MDM2 induction) and p53-independent mechanisms; nuclear MDMX reduces p53 DNA-binding activity and inhibits MDM2 expression. Subcellular fractionation; immunofluorescence; stable transfection; p53 DNA-binding assays Molecular and cellular biology Medium 12370303
2005 Casein kinase 1 alpha (CK1α) binds MDMX and phosphorylates it at serine 289; this phosphorylation stimulates MDMX binding to p53 and enhances MDMX-mediated inhibition of p53 transcriptional function. Co-immunoprecipitation; in vitro kinase assay; MDMX S289 mutant analysis; siRNA knockdown; p53 reporter assays Molecular and cellular biology High 16024788
2008 c-Abl phosphorylates Hdmx, including at tyrosine 99 within the p53-binding domain; this phosphorylation is enhanced by DNA damage and inhibits Hdmx interaction with p53, contributing to p53 activation. Co-immunoprecipitation; in vitro kinase assay; phospho-site mapping; crystal structure guidance for Y99 identification; p53-binding assays The Journal of biological chemistry High 19075013
2009 Wip1 phosphatase directly dephosphorylates MdmX at ATM-targeted Ser403 and indirectly suppresses phosphorylation at Ser342 and Ser367, thereby inhibiting damage-induced ubiquitination and degradation of MdmX and reducing p53 activity. In vitro dephosphorylation assay; site-specific mutagenesis; ubiquitination assays; DNA damage experiments Cancer research High 19808970
2009 USP2a deubiquitinates MdmX and stabilizes it independently of Mdm2; endogenous USP2a contributes to MdmX stability in tumor cells, and USP2a knockdown destabilizes MdmX. Co-immunoprecipitation; in vitro deubiquitination assay with catalytic mutant control; siRNA knockdown; MdmX protein stability assays Oncogene High 19838211
2011 MdmX activates Mdm2 to convert it from a monoubiquitination E3 ligase to a polyubiquitination E3 ligase for p53, requiring the RING domains of both proteins; non-GST-tagged Mdm2 alone only catalyzes p53 monoubiquitination even at high concentrations; cellular p53 polyubiquitination occurs primarily in the cytoplasm where both Mdm2 and MdmX are detectable. In vitro ubiquitination assay with native (non-GST) Mdm2; RING domain mutant analysis; siRNA knockdown; subcellular fractionation The Journal of biological chemistry High 21572037
2020 MDMX, likely working as part of an MDM2–MDMX complex, recruits UbcH5c (E2 ubiquitin-conjugating enzyme) through interaction at its C-terminal residues, thereby facilitating MDM2 E3 ligase activity and p53 degradation in vivo; this UbcH5c recruitment is essential for p53 polyubiquitination and degradation. Genetically engineered mouse models with inducible p53 and conditional MDM2/MDMX deletion; co-immunoprecipitation; domain-swap mutants grafting MDMX C-terminus onto MDM2 Cancer research High 33277368
2010 Mutational analysis of the MDMX RING domain identified two regions that, when replaced by the corresponding Mdm2 regions, confer active ubiquitin ligase activity to MdmX for p53; one region involves the dimer interface affecting UbcH5b interaction, and the second (near cryptic nucleolar localization signal) also controls UbcH5b functional interaction. RING domain mutagenesis; in vitro ubiquitination assays; UbcH5b interaction assays The Journal of biological chemistry High 20705607
2007 Quantitative analysis shows that the nuclear abundance of Hdm2 and Hdmx relative to P53 limits P53 activity under basal conditions; upon DNA damage, a switch in Hdm2 ubiquitin ligase preference from P53 to itself and Hdmx is central to P53 activation, regardless of initial Hdmx levels. Quantitative immunofluorescence; subcellular fractionation; biochemical analysis of protein levels in normal and cancer cells after DNA damage Proceedings of the National Academy of Sciences of the United States of America Medium 17640893
2014 HDMX, following ATM-mediated phosphorylation at S403, binds the nascent p53 mRNA via its C-terminal RING domain, promoting a conformation that supports the p53 mRNA–HDM2 interaction and induction of p53 synthesis; HDMX and HDM2 act as non-redundant IRES trans-acting factors (ITAFs) with different specificity. RNA-protein interaction assays; site-specific mutagenesis (S403); RNA secondary structure assays; ATM kinase inhibitor experiments Molecular cell High 24813712
2015 MDMX contains an intramolecular autoinhibitory interaction in which a hydrophobic peptide in its central disordered region mimics the p53 transactivation domain and binds the MDMX N-terminal domain; mutation of two tryptophan residues in this peptide disrupts intramolecular interaction and increases p53 binding. A second intramolecular interaction between the RING domain and central region regulates MDMX nuclear import. Proteolytic fragment release (PFR) assay; NMR spectroscopy; site-specific mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 25825738
2016 MDMX inhibits p53 sequence-specific DNA-binding activity through secondary interactions between the MDMX acidic domain and RING domain with the p53 DNA-binding domain core; these secondary interactions require CK1α-mediated phosphorylation of MDMX at S289 and occur only after the canonical N-terminal interaction. Proteolytic fragment release (PFR) assay; siRNA knockdown of MDMX or CK1α; p53 DNA-binding EMSA; domain interaction analysis Proceedings of the National Academy of Sciences of the United States of America High 27114532
2019 TOP2A binds MDM4 at residues 188–238 (which contains an auto-inhibitory segment), and this binding activates MDM4 for p53 binding, enhancing p53 inhibition; conversely, MDM4 binding stabilizes TOP2A protein post-translationally. Co-immunoprecipitation; domain-mapping experiments; protein stability assays; p53 reporter assays Molecular oncology Medium 30672125
2014 Mdmx associates with the Nbs1 subunit of the MRN (Mre11-Rad50-Nbs1) DNA repair complex; elevated Mdmx impairs early ATM-mediated DNA damage signaling and inhibits DNA double-strand break repair, leading to genomic instability independent of p53 and Mdm2. Co-immunoprecipitation; chromatin fractionation; ATM phosphorylation assays; chromosomal break analysis; p53-null cell experiments Oncogene Medium 24608433
2017 Otub1 suppresses MDM2-mediated MDMX ubiquitination independently of its deubiquitinating enzyme activity, stabilizing MDMX; Otub1-stabilized MDMX localizes to mitochondria and promotes p53 phosphorylation at S46 and mitochondria-mediated apoptosis. Co-immunoprecipitation; in vitro ubiquitination assay; subcellular fractionation; Otub1 catalytic mutant analysis; MDMX knockdown Oncotarget Medium 28035068
2019 CDK4/6 inhibitor palbociclib indirectly suppresses PRMT5 activity, which alters pre-mRNA splicing of MDM4, shifting from full-length MDM4 to a short isoform and decreasing MDM4 protein expression, leading to p53 activation and p21-dependent CDK2 inhibition. PRMT5 inhibitor and CDK4/6 inhibitor combination; MDM4 splicing analysis; p53/p21 western blot; siRNA experiments Proceedings of the National Academy of Sciences of the United States of America Medium 31439820
2015 In cancer cells, SRSF3 oncoprotein promotes exon 6 inclusion in MDM4 pre-mRNA, producing full-length MDM4 protein, whereas exon 6 skipping in normal adult tissue produces a nonsense-mediated decay-targeted short isoform (MDM4-S) with negligible protein output; antisense oligonucleotide-mediated exon 6 skipping reduces MDM4 abundance and inhibits tumor growth. Alternative splicing analysis; SRSF3 siRNA/overexpression; ASO-mediated exon skipping in melanoma cell lines and PDX mouse models The Journal of clinical investigation High 26595814
2021 MDM2 and MDMX, working as a heterocomplex, promote cell-cycle progression in a p53-independent manner by supporting the activity of E2F1, E2F3, and p73; loss of endogenous MDM2 or MDMX or inhibition of E3 ligase activity of the heterocomplex causes cell-cycle arrest correlated with reduction of these factors. siRNA/shRNA knockdown; p53-null cell lines; E2F and p73 protein/mRNA measurement; E3 ligase activity inhibition Proceedings of the National Academy of Sciences of the United States of America Medium 34716260
2020 MDM2 and MDMX, likely as a complex, facilitate ferroptosis by altering the cellular lipid profile; inhibition of MDM2 or MDMX increases FSP1 protein levels and coenzyme Q10, enhancing defense against lipid peroxidation; PPARα activity is required for MDM2–MDMX to promote ferroptosis. Small molecule inhibitors; RNAi; MDMX mutant forms; lipidomics; FSP1/CoQ10 measurements; p53-null cell experiments Genes & development Medium 32079652
2009 USP22 interacts with MDMX and upregulates MDMX protein expression; USP22 silencing downregulates MDMX protein and activates p53, while MDMX overexpression rescues USP22-knockdown phenotypes, placing USP22 as a stabilizer of MDMX upstream of p53. Co-immunoprecipitation; siRNA knockdown; rescue experiments; xenograft model International journal of molecular sciences Low 25547493
2014 USP2a binds to and deubiquitinates MDM4, and MDM4-USP2a complexes localize in the cytoplasmic fraction; MDM4 found in the mitochondrial fraction forms complexes with p53(Ser46P) and BCL-2, and USP2a-mediated MDM4 stabilization promotes mitochondrial p53 localization and apoptosis. Co-immunoprecipitation; subcellular fractionation; USP2a/MDM4 overexpression and knockdown; apoptosis assays Carcinogenesis Medium 24445145
2009 A fraction of MDM4 stably localizes at mitochondria; upon lethal stress, this mitochondrial MDM4 promotes localization of p53(Ser46P) to mitochondria, facilitates p53 binding to BCL-2, cytochrome c release, and apoptosis. Subcellular fractionation; co-immunoprecipitation (MDM4–p53, MDM4–BCL-2); MDM4 knockdown; apoptosis assays Cell cycle (Georgetown, Tex.) Medium 19887911
2012 Small molecules that bind the p53-binding pockets of MDM2 and MDMX induce MDM2–MDMX homo- and/or heterodimerization, occluding both p53 pockets simultaneously; crystal structures confirmed this induced-dimerization mechanism. X-ray crystallography of MDM2/MDMX with small molecules; biochemical p53 displacement assays; cell-based p53 activation assays Proceedings of the National Academy of Sciences of the United States of America High 22745160
2001 ARF interacts with MdmX and sequesters it in the nucleolus via a nucleolar localization signal on MdmX; sequestration of MdmX by ARF increases p53 transactivation. Co-expression of both ARF and MdmX leads to decreased Mdm2 protein levels compared to either alone. Co-immunoprecipitation; immunofluorescence (nucleolar co-localization); p53 reporter assays; western blot protein level analysis The Journal of biological chemistry Medium 11297540
2021 Matrix stiffness regulates MDM4 expression in lung myofibroblasts; reducing matrix stiffness downregulates MDM4, activating p53 and sensitizing myofibroblasts to apoptosis; genetic ablation of Mdm4 in lung fibroblasts activates the Mdm4–p53 pathway and promotes fibrosis resolution in aged mice. Tunable hydrogel stiffness experiments; primary human IPF myofibroblasts; Mdm4 conditional knockout mice; p53 activity assays The Journal of experimental medicine Medium 33688918

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 The p53 orchestra: Mdm2 and Mdmx set the tone. Trends in cell biology 366 20172729
2003 HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53. Proceedings of the National Academy of Sciences of the United States of America 289 14507994
2004 Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity. Molecular and cellular biology 278 15199139
2020 MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling. Genes & development 236 32079652
2010 A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer cell 232 21075307
2005 Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2. Molecular cell 227 15916963
2006 Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo. Proceedings of the National Academy of Sciences of the United States of America 221 16492744
2003 MDM2 promotes ubiquitination and degradation of MDMX. Molecular and cellular biology 204 12860999
2018 Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. Science translational medicine 201 29643228
2007 MDM2 and MDM4: p53 regulators as targets in anticancer therapy. The international journal of biochemistry & cell biology 195 17499002
2001 Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms. EMBO reports 190 11606419
2012 Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization. Proceedings of the National Academy of Sciences of the United States of America 182 22745160
2006 Levels of HdmX expression dictate the sensitivity of normal and transformed cells to Nutlin-3. Cancer research 169 16540668
2012 Molecular pathways: targeting Mdm2 and Mdm4 in cancer therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 159 23262034
2009 Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry? Molecular cancer research : MCR 149 19147532
2006 A mouse p53 mutant lacking the proline-rich domain rescues Mdm4 deficiency and provides insight into the Mdm2-Mdm4-p53 regulatory network. Cancer cell 148 16616333
2005 Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage. Proceedings of the National Academy of Sciences of the United States of America 147 15788536
2015 Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth. The Journal of clinical investigation 146 26595814
2011 The structure-based design of Mdm2/Mdmx-p53 inhibitors gets serious. Angewandte Chemie (International ed. in English) 126 21341346
2001 Aberrant expression of HDMX proteins in tumor cells correlates with wild-type p53. Cancer research 126 11280734
2000 Hdmx stabilizes Mdm2 and p53. The Journal of biological chemistry 125 10827196
2005 ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation. Cell cycle (Georgetown, Tex.) 118 16082221
2012 MDM2 and MDMX: Alone and together in regulation of p53. Translational cancer research 115 23002429
2020 Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet? Frontiers in cell and developmental biology 114 32300595
2021 The roles and regulation of MDM2 and MDMX: it is not just about p53. Genes & development 112 33888565
2012 Regulation of p53: a collaboration between Mdm2 and Mdmx. Oncotarget 107 22410433
2007 Haploinsufficiency of Mdm2 and Mdm4 in tumorigenesis and development. Molecular and cellular biology 107 17526734
2007 Quantitative analyses reveal the importance of regulated Hdmx degradation for p53 activation. Proceedings of the National Academy of Sciences of the United States of America 105 17640893
2019 Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma. Proceedings of the National Academy of Sciences of the United States of America 100 31439820
2006 Regulation of MDMX nuclear import and degradation by Chk2 and 14-3-3. The EMBO journal 100 16511560
2011 MdmX protein is essential for Mdm2 protein-mediated p53 polyubiquitination. The Journal of biological chemistry 97 21572037
2009 MdmX is a substrate for the deubiquitinating enzyme USP2a. Oncogene 89 19838211
2012 Mdm2 and MdmX partner to regulate p53. FEBS letters 86 22673503
2013 miR-661 downregulates both Mdm2 and Mdm4 to activate p53. Cell death and differentiation 81 24141721
2008 Mdm2 and Mdm4 loss regulates distinct p53 activities. Molecular cancer research : MCR 81 18567799
2005 Regulation of p53-MDMX interaction by casein kinase 1 alpha. Molecular and cellular biology 80 16024788
2018 Dual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response. Proceedings of the National Academy of Sciences of the United States of America 77 30598450
2006 Differential roles of ATM- and Chk2-mediated phosphorylations of Hdmx in response to DNA damage. Molecular and cellular biology 70 16943424
2001 Hdmx recruitment into the nucleus by Hdm2 is essential for its ability to regulate p53 stability and transactivation. The Journal of biological chemistry 69 11744695
2002 DNA damage induces MDMX nuclear translocation by p53-dependent and -independent mechanisms. Molecular and cellular biology 67 12370303
2017 The role of MDM2 and MDM4 in breast cancer development and prevention. Journal of molecular cell biology 66 28096293
2014 Targeting p53-MDM2-MDMX loop for cancer therapy. Sub-cellular biochemistry 65 25201201
2016 Medicinal Chemistry Strategies to Disrupt the p53-MDM2/MDMX Interaction. Medicinal research reviews 61 27302609
2008 Regulation of MDMX expression by mitogenic signaling. Molecular and cellular biology 60 18172009
2019 The long and the short of it: the MDM4 tail so far. Journal of molecular cell biology 59 30689920
2009 Beta-peptides with improved affinity for hDM2 and hDMX. Bioorganic & medicinal chemistry 59 19211253
2006 Distinct roles of Mdm2 and Mdm4 in red cell production. Blood 59 17105817
2001 MdmX binding to ARF affects Mdm2 protein stability and p53 transactivation. The Journal of biological chemistry 58 11297540
2023 Clonal hematopoiesis driven by chromosome 1q/MDM4 trisomy defines a canonical route toward leukemia in Fanconi anemia. Cell stem cell 57 36736290
2014 microRNAs and Alu elements in the p53-Mdm2-Mdm4 regulatory network. Journal of molecular cell biology 57 24868102
2019 MDM2 and MDM4 Are Therapeutic Vulnerabilities in Malignant Rhabdoid Tumors. Cancer research 56 30755442
2014 Mdmx promotes genomic instability independent of p53 and Mdm2. Oncogene 56 24608433
2019 Mutual regulation of MDM4 and TOP2A in cancer cell proliferation. Molecular oncology 55 30672125
2008 c-Abl phosphorylates Hdmx and regulates its interaction with p53. The Journal of biological chemistry 54 19075013
2020 α-Helix-Mimicking Sulfono-γ-AApeptide Inhibitors for p53-MDM2/MDMX Protein-Protein Interactions. Journal of medicinal chemistry 53 31971801
2014 Ubiquitin-specific protease 2a stabilizes MDM4 and facilitates the p53-mediated intrinsic apoptotic pathway in glioblastoma. Carcinogenesis 53 24445145
2013 Mdm2 and MdmX inhibitors for the treatment of cancer: a patent review (2011-present). Expert opinion on therapeutic patents 53 23374098
2009 Phosphorylation and degradation of MdmX is inhibited by Wip1 phosphatase in the DNA damage response. Cancer research 53 19808970
2016 MDMX (MDM4), a Promising Target for p53 Reactivation Therapy and Beyond. Cold Spring Harbor perspectives in medicine 51 27371671
2009 In Silico Improvement of beta3-peptide inhibitors of p53 x hDM2 and p53 x hDMX. Journal of the American Chemical Society 51 19415930
2008 Analysis of human MDM4 variants in papillary thyroid carcinomas reveals new potential markers of cancer properties. Journal of molecular medicine (Berlin, Germany) 48 18335186
2014 HDMX folds the nascent p53 mRNA following activation by the ATM kinase. Molecular cell 45 24813712
2015 Autoinhibition of MDMX by intramolecular p53 mimicry. Proceedings of the National Academy of Sciences of the United States of America 44 25825738
2008 BH3 activation blocks Hdmx suppression of apoptosis and cooperates with Nutlin to induce cell death. Cell cycle (Georgetown, Tex.) 44 18604177
2022 Design of stapled peptide-based PROTACs for MDM2/MDMX atypical degradation and tumor suppression. Theranostics 42 36185610
2011 p53 regulation: teamwork between RING domains of Mdm2 and MdmX. Cell cycle (Georgetown, Tex.) 41 22134240
2009 Mitochondrial MDM4 (MDMX): an unpredicted role in the p53-mediated intrinsic apoptotic pathway. Cell cycle (Georgetown, Tex.) 41 19887911
2021 Therapeutic opportunities in cancer therapy: targeting the p53-MDM2/MDMX interactions. American journal of cancer research 39 35018225
2016 Secondary interaction between MDMX and p53 core domain inhibits p53 DNA binding. Proceedings of the National Academy of Sciences of the United States of America 39 27114532
2003 MDM4 (MDMX) overexpression enhances stabilization of stress-induced p53 and promotes apoptosis. The Journal of biological chemistry 39 14660608
2017 Role of Mdm2 and Mdmx in DNA repair. Journal of molecular cell biology 38 27932484
2021 Paeoniflorin Suppresses Rheumatoid Arthritis Development via Modulating the Circ-FAM120A/miR-671-5p/MDM4 Axis. Inflammation 37 34423389
2021 MDM2, MDMX, and p73 regulate cell-cycle progression in the absence of wild-type p53. Proceedings of the National Academy of Sciences of the United States of America 37 34716260
2018 An Update on MDMX and Dual MDM2/X Inhibitors. Current topics in medicinal chemistry 36 29866007
2005 Rescue of Mdm4-deficient mice by Mdm2 reveals functional overlap of Mdm2 and Mdm4 in development. Oncogene 36 16027727
2021 Targeting mechanosensitive MDM4 promotes lung fibrosis resolution in aged mice. The Journal of experimental medicine 35 33688918
2020 Targeting MDMX for Cancer Therapy: Rationale, Strategies, and Challenges. Frontiers in oncology 35 32850448
2016 Dual function of MDM2 and MDMX toward the tumor suppressors p53 and RB. Genes & cancer 35 28050229
2020 MDMX Recruits UbcH5c to Facilitate MDM2 E3 Ligase Activity and Subsequent p53 Degradation In Vivo. Cancer research 34 33277368
2019 MDM4 Is Targeted by 1q Gain and Drives Disease in Burkitt Lymphoma. Cancer research 34 31000522
2018 The MDM2/MDMX-p53 Antagonist PM2 Radiosensitizes Wild-Type p53 Tumors. Cancer research 34 30026328
2017 Otub1 stabilizes MDMX and promotes its proapoptotic function at the mitochondria. Oncotarget 34 28035068
2015 MDM4 SNP34091 (rs4245739) and its effect on breast-, colon-, lung-, and prostate cancer risk. Cancer medicine 34 26471763
2017 Anatomy of Mdm2 and Mdm4 in evolution. Journal of molecular cell biology 33 28077607
2011 MDM2 and MDMX in cancer and development. Current topics in developmental biology 33 21295684
2011 Abrogation of Wip1 expression by RITA-activated p53 potentiates apoptosis induction via activation of ATM and inhibition of HdmX. Cell death and differentiation 33 21546907
2015 2,30-Bis(10H-indole) heterocycles: New p53/MDM2/MDMX antagonists. Bioorganic & medicinal chemistry letters 32 26584879
2020 Germline mutation of MDM4, a major p53 regulator, in a familial syndrome of defective telomere maintenance. Science advances 31 32300648
2014 USP22 promotes NSCLC tumorigenesis via MDMX up-regulation and subsequent p53 inhibition. International journal of molecular sciences 30 25547493
2008 MdmX regulates transformation and chromosomal stability in p53-deficient cells. Cell cycle (Georgetown, Tex.) 29 18818521
2016 Development of cell-penetrating peptide-based drug leads to inhibit MDMX:p53 and MDM2:p53 interactions. Biopolymers 28 27287767
2009 Inhibitors of MDM2 and MDMX: a structural perspective. Future medicinal chemistry 28 21425995
2008 Full-length hdmX transcripts decrease following genotoxic stress. Oncogene 28 18711402
2009 MDM2 and MDM4 splicing: an integral part of the cancer spliceome. Frontiers in bioscience (Landmark edition) 27 19273224
2007 Distinct roles of MDMX in the regulation of p53 response to ribosomal stress. Cell cycle (Georgetown, Tex.) 27 17327702
2023 Verbenalin attenuates hepatic damage and mitochondrial dysfunction in alcohol-associated steatohepatitis by regulating MDMX/PPARα-mediated ferroptosis. Journal of ethnopharmacology 26 36739928
2010 Turning the RING domain protein MdmX into an active ubiquitin-protein ligase. The Journal of biological chemistry 26 20705607
2008 Expression of p14ARF, MDM2, and MDM4 in human retinoblastoma. Biochemical and biophysical research communications 25 18644346
2021 Mdm2 and MdmX: Partners in p53 Destruction. Cancer research 24 34003788
2019 Structural States of Hdm2 and HdmX: X-ray Elucidation of Adaptations and Binding Interactions for Different Chemical Compound Classes. ChemMedChem 24 31066983