Affinage

MDM4

Protein Mdm4 · UniProt O15151

Length
490 aa
Mass
54.9 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MDM4 (MDMX/HDMX) is an essential, non-redundant negative regulator of p53 whose loss in mice causes p53-dependent embryonic lethality rescued by concomitant p53 deletion (PMID:12101245, PMID:16492744). It restrains p53 by at least three biochemically distinct routes: direct N-terminal binding that blocks p53 transcriptional activation without itself degrading p53 (PMID:10827196), secondary engagement of the p53 DNA-binding domain by its acidic and RING domains—dependent on CK1α-mediated S289 phosphorylation—that suppresses sequence-specific DNA binding (PMID:27114532), and activation of MDM2's E3 ligase, converting MDM2 from a mono- to a poly-ubiquitin ligase toward p53 via RING–RING heterodimerization (PMID:14507994, PMID:21572037). MDM4 stability is itself governed by a regulatory web in which MDM2 ubiquitinates it for degradation (PMID:12874296) while the deubiquitinases USP7/HAUSP, USP2a, and OTUB1 oppose this to stabilize it (PMID:15916963, PMID:19838211, PMID:28035068). Upon DNA damage, ATM phosphorylates MDM4 directly at S403 and Chk2 phosphorylates S367, while AMPK phosphorylates S342 under metabolic stress; these marks recruit 14-3-3, drive nuclear import, and trigger MDM2-mediated MDM4 degradation, relieving p53 (PMID:15788536, PMID:16227609, PMID:16511560, PMID:16943424, PMID:24190973). Beyond transcriptional control, MDM4 localizes to mitochondria where it facilitates p53(Ser46P)–BCL2 interaction and apoptosis (PMID:19521340), and after ATM/S403 phosphorylation its RING binds nascent p53 mRNA as an IRES trans-acting factor to promote p53 translation (PMID:24813712). MDM4 also drives p53-independent oncogenic outputs, activating Wnt/β-Catenin signaling through CK1α binding (PMID:33667384) and impairing MRN-dependent double-strand break repair via association with Nbs1 (PMID:24608433). In cancer, MDM4 overexpression arises chiefly through an SRSF3-dependent splicing switch favoring exon 6 inclusion and full-length protein (PMID:26595814), and MDM4 amplification or trisomy confers fitness in Fanconi anemia hematopoietic progenitors and leukemia (PMID:36736290).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 Medium

    Established that MDM4 binds p53-family members beyond p53 itself, but with opposite consequence for stability, hinting at context-specific output.

    Evidence Co-IP and protein half-life assay of MDMX with p73α/β

    PMID:10469568

    Open questions at the time
    • Does not establish in vivo relevance of p73 stabilization
    • No mapping of which MDMX domain mediates p73 binding
  2. 2000 Medium

    Resolved the core puzzle that MDMX inhibits p53 transcription without degrading it, attributing stabilization of both p53 and MDM2 to MDMX RING–MDM2 RING hetero-oligomerization.

    Evidence Co-IP, reporter assays, and RING deletion mutants forming a trimeric MDMX–MDM2–p53 complex

    PMID:10827196

    Open questions at the time
    • No in vitro reconstitution of RING hetero-oligomerization
    • Stoichiometry of the trimeric complex undefined
  3. 2001 Medium

    Defined MDM4 inhibitory specificity (acts on p53 but not p63) and showed MDM2 controls MDMX nuclear localization while nuclear MDMX blocks MDM2-mediated p53 export and ubiquitination.

    Evidence Localization microscopy, Co-IP, ubiquitination and reporter assays comparing p53 vs p63

    PMID:11494153 PMID:11744695

    Open questions at the time
    • Conducted in overexpression systems
    • Cytoplasmic-to-nuclear shuttling signals not fully mapped
  4. 2002 High

    Genetically proved MDM4 is an essential, non-redundant p53 inhibitor with no p53-independent proliferative role in development, and showed DNA damage and MDM2/p53 drive MDMX nuclear translocation while MDMX reduces p53 DNA binding.

    Evidence Mdm4 gene-trap knockout with p53-null epistasis rescue; subcellular fractionation and p53 DNA-binding assays

    PMID:12101245 PMID:12370303

    Open questions at the time
    • Molecular basis of p53 DNA-binding inhibition not yet defined
    • Mechanism of damage-induced translocation unresolved at this stage
  5. 2003 High

    Reconciled the apparent paradox by showing MDM4 lacks intrinsic E3 activity but stimulates MDM2-mediated p53 ubiquitination/degradation, while MDM2 reciprocally ubiquitinates MDM4 for proteasomal turnover.

    Evidence In vitro ubiquitination with MDMX deletion mutants, siRNA knockdown, proteasome inhibition

    PMID:12874296 PMID:14507994

    Open questions at the time
    • Did not define how MDMX stimulates MDM2 catalysis mechanistically
    • Mono- vs poly-ubiquitin nature not distinguished
  6. 2005 High

    Identified the DNA-damage degradation switch: ATM phosphorylates MDMX at S403 and damage requires S367/S342, lowering HAUSP affinity and licensing MDM2-mediated MDMX degradation, with USP7/HAUSP normally stabilizing MDMX.

    Evidence In vitro ATM kinase assay, phospho-site mutagenesis, HAUSP Co-IP and deubiquitination assays in ATM-deficient cells

    PMID:15788536 PMID:15916963

    Open questions at the time
    • Relative contribution of each phosphosite to degradation not quantified
    • ARF-mediated MDMX sumoylation role (15876864) not integrated
  7. 2006 High

    Defined the 14-3-3/nuclear-import arm: Chk2 phosphorylation at S367 (with S342) creates a 14-3-3 site driving MDMX nuclear import and MDM2-dependent degradation, distinguishing ATM (S403) from Chk2 (S367) target sites; established MDM2/MDM4 non-redundancy in vivo.

    Evidence Chk2/ATM kinase assays, S367/S342/S403 mutagenesis, 14-3-3 Co-IP, nuclear import assays, conditional knock-in/knockout epistasis

    PMID:16082221 PMID:16227609 PMID:16492744 PMID:16511560 PMID:16943424

    Open questions at the time
    • Cryptic nuclear import signal not structurally defined
    • How nuclear localization couples to ubiquitination not fully resolved
  8. 2007 High

    Provided a quantitative systems view: relative nuclear abundance of MDM2/MDMX versus p53 sets the threshold for p53 activity, and damage switches MDM2 ligase preference from p53 to itself and MDMX.

    Evidence Quantitative immunofluorescence, fractionation, shRNA knockdown, pulse-chase in normal and cancer cells

    PMID:17640893

    Open questions at the time
    • Single-lab quantitation
    • Cell-type generality of stoichiometric thresholds untested
  9. 2008 Medium

    Connected MDMX to upstream mitogenic and stress kinase inputs: c-Abl phosphorylates MDMX at Y99 to disrupt p53 binding, while K-Ras/IGF-1–MAPK/c-Ets-1 signaling transcriptionally induces MDMX.

    Evidence c-Abl Co-IP and kinase assay with Y99 mutant; MDMX promoter reporter with K-Ras/IGF-1 stimulation and MEK inhibition

    PMID:18172009 PMID:19075013

    Open questions at the time
    • In vivo importance of Y99 phosphorylation not established
    • c-Ets-1 binding sites on the promoter not mapped
  10. 2009 High

    Revealed a transcription-independent, mitochondrial pro-apoptotic function: MDM4 binds BCL2 and promotes p53(Ser46P)–BCL2 interaction, cytochrome C release, and apoptosis; USP2a was added as a MDMX-stabilizing deubiquitinase.

    Evidence Mitochondrial fractionation, MDM4–BCL2 and p53S46P–BCL2 Co-IP, RNAi, cytochrome C release; USP2a Co-IP/catalytic mutant/siRNA

    PMID:19521340 PMID:19838211

    Open questions at the time
    • Signal targeting MDM4 to mitochondria undefined
    • Reconciliation of pro-apoptotic vs anti-p53 roles unresolved
  11. 2011 High

    Mechanistically resolved how MDMX activates MDM2: MDMX converts MDM2 from a mono- to a poly-ubiquitin ligase toward p53 through RING–RING heterodimerization, with polyubiquitination occurring predominantly in the cytoplasm.

    Evidence In vitro ubiquitination with non-GST-tagged proteins, RING mutagenesis, RNAi, subcellular fractionation

    PMID:21572037

    Open questions at the time
    • Structural basis of the active heterodimeric RING undefined
    • Determinants of cytoplasmic versus nuclear ubiquitination unclear
  12. 2013 High

    Extended kinase regulation to metabolic stress: AMPK phosphorylates MDMX at S342 to enhance 14-3-3 binding and stabilize/activate p53, without acting on MDM2.

    Evidence In vitro AMPK kinase assay, phospho-specific antibody, triple-mutant knock-in MEFs, metformin/salicylate treatment

    PMID:24190973

    Open questions at the time
    • Whether S342 phosphorylation promotes MDMX degradation like damage signaling not fully separated
    • Tissue contexts of metabolic regulation untested
  13. 2014 High

    Uncovered two new functions: MDMX RING acts as an ATM/S403-dependent IRES trans-acting factor promoting p53 mRNA translation, and MDMX promotes p53/MDM2-independent genomic instability by binding Nbs1 and impairing MRN-mediated break repair.

    Evidence RNA pull-down, IRES reporter, RNA structure probing; MDMX–Nbs1 Co-IP, ChIP, chromosome break and ATM signaling assays in p53/Mdm2-null cells

    PMID:24608433 PMID:24813712

    Open questions at the time
    • How a p53 inhibitor also promotes p53 synthesis is paradoxical and context-dependent
    • Structural basis of MDMX RING–RNA binding undefined
  14. 2016 High

    Defined a second p53-inhibitory interaction surface: MDMX acidic and RING domains engage the p53 DNA-binding domain after initial N-terminal binding to block sequence-specific DNA binding, requiring CK1α-mediated S289 phosphorylation.

    Evidence Proteolytic fragment release, interaction mapping, CK1α knockdown, phospho-S289 mutant, p53 DNA-binding assays

    PMID:27114532

    Open questions at the time
    • Structural model of the secondary acidic/RING–p53 DBD interface not solved
    • Interplay with MDM2-driven degradation arm not quantified
  15. 2019 High

    Added structural and partner-based regulation: high-resolution crystal structures defined the HdmX p53-binding cleft for selective inhibitor design, and TOP2A binding relieves MDM4 auto-inhibition to enhance p53 inhibition while MDM4 reciprocally stabilizes TOP2A.

    Evidence X-ray crystallography of HdmX–ligand complexes; TOP2A Co-IP and domain mapping with p53 interaction and stability readouts

    PMID:30672125 PMID:31066983

    Open questions at the time
    • Structures cover the p53-cleft only, not the acidic/RING secondary interface
    • In vivo significance of MDM4–TOP2A axis untested
  16. 2021 High

    Established p53-independent and disease-relevant outputs: MDMX–CK1α binding activates Wnt/β-Catenin in preleukemic stem cells, MDM4 trisomy drives clonal fitness in Fanconi anemia and leukemia, MDM2/MDMX promote ferroptosis via FSP1/CoQ10/PPARα, matrix stiffness regulates MDM4 in lung fibrosis, and MDM2/MDMX loss arrests p53-null cells via p73.

    Evidence Co-IP and murine overexpression models (Wnt); patient genomics and triplication transplantation models (FA); inhibitors/RNAi with lipidomics (ferroptosis); conditional KO and bleomycin model (fibrosis); knockdown with p73 epistasis (cell cycle)

    PMID:32079652 PMID:33667384 PMID:33688918 PMID:34716260 PMID:36736290

    Open questions at the time
    • How MDMX–CK1α mechanistically stabilizes β-Catenin not fully resolved
    • Whether ferroptosis and Wnt functions require the same domains as p53 inhibition unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MDM4's many regulatory inputs and outputs are integrated into a unified structural and quantitative model remains unresolved.
  • No structure of the active MDMX–MDM2 RING heterodimer or the secondary acidic/RING–p53 DBD interface
  • How p53-inhibitory, pro-apoptotic, pro-translational, and p53-independent oncogenic activities are partitioned within a cell is undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140110 transcription regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2 GO:0003723 RNA binding 1 GO:0045182 translation regulator activity 1
Localization
GO:0005634 nucleus 4 GO:0005739 mitochondrion 2 GO:0005829 cytosol 2 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1640170 Cell Cycle 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 1
Partners
CSNK1A1MDM2NBNOTUB1TOP2ATP53USP2AUSP7
Complex memberships
MDMX-MDM2 RING heterodimerMDMX-MDM2-p53 trimeric complex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 HDMX stimulates HDM2-mediated ubiquitination and degradation of p53 in vitro; HDMX alone lacks appreciable E3 ubiquitin ligase activity but acts as a stimulator of HDM2's E3 activity, and also facilitates mutual ubiquitination between HDMX and HDM2. Knockdown of HDMX in cells results in accumulation of both p53 and HDM2. In vitro ubiquitination assay, siRNA knockdown, co-immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America High 14507994
2002 Mdm4 knockout causes p53-dependent embryonic lethality at E10.5, with G1 cell cycle arrest and extensive p53-dependent cell death in the developing CNS; lethality is fully rescued by concomitant p53 knockout, establishing Mdm4 as an essential negative regulator of p53 in vivo with no p53-independent role in proliferation. Gene-trap knockout mouse, genetic epistasis with p53-null background, BrdU incorporation, in situ analysis of p21/CyclinE/PCNA Molecular and cellular biology High 12101245
2003 Hdmx protein stability is regulated by MDM2-mediated ubiquitination; MDM2 requires only an intact RING domain to ubiquitinate Hdmx and target it for proteasomal degradation, while Hdmx stability is partly dependent on its internal acidic domain. Ubiquitination assay with Hdmx deletion mutants, proteasome inhibitor treatment, co-expression experiments The Journal of biological chemistry High 12874296
2005 HAUSP (USP7) directly deubiquitinates and stabilizes Hdmx; loss of HAUSP activity reduces Hdmx protein levels. ATM-dependent phosphorylation of Hdmx/Hdm2 after DNA damage reduces their affinity for HAUSP, thereby contributing to DNA damage-induced degradation of Hdmx. Co-immunoprecipitation of HAUSP-Hdmx, in vitro deubiquitination assay, siRNA knockdown of HAUSP, DNA damage experiments Molecular cell High 15916963
2005 Efficient DNA damage-induced degradation of Hdmx depends on functional ATM and phosphorylation at three sites (S403 as a direct ATM target, S367, S342); each site is required for Hdm2-mediated ubiquitination of Hdmx after double-strand break induction. Phosphorylation mapping with site-directed mutagenesis, in vitro kinase assay, ubiquitination assay, ATM-deficient cells Proceedings of the National Academy of Sciences of the United States of America High 15788536
2005 DNA damage-induced phosphorylation of MdmX at S367 (by Chk2) creates a binding site for 14-3-3 proteins, which promotes MdmX nuclear import and subsequent Mdm2-dependent degradation; the S367A mutant is resistant to Mdm2-mediated ubiquitination and degradation. Co-immunoprecipitation of 14-3-3–MdmX, site-directed mutagenesis (S367A), ubiquitination assay, nuclear translocation assay, Chk2 kinase assay Molecular and cellular biology High 16227609
2006 Chk2 phosphorylates MDMX on S367, stimulating 14-3-3 binding, MDMX nuclear import via a cryptic nuclear import signal, and MDM2-mediated degradation; 14-3-3 expression stimulates degradation of phosphorylated MDMX and overcomes MDMX-mediated inhibition of p53. Co-purification of MDMX with 14-3-3, Chk2 kinase assay, S367 mutagenesis, nuclear import assay, ubiquitination assay The EMBO journal High 16511560
2006 Mdm2 and Mdm4 are essential in a non-redundant manner for preventing p53 activity in the same cell type regardless of proliferation/differentiation status; Mdm2 primarily prevents p53 protein accumulation while Mdm4 fine-tunes p53 transcriptional activity independently of Mdm2. Conditional p53 knock-in combined with mdm2-null and mdm4-null alleles, Cre-mediated activation, genetic epistasis in vivo and in vitro Proceedings of the National Academy of Sciences of the United States of America High 16492744
2006 ATM-dependent phosphorylation of Mdmx and Mdm2 reduces their affinity for the deubiquitinating enzyme HAUSP, thereby decreasing HAUSP-mediated stabilization and contributing to their DNA damage-induced degradation in favor of p53 activation. Co-immunoprecipitation of HAUSP with Mdmx/Mdm2 post-DNA damage, phosphorylation mapping, ATM inhibitor/deficiency experiments Cell cycle (Georgetown, Tex.) Medium 16082221
2006 ATM phosphorylates Hdmx at S403 directly; Chk2 (downstream of ATM) phosphorylates Hdmx at S367. S367 and S342 phosphorylation, but not S403, promote 14-3-3 binding and nuclear accumulation of Hdmx, which is an essential step for its degradation after DNA double-strand breaks. In vitro kinase assays with ATM and Chk2, site-directed mutagenesis, 14-3-3 binding assay, nuclear localization assay Molecular and cellular biology High 16943424
2000 Hdmx inhibits p53 transcriptional activation without promoting p53 degradation; Hdmx stabilizes both p53 and Mdm2 by counteracting Mdm2-mediated degradation. The RING finger of Hdmx is necessary and sufficient for this stabilization, likely through hetero-oligomerization with the Mdm2 RING finger inhibiting Mdm2 ubiquitin ligase activity. A trimeric Hdmx–Mdm2–p53 complex forms. Co-immunoprecipitation, transcription reporter assay, protein stability assay, RING domain deletion mutants The Journal of biological chemistry Medium 10827196
2001 Overexpressed Hdmx is cytoplasmic; Hdm2 recruits Hdmx into the nucleus, where nuclear Hdmx blocks Hdm2-mediated nuclear export of p53, inhibits p53-dependent transcription, and inhibits Hdm2-mediated p53 ubiquitination. A regulatory loop exists in which Hdm2 controls Hdmx localization and nuclear Hdmx regulates Hdm2 activity. Fluorescence microscopy of subcellular localization, co-immunoprecipitation, ubiquitination assay, transcription reporter assay The Journal of biological chemistry Medium 11744695
2002 DNA damage promotes nuclear translocation of MDMX independently of p53; coexpression of MDM2 or p53 is sufficient to induce MDMX nuclear translocation. MDMX expression reduces p53 DNA-binding activity and MDM2 expression, and inhibits ARF-mediated p53 activation. Subcellular fractionation and immunofluorescence of MDMX localization, p53 DNA-binding assay, ARF co-expression experiments Molecular and cellular biology Medium 12370303
2007 Nuclear abundance of Hdm2 and Hdmx relative to p53 limits p53 activity in unstressed cells; upon DNA damage, Hdmx stability decreases while p53 nuclear abundance increases, and quantitative analysis shows that damage-activated switching of Hdm2 ubiquitin ligase preference from p53 to itself and Hdmx is central to p53 activation. Quantitative immunofluorescence, subcellular fractionation, shRNA knockdown, pulse-chase analysis in normal and cancer cells Proceedings of the National Academy of Sciences of the United States of America High 17640893
2011 MdmX is the cellular activator that converts Mdm2 from a monoubiquitination E3 ligase to a polyubiquitination E3 ligase toward p53; this activation requires the RING domains of both MdmX and Mdm2. Non-GST-tagged Mdm2 alone only monoubiquitinates p53; co-overexpression of MdmX and Mdm2 consistently triggers p53 degradation in cells; cellular p53 polyubiquitination occurs predominantly in the cytoplasm where both Mdm2 and MdmX are detectable. In vitro ubiquitination assay with non-GST-tagged proteins, RING domain mutagenesis, RNAi knockdown, subcellular fractionation The Journal of biological chemistry High 21572037
2009 MdmX is a substrate for the deubiquitinating enzyme USP2a; USP2a binds MdmX independently of Mdm2 and prevents Mdm2-mediated degradation of MdmX via its catalytic deubiquitinase activity. Endogenous USP2a participates in regulation of MdmX stability in cancer cells. Co-immunoprecipitation, catalytic mutant USP2a, siRNA knockdown of USP2a, western blot for MdmX levels Oncogene Medium 19838211
2013 AMPK phosphorylates MDMX on Ser342 (human; S341 in mouse) in vitro and in cells in response to metabolic stress, enhancing MDMX association with 14-3-3, inhibiting p53 ubiquitylation and significantly stabilizing and activating p53. No phosphorylation of MDM2 by AMPK was detected. MDMX triple mutant (S341A/S367A/S402A) knock-in mouse embryo fibroblasts show drastically reduced MDMX–14-3-3 binding and p53 activation. In vitro kinase assay, AMPK-S342 phospho-specific antibody, knock-in MEFs, AMPK activators (metformin, salicylate), co-immunoprecipitation Molecular and cellular biology High 24190973
2008 c-Abl tyrosine kinase interacts with and phosphorylates Hdmx; this phosphorylation is enhanced by DNA damage and maps to the p53-binding domain of Hdmx. Phosphorylation at tyrosine 99 inhibits Hdmx interaction with p53, consistent with the predicted role of Y99 in the p53-binding interface from crystal structure analysis. Co-immunoprecipitation of c-Abl–Hdmx, in vitro kinase assay, phosphorylation site mapping, co-immunoprecipitation of Hdmx–p53 interaction with Y99 mutant The Journal of biological chemistry Medium 19075013
2009 MDM4 stably localizes at mitochondria where it (i) binds BCL2, (ii) facilitates mitochondrial localization of p53 phosphorylated at Ser46 (p53S46P), and (iii) promotes binding between p53S46P and BCL2, cytochrome C release, and apoptosis. MDM4 knockdown increases resistance to DNA-damage-induced apoptosis in a p53-dependent, transcription-independent manner. Subcellular fractionation (mitochondrial), co-immunoprecipitation (MDM4–BCL2, p53S46P–BCL2), RNAi knockdown, cytochrome C release assay, live-cell imaging The EMBO journal High 19521340
1999 MDMX binds p73α and p73β (p53 family members) and stabilizes p73 protein levels (in contrast to MDM2/MDMX binding to p53 which promotes p53 degradation); MDMX binding increases p73 half-life. Co-immunoprecipitation of MDMX–p73, protein half-life assay Current biology : CB Medium 10469568
2001 Hdmx and Mdm2 can repress p53-induced transcription but neither can interact with p63 or repress p63-induced transcription or affect p63 half-life, demonstrating specificity of Hdmx inhibitory function. Co-immunoprecipitation, transcription reporter assay, protein half-life assay with p63 vs p53 Oncogene Medium 11494153
2002 MdmX inhibits Smad-induced transactivation independently of p53 and Mdm2 interaction domains, requiring MdmX residues 128–444. MdmX binds p300, Smad3, and Smad4 in vitro, and the inhibition of Smad transactivation can be reversed by p300. MEFs lacking p53 and MdmX show enhanced Smad transactivation. Transcription reporter assay, co-immunoprecipitation of MdmX with p300/Smad3/Smad4, deletion mutant analysis, MEF genetic epistasis Oncogene Medium 12483531
2005 MdmX undergoes ARF-mediated sumoylation; when coexpressed, MdmX overexpression inhibits Mdm2 sumoylation in a dose-dependent manner and concurrently increases Mdm2 ubiquitination. A MdmX miniprotein capable of binding ARF (but not p53 or Mdm2) can competitively inhibit Mdm2 sumoylation. Sumoylation assay, co-immunoprecipitation, MdmX deletion mutants, ARF co-expression Cell cycle (Georgetown, Tex.) Medium 15876864
2014 Following ATM-mediated phosphorylation at S403, the C-terminal RING domain of HDMX binds the nascent p53 mRNA to promote a conformation that supports the p53 mRNA–HDM2 interaction and induction of p53 synthesis. HDMX and HDM2 bind the same p53 IRES structure but with different specificity and function, acting as non-redundant IRES trans-acting factors (ITAFs) to synergistically increase p53 expression during genotoxic stress. RNA pull-down, IRES-reporter assay, ATM kinase assay (S403 phosphorylation), RNA structure probing, co-immunoprecipitation of HDMX with p53 mRNA Molecular cell High 24813712
2014 MDMX promotes genomic instability independent of p53 and Mdm2 by inhibiting double-strand DNA break repair and inducing chromosome/chromatid breaks; MDMX is associated with Nbs1 of the MRN (Mre11-Rad50-Nbs1) DNA repair complex, and this association increases upon DNA damage and is detected at chromatin. MDMX impairs early ATM-mediated DNA damage signaling. These phenotypes are independent of the RING (Mdm2-binding) domain of MDMX. Co-immunoprecipitation of MDMX–Nbs1, chromatin immunoprecipitation, chromosome break analysis, ATM signaling assays in p53- and Mdm2-null cells Oncogene Medium 24608433
2016 MDMX inhibits sequence-specific DNA binding activity of p53 through secondary interactions: the MDMX acidic domain and RING domain interact stably with the p53 DNA-binding domain after initial N-terminal binding. This function requires CK1α-mediated phosphorylation of S289 on MDMX. Depletion of MDMX or CK1α increases p53 DNA binding without stabilizing p53 protein. Proteolytic fragment release assay, MDMX-p53 interaction mapping, CK1α knockdown, p53 DNA-binding assay, phospho-S289 mutant analysis Proceedings of the National Academy of Sciences of the United States of America High 27114532
2010 p53 activation induces transcription of a novel HDMX mRNA from an intronic p53-responsive promoter (P2), producing a long form HDMX-L that is more efficiently translated than the P1-derived form. HDMX-L cooperates with HDM2 to promote p53 ubiquitination and participates in attenuation of the p53 response. Promoter-reporter assay, RT-PCR, western blot, ubiquitination assay with HDMX-L The Journal of biological chemistry Medium 20659896
2020 MDM2 and MDMX, likely working as a complex, facilitate ferroptosis in cells with or without p53 by altering the cellular lipid profile. Inhibition of MDM2 or MDMX leads to increased FSP1 protein levels and consequent increase in coenzyme Q10, an endogenous lipophilic antioxidant. PPARα activity is essential for MDM2 and MDMX to promote ferroptosis. Small-molecule inhibitors, RNAi, MDMX mutant forms, lipidomic profiling, FSP1/CoQ10 measurement, PPARα genetic perturbation Genes & development Medium 32079652
2021 MDMX binds CK1α and leads to accumulation of β-Catenin in a p53-independent manner, activating Wnt/β-Catenin signaling in preleukemic stem cells and driving progression to AML. Wnt/β-Catenin inhibitors reverse MDMX-induced preleukemic stem cell properties. Co-immunoprecipitation of MDMX–CK1α, five murine MDMX overexpression models, transcriptomic/proteomic analysis, Wnt pathway inhibitor rescue Cancer cell High 33667384
2017 Otub1 suppresses MDM2-mediated MDMX ubiquitination and stabilizes MDMX independently of its deubiquitinase catalytic activity. Otub1-stabilized MDMX localizes to mitochondria, enhances p53 phosphorylation at S46, and promotes mitochondria-mediated apoptosis; MDMX depletion reduces Otub1-induced p53S46P. Co-immunoprecipitation, in vitro ubiquitination assay, Otub1 catalytic mutant, MDMX knockdown, mitochondrial fractionation, p53S46P detection Oncotarget Medium 28035068
2008 MDMX expression is transcriptionally regulated by mitogenic signaling: activated K-Ras and IGF-1 induce MDMX expression at the transcriptional level through MAPK/MEK signaling and c-Ets-1 transcription factors. Pharmacological MEK inhibition down-regulates MDMX in tumor cell lines. MDMX promoter reporter assay, K-Ras/IGF-1 stimulation, MEK inhibitor treatment, RT-PCR, western blot Molecular and cellular biology Medium 18172009
2015 MDM4 upregulation in cancer cells depends mainly on an alternative splicing switch: exon 6 skipping produces a nonsense-mediated decay-targeted isoform (MDM4-S) in normal adult tissues, while enhanced exon 6 inclusion produces full-length MDM4 in cancer. SRSF3 is identified as a key enhancer of exon 6 inclusion. Antisense oligonucleotide-mediated exon 6 skipping decreases MDM4 abundance, inhibits melanoma growth, and enhances sensitivity to MAPK-targeting therapies. Splice isoform analysis, SRSF3 knockdown, antisense oligonucleotide-mediated splicing modulation, melanoma PDX mouse models The Journal of clinical investigation High 26595814
2019 MDM4 and Topoisomerase IIα (TOP2A) bind to each other; the C-terminal region (CTR) of TOP2A binds residues 188–238 of MDM4, which contains an auto-inhibitory segment. TOP2A binding activates MDM4 for p53 binding, enhancing p53 inhibition. Reciprocally, MDM4 binding stabilizes TOP2A protein post-translationally. Co-immunoprecipitation, domain deletion mapping, western blot for protein stability, p53 interaction assay Molecular oncology Medium 30672125
2021 In cells lacking p53 or expressing tumor-derived mutant p53, loss of endogenous MDM2 or MDMX, or inhibition of their E3 ligase heterocomplexes activity, causes p53-independent cell-cycle arrest correlated with reduced E2F1, E2F3, and p73 levels. Direct ablation of p73 recapitulates this cell-cycle effect. MDMX/MDM2 knockdown in p53-null and mutant-p53 cells, p73 knockdown, cell-cycle analysis, E2F/p73 protein level measurement Proceedings of the National Academy of Sciences of the United States of America Medium 34716260
2021 MDM4 trisomy driven by chromosome 1q gain downmodulates p53 signaling, confers greater fitness to Fanconi anemia hematopoietic stem/progenitor cells, rescues inflammation-mediated bone marrow failure, and drives clonal dominance in FA mouse models. Targeting MDM4 impairs FA leukemia cells in vitro and in vivo. Patient cohort genomics, MDM4 triplication in murine/human primary FA HSPCs, competitive transplantation, MDM4 knockdown with functional leukemia cell assays Cell stem cell High 36736290
2021 MDM4 is identified as a matrix stiffness-regulated inhibitor of p53 in lung myofibroblasts; reducing matrix stiffness down-regulates MDM4 expression, activating p53. Genetic ablation of Mdm4 in lung (myo)fibroblasts activates the Mdm4-p53 pathway and promotes lung fibrosis resolution in aged mice. Soft/stiff matrix culture, MDM4 expression measurement, primary IPF myofibroblasts, conditional Mdm4 knockout in fibroblasts, bleomycin lung fibrosis model The Journal of experimental medicine Medium 33688918
2019 X-ray crystallography of HdmX in complex with multiple chemical compound classes revealed structural adaptations of the HdmX p53-binding cleft (including flip of H55, dimer induction) and identified a crown-ether additive enabling HdmX crystallization. Crystal structures provide molecular basis for compound binding modes and design of selective HDMX inhibitors. X-ray crystallography of HdmX–ligand complexes (multiple structures, resolution up to 1.20 Å) ChemMedChem High 31066983

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 279 15199139
2002 Mdm4 (Mdmx) regulates p53-induced growth arrest and neuronal cell death during early embryonic mouse development. Molecular and cellular biology 269 12101245
2020 MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling. Genes & development 241 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 224 16492744
2018 Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. Science translational medicine 203 29643228
2007 MDM2 and MDM4: p53 regulators as targets in anticancer therapy. The international journal of biochemistry & cell biology 198 17499002
2007 MDMX: from bench to bedside. Journal of cell science 189 17251377
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 162 23262034
2009 Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry? Molecular cancer research : MCR 149 19147532
2015 Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth. The Journal of clinical investigation 147 26595814
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
2006 Hdmx modulates the outcome of p53 activation in human tumor cells. The Journal of biological chemistry 139 16905769
2011 The structure-based design of Mdm2/Mdmx-p53 inhibitors gets serious. Angewandte Chemie (International ed. in English) 127 21341346
2003 Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2. The Journal of biological chemistry 127 12874296
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
1999 MDM2 and MDMX bind and stabilize the p53-related protein p73. Current biology : CB 119 10469568
2021 The roles and regulation of MDM2 and MDMX: it is not just about p53. Genes & development 118 33888565
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 117 23002429
2020 Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet? Frontiers in cell and developmental biology 116 32300595
2005 DNA damage-induced phosphorylation of MdmX at serine 367 activates p53 by targeting MdmX for Mdm2-dependent degradation. Molecular and cellular biology 109 16227609
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
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 99 21572037
2009 MdmX is a substrate for the deubiquitinating enzyme USP2a. Oncogene 90 19838211
2013 AMP-activated protein kinase induces p53 by phosphorylating MDMX and inhibiting its activity. Molecular and cellular biology 88 24190973
2012 Mdm2 and MdmX partner to regulate p53. FEBS letters 86 22673503
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
2009 MDM4 (MDMX) localizes at the mitochondria and facilitates the p53-mediated intrinsic-apoptotic pathway. The EMBO journal 73 19521340
2004 Mdmx and Mdm2: brothers in arms? Cell cycle (Georgetown, Tex.) 72 15254433
2006 Differential roles of ATM- and Chk2-mediated phosphorylations of Hdmx in response to DNA damage. Molecular and cellular biology 71 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
2017 The role of MDM2 and MDM4 in breast cancer development and prevention. Journal of molecular cell biology 67 28096293
2002 DNA damage induces MDMX nuclear translocation by p53-dependent and -independent mechanisms. Molecular and cellular biology 67 12370303
2014 Targeting p53-MDM2-MDMX loop for cancer therapy. Sub-cellular biochemistry 66 25201201
2016 Medicinal Chemistry Strategies to Disrupt the p53-MDM2/MDMX Interaction. Medicinal research reviews 61 27302609
2023 Clonal hematopoiesis driven by chromosome 1q/MDM4 trisomy defines a canonical route toward leukemia in Fanconi anemia. Cell stem cell 60 36736290
2019 The long and the short of it: the MDM4 tail so far. Journal of molecular cell biology 60 30689920
2008 Regulation of MDMX expression by mitogenic signaling. Molecular and cellular biology 60 18172009
2009 Beta-peptides with improved affinity for hDM2 and hDMX. Bioorganic & medicinal chemistry 59 19211253
2019 MDM2 and MDM4 Are Therapeutic Vulnerabilities in Malignant Rhabdoid Tumors. Cancer research 57 30755442
2014 Mdmx promotes genomic instability independent of p53 and Mdm2. Oncogene 57 24608433
2014 microRNAs and Alu elements in the p53-Mdm2-Mdm4 regulatory network. Journal of molecular cell biology 57 24868102
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
2016 MDMX (MDM4), a Promising Target for p53 Reactivation Therapy and Beyond. Cold Spring Harbor perspectives in medicine 53 27371671
2013 Mdm2 and MdmX inhibitors for the treatment of cancer: a patent review (2011-present). Expert opinion on therapeutic patents 53 23374098
2001 Hdmx and Mdm2 can repress transcription activation by p53 but not by p63. Oncogene 53 11494153
2009 In Silico Improvement of beta3-peptide inhibitors of p53 x hDM2 and p53 x hDMX. Journal of the American Chemical Society 51 19415930
2005 Identification of an aberrantly spliced form of HDMX in human tumors: a new mechanism for HDM2 stabilization. Cancer research 50 16266988
2014 HDMX folds the nascent p53 mRNA following activation by the ATM kinase. Molecular cell 45 24813712
2008 BH3 activation blocks Hdmx suppression of apoptosis and cooperates with Nutlin to induce cell death. Cell cycle (Georgetown, Tex.) 44 18604177
2010 HDMX-L is expressed from a functional p53-responsive promoter in the first intron of the HDMX gene and participates in an autoregulatory feedback loop to control p53 activity. The Journal of biological chemistry 43 20659896
2021 Therapeutic opportunities in cancer therapy: targeting the p53-MDM2/MDMX interactions. American journal of cancer research 42 35018225
2011 p53 regulation: teamwork between RING domains of Mdm2 and MdmX. Cell cycle (Georgetown, Tex.) 42 22134240
2009 Mitochondrial MDM4 (MDMX): an unpredicted role in the p53-mediated intrinsic apoptotic pathway. Cell cycle (Georgetown, Tex.) 41 19887911
2021 Recent Progress and Clinical Development of Inhibitors that Block MDM4/p53 Protein-Protein Interactions. Journal of medicinal chemistry 40 34286973
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 39 34716260
2019 Context-dependent roles of MDMX (MDM4) and MDM2 in breast cancer proliferation and circulating tumor cells. Breast cancer research : BCR 39 30642351
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
2016 Estrogen receptor alpha (ERα/ESR1) mediates the p53-independent overexpression of MDM4/MDMX and MDM2 in human breast cancer. Oncotarget 38 26909605
2007 Targeting MDM2 and MDMX in retinoblastoma. Current cancer drug targets 38 18045074
2021 Targeting mechanosensitive MDM4 promotes lung fibrosis resolution in aged mice. The Journal of experimental medicine 36 33688918
2018 An Update on MDMX and Dual MDM2/X Inhibitors. Current topics in medicinal chemistry 36 29866007
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
2019 MDM4 Is Targeted by 1q Gain and Drives Disease in Burkitt Lymphoma. Cancer research 34 31000522
2017 Otub1 stabilizes MDMX and promotes its proapoptotic function at the mitochondria. Oncotarget 34 28035068
2017 Anatomy of Mdm2 and Mdm4 in evolution. Journal of molecular cell biology 34 28077607
2015 MDM4 SNP34091 (rs4245739) and its effect on breast-, colon-, lung-, and prostate cancer risk. Cancer medicine 34 26471763
2009 MDM4 (MDMX) and its Transcript Variants. Current genomics 34 19721810
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
2021 MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism. Cancer cell 32 33667384
2002 MdmX inhibits Smad transactivation. Oncogene 32 12483531
2021 MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma. Scientific reports 30 33536467
2008 MdmX regulates transformation and chromosomal stability in p53-deficient cells. Cell cycle (Georgetown, Tex.) 30 18818521
2023 Verbenalin attenuates hepatic damage and mitochondrial dysfunction in alcohol-associated steatohepatitis by regulating MDMX/PPARα-mediated ferroptosis. Journal of ethnopharmacology 29 36739928
2022 Discovery of MDM2-p53 and MDM4-p53 protein-protein interactions small molecule dual inhibitors. European journal of medicinal chemistry 29 35961068
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
1999 Constitutive mdmx expression during cell growth, differentiation, and DNA damage. DNA and cell biology 26 10492400
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
2019 Benzimidazoles Downregulate Mdm2 and MdmX and Activate p53 in MdmX Overexpressing Tumor Cells. Molecules (Basel, Switzerland) 24 31181622
2012 High levels of Hdmx promote cell growth in a subset of uveal melanomas. American journal of cancer research 24 22957303
2005 MdmX inhibits ARF mediated Mdm2 sumoylation. Cell cycle (Georgetown, Tex.) 24 15876864
2011 Regulation of MDM4. Frontiers in bioscience (Landmark edition) 23 21196223
2010 Puzzling over MDM4-p53 network. The international journal of biochemistry & cell biology 23 20417304

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