Affinage

MDM2

E3 ubiquitin-protein ligase Mdm2 · UniProt Q00987

Round 2 corrected
Length
491 aa
Mass
55.2 kDa
Annotated
2026-04-28
130 papers in source corpus 57 papers cited in narrative 57 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MDM2 is the principal E3 ubiquitin-protein ligase governing p53 stability and transcriptional activity, forming an autoregulatory negative-feedback loop in which p53 transcriptionally induces MDM2, which in turn ubiquitinates p53 for proteasomal degradation (PMID:9153396, PMID:9450543). The MDM2 N-terminal hydrophobic cleft engages the p53 transactivation-domain helix (Phe19, Trp23, Leu26), while the C-terminal RING domain provides E3 ligase activity; heterodimerization of the MDM2 RING with MDMX converts MDM2 from a mono- to a polyubiquitination ligase, and dose-dependent ubiquitin chain length dictates whether p53 is exported from the nucleus or degraded in situ (PMID:8875929, PMID:14671306, PMID:22134240). This feedback circuit is tuned by upstream signals including ARF-mediated nucleolar sequestration of MDM2, Akt phosphorylation of MDM2 Ser166/186 promoting nuclear entry, ribosomal stress proteins (RPL5, RPL11, RPL23, RPL6) that inhibit MDM2 E3 activity, and Daxx/HAUSP-mediated MDM2 stabilization (PMID:9529249, PMID:11504915, PMID:12842086, PMID:16845383). Beyond p53, MDM2 ubiquitinates HIF-1α, MDMX, Ku70, and β-arrestin, interacts with pRB and Nbs1 to modulate cell-cycle control and DNA repair, and associates with polycomb repressive complexes to regulate chromatin (PMID:10640274, PMID:7691904, PMID:18541670, PMID:27927750).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1992 High

    Identification of MDM2 as a direct physical inhibitor of p53 transactivation established the founding oncogene–tumor-suppressor antagonism that all subsequent work elaborated.

    Evidence Co-immunoprecipitation and cotransfection transactivation assays showing MDM2 binds and inhibits wild-type and mutant p53; gene amplification in sarcomas

    PMID:1535557 PMID:1614537

    Open questions at the time
    • Mechanism of inhibition (direct occlusion vs. degradation) unknown
    • No structural information on the binding interface
  2. 1993 High

    Domain mapping localized the interaction to the MDM2 N-terminus and p53 transactivation domain, defining the minimal interaction surfaces and guiding structural studies.

    Evidence Deletion mutagenesis and epitope-mapped co-immunoprecipitation

    PMID:7686617

    Open questions at the time
    • Atomic-resolution contacts unresolved
    • Whether MDM2 binding alone suffices to eliminate p53 function unclear
  3. 1996 High

    The crystal structure of MDM2 bound to p53 peptide revealed a deep hydrophobic cleft accommodating p53 residues Phe19, Trp23, and Leu26, providing the atomic blueprint for the interaction and for drug design.

    Evidence X-ray crystallography of MDM2(1–109)–p53 peptide complex

    PMID:8875929

    Open questions at the time
    • Role of full-length MDM2 domains beyond N-terminus unresolved
    • Mechanism of p53 elimination still unknown
  4. 1997 High

    Discovery that MDM2 promotes proteasome-dependent p53 degradation and that p53 transcriptionally activates MDM2 established the negative-feedback loop as the core regulatory circuit, while identification of MDM2 as a RING-dependent E3 ubiquitin ligase provided the enzymatic mechanism.

    Evidence Pulse-chase and proteasome-inhibitor experiments showing MDM2-dependent p53 degradation; in vitro ubiquitination reconstitution with E1/UbcH5/MDM2; RING cysteine mutagenesis abolishing activity

    PMID:9153395 PMID:9153396 PMID:9450543

    Open questions at the time
    • Mono- vs. polyubiquitination consequences not distinguished
    • Identity of signals that break the feedback loop after stress unclear
  5. 1997 High

    DNA-damage-induced phosphorylation of p53 Ser15 was shown to reduce MDM2 binding, providing the first mechanism by which genotoxic stress uncouples p53 from MDM2-mediated destruction.

    Evidence In vitro DNA-PK kinase assay and co-immunoprecipitation showing reduced MDM2–p53 interaction upon Ser15 phosphorylation

    PMID:9363941

    Open questions at the time
    • Whether DNA-PK is the physiological kinase in vivo debated (ATM later implicated)
    • Contribution of other p53 phospho-sites not yet assessed
  6. 1998 High

    ARF was identified as a direct MDM2-binding protein that blocks MDM2-mediated p53 degradation, linking oncogene-induced signaling (e.g., Myc, Ras) to p53 activation through MDM2 inhibition.

    Evidence Reciprocal co-immunoprecipitation, pulse-chase showing increased p53 half-life (15→75 min), cell-cycle rescue experiments

    PMID:9529249 PMID:9653180 PMID:9724636

    Open questions at the time
    • Whether ARF inhibits MDM2 E3 activity directly or by sequestration debated
    • Subcellular compartment of ARF action not yet defined
  7. 1999 High

    ARF was shown to sequester MDM2 into the nucleolus, and MDM2 nucleocytoplasmic shuttling was shown to be required for p53 degradation, establishing compartmentalization as a key regulatory layer.

    Evidence Immunofluorescence colocalization in nucleoli; NLS/NES mutant analysis in p53/mdm2-null cells

    PMID:10077639 PMID:10559859

    Open questions at the time
    • Whether nuclear export is absolutely required or whether co-compartmentalization suffices was later debated
  8. 2000 High

    MDMX was identified as a RING-domain heterodimerization partner that modulates MDM2 E3 activity and p53 stability, and MDM2 was shown to ubiquitinate HIF-1α in a p53-dependent manner, expanding its substrate repertoire.

    Evidence RING domain deletion/mutagenesis, stability assays, co-IP showing MDMX–MDM2 heterodimers; HIF-1α ubiquitination in p53-knockout versus wild-type cells

    PMID:10629057 PMID:10640274 PMID:10722742 PMID:10827196

    Open questions at the time
    • Whether MDMX stimulates or inhibits MDM2 E3 activity was conflicting across studies
    • HIF-1α ubiquitination mechanism (direct vs. scaffolded) not fully resolved
  9. 2001 High

    Akt-mediated phosphorylation of MDM2 at Ser166/186 was shown to promote MDM2 nuclear translocation and enhance p53 ubiquitination, connecting growth-factor signaling to p53 suppression; additional p53-independent targets (pRB, β-arrestin) broadened MDM2's functional scope.

    Evidence Phospho-site mutagenesis with dominant-negative/constitutive-active Akt; subcellular fractionation; co-IP with pRB; β-arrestin ubiquitination in Mdm2-null cells

    PMID:11504915 PMID:11588219 PMID:11715018 PMID:7791904

    Open questions at the time
    • Relative importance of Akt vs. other kinases (MK2, AURKA) at overlapping sites not resolved
    • Whether β-arrestin ubiquitination is MDM2's primary non-p53 role in normal physiology unclear
  10. 2003 High

    Ribosomal proteins (L11, L23) were identified as MDM2-binding inhibitors that suppress its E3 activity upon nucleolar stress, establishing the ribosomal stress–p53 surveillance pathway; concurrently, MDM2 dose was shown to dictate mono- vs. polyubiquitination fate of p53.

    Evidence Co-IP of L11 and L23 with MDM2 central acidic domain; actinomycin-D-induced endogenous interaction; titration of Mdm2 showing monoubiquitination leads to nuclear export and polyubiquitination to degradation

    PMID:12842086 PMID:14671306 PMID:15314174

    Open questions at the time
    • Whether all ribosomal proteins act via the same acidic-domain surface not established
    • Physiological Mdm2 concentration thresholds in tissues unknown
  11. 2004 High

    Nutlin small molecules binding the MDM2 p53-pocket validated the interface as a drug target, and SNP309 in the MDM2 promoter linked Sp1-driven MDM2 overexpression to accelerated human tumorigenesis.

    Evidence Crystal structure of Nutlin–MDM2 complex with in vivo xenograft efficacy; Sp1 gel-shift and reporter assay with human cancer cohort genotyping

    PMID:14704432 PMID:15550242

    Open questions at the time
    • Clinical efficacy of MDM2 antagonists not yet demonstrated
    • SNP309 penetrance varies across populations and hormonal contexts
  12. 2006 High

    Daxx was shown to bridge HAUSP deubiquitinase to MDM2, stabilizing MDM2 under non-stress conditions; DNA damage dissociates this complex, enabling MDM2 self-ubiquitination and p53 activation.

    Evidence Ternary co-IP (Daxx–MDM2–HAUSP), siRNA knockdown, MDM2 stability measurements before and after DNA damage

    PMID:16845383

    Open questions at the time
    • Whether Daxx–HAUSP is the sole MDM2-stabilizing axis or one of several not resolved
    • Signal triggering Daxx dissociation not identified
  13. 2008 High

    p53 acetylation was shown to be indispensable for blocking MDM2 recruitment to promoters and enabling target-gene activation, and MDM2's direct interaction with Nbs1 was found to delay DNA repair independently of its E3 activity, revealing a ligase-independent oncogenic function.

    Evidence Acetylation-deficient p53 knock-in plus ChIP; Nbs1-binding domain mutagenesis with DNA-damage foci resolution assay in p53-null cells

    PMID:18485870 PMID:18541670

    Open questions at the time
    • Relative contribution of MDM2–Nbs1 interaction to genome instability in tumors unclear
    • Whether acetylation fully explains DNA-damage-induced uncoupling from MDM2 not settled
  14. 2009 Medium

    MDM2 was found to bind its own mRNA (and XIAP mRNA) via its RING domain, stimulating p53 translation while suppressing E3 ligase activity, revealing a dual RNA-binding/E3 ligase switch.

    Evidence RNA co-immunoprecipitation, translation assays, Phe19Ala p53 mutant analysis showing RNA binding inhibits ubiquitination

    PMID:19106616

    Open questions at the time
    • RNA-binding specificity determinants not fully mapped
    • Physiological RNA targets beyond p53 and XIAP mRNAs unknown
    • Independent replication limited
  15. 2011 High

    In vivo knock-in of RING-mutant MdmX confirmed that MDMX RING heterodimerization is essential to convert MDM2 from mono- to polyubiquitination E3 activity toward p53, resolving conflicting reports on whether MDMX stimulates or inhibits MDM2.

    Evidence In vitro ubiquitination reconstitution plus MdmX RING knock-in mouse showing p53-dependent embryonic lethality

    PMID:22134240

    Open questions at the time
    • How RING heterodimer alters ubiquitin-chain topology not structurally resolved at this point
  16. 2017 Medium

    MDM2 was found to associate with polycomb repressive complexes (EZH2, RING1B), enhancing H3K27me3 and H2AK119ub1 at target promoters independently of p53, revealing a chromatin-regulatory function.

    Evidence Co-IP with EZH2/RING1B, ChIP showing MDM2 at PcG target promoters, gene expression and stem-cell pluripotency assays

    PMID:27927750

    Open questions at the time
    • Genome-wide scope of MDM2-PcG targets not established
    • Whether MDM2 E3 activity contributes to chromatin ubiquitination or serves a scaffolding role unclear
    • Independent replication pending

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the full-length MDM2–MDMX–E2 complex during polyubiquitination, the physiological significance and selectivity of MDM2's RNA-binding function, the relative contributions of p53-independent MDM2 activities (chromatin remodeling, DNA repair inhibition) to tumorigenesis, and how tissue-specific MDM2 levels are set in vivo.
  • Full-length MDM2–MDMX–E2 structural model absent
  • In vivo relevance of MDM2 RNA-binding activity not demonstrated genetically
  • Tissue-specific regulation of MDM2 expression incompletely understood

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0003723 RNA binding 2 GO:0016874 ligase activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005654 nucleoplasm 2 GO:0005730 nucleolus 1
Pathway
R-HSA-1640170 Cell Cycle 5 R-HSA-392499 Metabolism of proteins 5 R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1643685 Disease 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
CDKN2ADAXXMDM4NBS1RPL11RPL23TP53USP7
Complex memberships
MDM2-Daxx-HAUSP complexMDM2-MDMX RING heterodimerMDM2-p53 complex

Evidence

Reading pass · 57 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 The MDM2 (mdm-2) gene product forms a tight complex with both mutant and wild-type p53 protein and inhibits p53-mediated transactivation of a p53-responsive element. Co-immunoprecipitation, cotransfection transactivation assay Cell High 1535557
1992 Human MDM2 protein binds human p53 in vitro; the MDM2 gene is amplified in over a third of human sarcomas, consistent with MDM2 amplification leading to escape from p53-regulated growth control. In vitro binding assay with recombinant proteins, Southern blot for gene amplification Nature High 1614537
1993 The N-terminal domain of MDM2 (mapped by deletion mutants) is required for complex formation with p53; the interaction domain on p53 maps to its N-terminal 52 amino acids encompassing the transactivation domain. Deletion mutagenesis, co-immunoprecipitation, monoclonal antibody epitope mapping Molecular and cellular biology High 7686617
1996 Crystal structure of the 109-residue N-terminal domain of MDM2 bound to a 15-residue p53 transactivation domain peptide revealed a deep hydrophobic cleft in MDM2 that accommodates an amphipathic alpha helix of p53, with critical contacts at p53 residues Phe19, Trp23, and Leu26. X-ray crystallography Science High 8875929
1997 MDM2 promotes rapid proteasome-dependent degradation of p53; a small domain of p53 encompassing the MDM2-binding site confers MDM2-dependent destabilization on heterologous proteins, and endogenous MDM2 induction after DNA damage coincides with rapid p53 loss. Cotransfection, pulse-chase, proteasome inhibitor treatment, heterologous fusion constructs Nature High 9153395
1997 Interaction with MDM2 leads to large reduction in p53 protein levels through enhanced proteasome-dependent degradation; endogenous levels of MDM2 are sufficient to regulate p53 stability, and the mdm2 gene is transcriptionally activated by p53 forming a degradative feedback loop. Cotransfection, proteasome inhibitor treatment, endogenous protein analysis Nature High 9153396
1997 MDM2 oncoprotein functions as a ubiquitin ligase E3 for p53: p53 is polyubiquitinated in the presence of E1, UbcH5 (E2), and MDM2; a cysteine residue in the MDM2 C-terminus (RING domain) is essential for this E3 ligase activity. In vitro ubiquitination reconstitution assay, site-directed mutagenesis FEBS letters High 9450543
1997 DNA damage-induced phosphorylation of p53 at serine 15 (and serine 37) by DNA-PK reduces the interaction between p53 and MDM2 in vivo and in vitro, and impairs MDM2's ability to inhibit p53-dependent transactivation. In vitro kinase assay with purified DNA-PK, co-immunoprecipitation, transactivation assay Cell High 9363941
1997 The molecular basis of the HDM2-p53 interaction was characterized biochemically: p53 residues F19, W23, and L26 are critical contact points for binding to HDM2, consistent with the crystal structure. Peptide inhibitor ELISA assay, electrophoretic mobility shift assay, monoclonal antibody epitope mapping Journal of molecular biology High 9223638
1998 ARF (p19Arf/p14ARF) binds directly to MDM2 and promotes MDM2 degradation, resulting in concurrent p53 stabilization and accumulation; this ARF-MDM2 interaction restores p53-dependent G1 cell cycle arrest otherwise abrogated by MDM2. Co-immunoprecipitation, pulse-chase degradation assay, cell cycle analysis, epistasis rescue experiment Cell High 9529249
1998 p19ARF physically interacts with MDM2 and blocks MDM2-induced p53 degradation and transcriptional silencing, thereby preventing MDM2's neutralization of p53; p19ARF overexpression increases p53 half-life from ~15 to ~75 minutes. Baculovirus co-expression, co-immunoprecipitation, pulse-chase half-life measurement Proceedings of the National Academy of Sciences High 9653180
1998 p14ARF binds directly to MDM2, resulting in stabilization of both p53 and MDM2; p14ARF participates in a regulatory feedback loop with p53 and MDM2 and acts upstream of p53 in a pathway distinct from DNA damage response. Co-immunoprecipitation, cell cycle analysis, epistasis with p53 pathway components The EMBO journal High 9724636
1999 ARF sequesters MDM2 into the nucleolus, thereby preventing MDM2-mediated negative feedback regulation of p53 and leading to p53 activation in the nucleoplasm; ARF and MDM2 co-localize in the nucleolus in response to Myc activation and during replicative senescence. Co-immunoprecipitation, co-localization by immunofluorescence, subcellular fractionation Nature cell biology High 10559859
1999 Nucleocytoplasmic shuttling of HDM2 is required for HDM2-mediated p53 degradation; HDM2 must enter the nucleus (via NLS) and export (via NES) to promote p53 degradation, establishing that HDM2 shuttles p53 from the nucleus to the cytoplasm for proteasomal degradation. NLS/NES mutant analysis in p53/mdm2 double-knockout cells, cotransfection degradation assay Proceedings of the National Academy of Sciences High 10077639
2000 Mdm2 is a RING finger-dependent ubiquitin protein ligase (E3) for both p53 and itself; Mdm2 mediates autoubiquitination intrinsically (requiring only E1 and E2); zinc coordination via RING finger is essential; the Mdm2 RING shows substrate specificity in recognizing p53. In vitro ubiquitination reconstitution with purified proteins, RING finger mutagenesis, zinc chelation, RING domain swap experiment The Journal of biological chemistry High 10722742
2000 MdmX (MDMX) does not induce p53 degradation or nuclear export but can reverse Mdm2-targeted degradation of p53 while maintaining suppression of p53 transactivation; the MdmX RING finger domain stabilizes p53 by retaining it in the nucleus and increasing p53 transactivation. Deletion mutagenesis, cotransfection, subcellular localization by immunofluorescence, p53 stability assay Molecular and cellular biology High 10629057
2000 Hdmx stabilizes both p53 and Mdm2; hetero-oligomerization of the Hdmx RING finger with the Mdm2 RING finger inhibits Mdm2 ubiquitin ligase activity, leading to stabilization; a trimeric complex of Hdmx-Mdm2-p53 can form but p53 transcription remains inhibited. Co-immunoprecipitation, protein stability assay, RING finger deletion analysis The Journal of biological chemistry High 10827196
2001 Akt/PI3K signaling promotes nuclear translocation of Mdm2 by phosphorylating Mdm2 at serine 166 and serine 186; mutation of these Akt phosphorylation sites prevents nuclear entry of Mdm2, increases p53 levels, and augments p53 transcriptional activity. Subcellular fractionation, mutagenesis of Akt phosphorylation sites, dominant-negative/constitutively active Akt constructs, PI3K pharmacological inhibition Proceedings of the National Academy of Sciences High 11504915
2001 Mdmx stabilizes Mdm2 by inhibiting Mdm2 self-ubiquitination (autoubiquitination) via RING-RING heterodimerization, while Mdmx expression leads to accumulation of ubiquitinated, nuclear p53 without significantly affecting Mdm2-mediated ubiquitination of p53. Ubiquitination assay, RING finger mutagenesis, nuclear/cytoplasmic fractionation, cotransfection EMBO reports High 11606419
2001 HER-2/neu promotes Akt-mediated phosphorylation of MDM2 at Ser166 and Ser186, enhancing MDM2 nuclear localization, increasing its interaction with p300, inhibiting its interaction with p19ARF, and thereby increasing p53 ubiquitination and degradation. In vitro kinase assay, co-immunoprecipitation, ubiquitination assay, nuclear localization assay Nature cell biology High 11715018
2001 An alternatively spliced HDM2 product (HDM2-ALT1), which lacks the p53-binding domain and NLS, binds and sequesters full-length HDM2 in the cytoplasm, thereby inhibiting HDM2-p53 interaction and enhancing p53 transcriptional activity. Cotransfection, co-immunoprecipitation, p53 transcriptional activity assay, immunofluorescence localization Oncogene Medium 11494132
2001 MDM2 interacts physically and functionally with the retinoblastoma protein (pRB) and inhibits pRB growth regulatory function, demonstrating that MDM2 can negatively regulate both p53 and pRB. Co-immunoprecipitation, cotransfection growth inhibition assay Nature High 7791904
2002 Akt enhances Mdm2-mediated ubiquitination and degradation of p53 by phosphorylating Mdm2 at Ser186; Ser186Ala mutation renders Mdm2 resistant to Akt-mediated enhancement of p53 ubiquitination. In vivo ubiquitination assay, site-directed mutagenesis (S186A), phospho-specific analysis The Journal of biological chemistry High 11923280
2002 Mdm2 acidic domain phosphorylation (residues 244–260) is required for p53 degradation independently of Mdm2 E3 ligase activity and p14ARF binding; ionizing radiation causes hypophosphorylation of these residues, which precedes p53 accumulation, uncoupling ubiquitination from degradation. Alanine-scanning mutagenesis, 2D phosphopeptide mapping, phospho-specific antibodies, p53 degradation assay Molecular and cellular biology High 12167711
2003 MDM2 is the principal cellular E3 ubiquitin ligase for p53; in unstressed cells MDM2 constantly monoubiquitinates p53 as a critical step mediating its degradation by nuclear and cytoplasmic proteasomes; the p53-MDM2 interaction is conformation-based. Review consolidating in vitro ubiquitination assays, cell-based degradation assays, structural data Molecular cancer research High 14707283
2003 MDM2 promotes ubiquitination and proteasomal degradation of MDMX; this effect is stimulated by ARF and requires an intact MDM2 RING domain for both MDMX binding and E3 ligase function; ARF differentially regulates MDM2-mediated ubiquitination of p53 versus MDMX. Cotransfection ubiquitination assay, proteasome inhibitor treatment, ARF domain analysis, inducible MDM2 expression system Molecular and cellular biology High 12860999
2003 HdmX stimulates Hdm2-mediated ubiquitination of p53 in vitro and facilitates reciprocal ubiquitination between Hdm2 and HdmX; downregulation of HdmX in cells causes accumulation of both p53 and Hdm2, indicating HdmX is an activator of Hdm2 E3 activity rather than an inhibitor. In vitro ubiquitination reconstitution assay, siRNA knockdown, protein stability assay Proceedings of the National Academy of Sciences High 14507994
2003 Ribosomal protein L11 interacts with HDM2 (via HDM2's central acidic domain) and inhibits HDM2 E3 ligase function, leading to p53 stabilization and activation; treatment with low-dose actinomycin D enhances the endogenous L11-HDM2 interaction, linking ribosome biogenesis stress to p53 activation. Co-immunoprecipitation, p53 stability assay, p53 transcriptional target induction, actinomycin D treatment Cancer cell High 12842086
2003 Low levels of Mdm2 activity induce monoubiquitination and nuclear export of p53, whereas high levels of Mdm2 promote polyubiquitination and nuclear degradation of p53; a p53-ubiquitin fusion mimicking monoubiquitinated p53 accumulates in the cytoplasm in an Mdm2-independent manner. In vivo ubiquitination assay with titrated Mdm2, p53-ubiquitin fusion construct, subcellular localization Science High 14671306
2004 Ribosomal protein L23 interacts with HDM2 (via HDM2 central acidic domain and L23 N-terminal domain) and inhibits HDM2-induced p53 polyubiquitination and degradation; L23 and L11 can simultaneously form a ternary complex with HDM2; L23 knockdown triggers nucleolar stress and p53 activation. Co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown, cell cycle analysis Molecular and cellular biology High 15314174
2004 Potent small-molecule MDM2 antagonists (Nutlins) bind the p53-binding pocket of MDM2 (confirmed by crystal structures of complexes), activate the p53 pathway in cancer cells, and inhibit tumor xenograft growth in vivo. Crystal structure of Nutlin-MDM2 complex, cell-based p53 activation assay, xenograft tumor model Science High 14704432
2004 SNP309 in the MDM2 promoter increases binding affinity of transcriptional activator Sp1, resulting in higher MDM2 RNA and protein levels and consequent attenuation of the p53 pathway, accelerating tumor formation in humans. Reporter assay, gel shift (Sp1 binding), protein level analysis, human cancer cohort genotyping Cell High 15550242
2001 Cocompartmentalization of p53 and Mdm2 is the major determinant for Mdm2-mediated degradation; Mdm2 can promote p53 ubiquitination and proteasomal degradation in either the nucleus or cytoplasm when both proteins are co-localized, with no absolute requirement for nuclear-to-cytoplasmic transport. NES mutagenesis, leptomycin B nuclear export inhibition, proteasome inhibitor treatment, ubiquitination assay Experimental cell research High 11597128
2004 Dynamics of the p53-Mdm2 feedback loop in individual living cells revealed that p53 is expressed in discrete pulses after DNA damage; pulse height and duration are fixed regardless of damage level, but the number of pulses increases with damage, demonstrating a digital signaling mechanism. Time-lapse fluorescence microscopy of p53-CFP and Mdm2-YFP fusion proteins in single cells Nature genetics High 14730303
2005 MDM2 stabilizes E2F1 protein in a p53-independent manner by inhibiting E2F1 ubiquitination; MDM2 displaces the E2F1 E3 ligase SCF(SKP2) and requires direct binding to E2F1 for this effect. Co-immunoprecipitation, ubiquitination assay, MDM2 knockdown, half-life measurement Oncogene Medium 16170383
2005 Gankyrin oncoprotein binds MDM2, facilitates p53-MDM2 binding, and increases ubiquitylation and degradation of p53; gankyrin also enhances MDM2 autoubiquitylation; knockdown of gankyrin reduces amounts of MDM2 and p53 associated with the 26S proteasome. In vitro binding assay, in vivo ubiquitination assay, siRNA knockdown, 26S proteasome co-IP Cancer cell Medium 16023600
2005 MTBP promotes MDM2-mediated ubiquitination and degradation of p53 and stabilizes MDM2 in an MDM2 RING finger-dependent manner; siRNA-mediated MTBP knockdown shows MTBP contributes significantly to MDM2-mediated regulation of p53 levels in unstressed cells; UV (but not gamma) irradiation destabilizes MTBP. siRNA knockdown, co-immunoprecipitation, p53 stability assay, ubiquitination assay Molecular and cellular biology Medium 15632057
2005 MAPKAP kinase 2 (MK2) phosphorylates HDM2 at serine 157 and serine 166 in vitro and in vivo; phospho-mimetic mutation at these sites slightly increases HDM2 activity in p53 degradation; MK2-deficient mouse cells show reduced Mdm2 phosphorylation and elevated p53, suggesting MK2 dampens p53 response. In vitro kinase assay, in vivo phosphorylation analysis, MK2-deficient cell comparison Oncogene Medium 15688025
2001 Inhibition of hsp90 function accelerates degradation of MDM2 and mutant p53; mutant p53 promotes MDM2-p53-hsp90 ternary complex formation that prevents MDM2 from binding ARF and accumulating in the nucleolus, thereby inhibiting MDM2 E3 ligase function in an hsp90-dependent manner. Co-immunoprecipitation, geldanamycin (hsp90 inhibitor) treatment, protein stability assay The Journal of biological chemistry Medium 11507088
2006 Daxx is required for MDM2 stability: Daxx simultaneously binds Mdm2 and the deubiquitinase HAUSP, mediating HAUSP's stabilizing effect on Mdm2; Daxx also enhances Mdm2's E3 activity toward p53; upon DNA damage, Daxx dissociates from Mdm2, correlating with Mdm2 self-degradation. Co-immunoprecipitation, siRNA knockdown, Mdm2 stability assay, E3 ligase activity assay Nature cell biology High 16845383
2006 Nucleolin binds to Hdm2 and inhibits both p53 ubiquitination by Hdm2 and Hdm2 auto-ubiquitination, while also reducing Hdm2 protein levels, thereby stabilizing and activating p53; this effect is specific to Hdm2 (not HPV E6). Co-immunoprecipitation, in vivo ubiquitination assay, protein level analysis Oncogene Medium 16751805
2008 p53 acetylation is indispensable for p53 activation: acetylation of p53 abrogates Mdm2-mediated repression by blocking MDM2 recruitment to p53-responsive promoters, enabling p53 activation independent of its phosphorylation status; unacetylated p53 retains the ability to induce the p53-Mdm2 feedback loop but cannot induce growth arrest or apoptosis. Knock-in of acetylation-deficient p53 mutants, chromatin immunoprecipitation, p53 target gene analysis Cell High 18485870
2008 Wip1 phosphatase dephosphorylates Mdm2 at Ser395 (an ATM phosphorylation site), resulting in stabilization of Mdm2, enhanced Mdm2-p53 binding, and enhanced ubiquitination of p53 by Mdm2, facilitating return to pre-stress p53 levels. In vitro phosphatase assay, co-immunoprecipitation, ubiquitination assay, Wip1-deficient cell analysis Cell cycle Medium 18333294
2008 Increased Mdm2 expression in p53-null cells induces chromosome/chromatid breaks and delays DNA double-strand break repair through a direct interaction between Mdm2 and Nbs1 (of the MRN DNA repair complex); a 31-amino-acid domain of Mdm2 is necessary for Nbs1 binding, and this interaction inhibits DNA break repair independently of Mdm2 ubiquitin ligase activity. Domain mutagenesis (Nbs1-binding domain), DNA damage foci resolution assay, chromosome break analysis, transformation assay in p53-null cells Molecular and cellular biology High 18541670
2009 NEDP1 is a chemotherapy-induced isopeptidase that deneddylates MDM2, resulting in MDM2 destabilization and concomitant p53 activation; RNAi knockdown of NEDP1 blocks MDM2 destabilization and increases chemoresistance, revealing NEDD8-dependent regulation of MDM2 stability. RNAi knockdown, protein stability assay, co-immunoprecipitation, in vitro deneddylation assay Oncogene Medium 19784069
2009 Hdm2 is a ubiquitin ligase for Ku70; Akt promotes cell survival by stimulating Hdm2 nuclear translocation (via phosphorylation), thereby reducing cytosolic Ku70 degradation and preventing Bax-mediated apoptosis. Co-immunoprecipitation, in vivo ubiquitination assay, subcellular fractionation, Ku70 knockdown functional rescue Cell death and differentiation Medium 19247369
2000 p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation of HIF-1alpha, thereby regulating tumor angiogenesis; loss of p53 enhances HIF-1alpha levels and augments VEGF expression in response to hypoxia. Co-immunoprecipitation, ubiquitination assay, homologous recombination p53 knockout cell line, xenograft angiogenesis assay Genes & development High 10640274
2001 Mdm2 acts as a ubiquitin ligase for beta-arrestin in GPCR signaling; agonist-stimulated beta2-adrenergic receptor ubiquitination required beta-arrestin, which bound to MDM2; abrogation of beta-arrestin ubiquitination by Mdm2-null cells or dominant-negative Mdm2 inhibited receptor internalization. Mdm2-null cell complementation, dominant-negative Mdm2, co-immunoprecipitation, receptor internalization assay Science Medium 11588219
2006 MDM2 interacts with the sarcomeric protein TCAP (telethonin) and promotes its proteasomal degradation through a ubiquitin-independent pathway; elevated MDM2 expression alters TCAP subcellular localization; p14ARF inhibits MDM2-mediated TCAP degradation. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, confocal colocalization, proteasome inhibitor treatment, siRNA Biochemical and biophysical research communications Medium 16678796
2008 RYBP (RING1- and YY1-binding protein) interacts with MDM2 and decreases MDM2-mediated p53 ubiquitination, leading to p53 stabilization and increased p53 activity; RYBP contributes to p53 response to DNA damage. Co-immunoprecipitation, in vivo ubiquitination assay, p53 stability assay, DNA damage assay EMBO reports Medium 19098711
2011 MdmX RING domain is essential for p53 degradation in vivo: MdmX converts Mdm2 from a monoubiquitination E3 ligase into a polyubiquitination E3 ligase through RING-RING interactions, enabling p53 proteasomal degradation; knock-in of RING-mutant MdmX causes p53-dependent embryonic lethality. In vitro ubiquitination reconstitution, RING domain mutagenesis, MdmX RING knock-in mouse model Cell cycle High 22134240
2013 Ribosomal protein L6 (RPL6) binds to HDM2 and suppresses its E3 ubiquitin ligase activity, attenuating HDM2-mediated p53 polyubiquitination and degradation; RPL6 translocates from the nucleolus to nucleoplasm under ribosomal stress, facilitating binding to HDM2; HDM2 also ubiquitinates RPL6, forming an autoregulatory feedback loop. Co-immunoprecipitation, in vitro ubiquitination assay, siRNA knockdown, subcellular localization, cell cycle analysis Nucleic acids research Medium 24174547
2013 Aurora kinase A (AURKA) directly interacts with and phosphorylates HDM2, leading to increased HDM2 protein levels, enhanced P53 ubiquitination, and attenuation of cisplatin-induced P53 activation; AURKA inhibition decreases HDM2 levels and induces P53 activity. In vitro kinase assay with recombinant proteins, co-immunoprecipitation, ubiquitination assay, kinase inhibitor treatment Clinical cancer research Medium 24240108
2010 MDM2 can be degraded through chaperone-mediated autophagy (CMA) via the lysosomal pathway; Hsc70 recognizes MDM2 and delivers it to LAMP2A for lysosomal degradation; hispolon treatment induces this CMA-mediated MDM2 downregulation independent of the proteasome. Proteasome inhibitor (MG132) non-response, LAMP2A siRNA knockdown, Hsc70 siRNA, competing antibody assay (SMP14), lysosome inhibitor (NH4Cl) Biochemical and biophysical research communications Medium 20540933
2017 MDM2 acts as a chromatin modifier by directly interacting with polycomb group (PcG) proteins EZH2 and RING1B; MDM2 is recruited to target gene promoters by EZH2 and enhances PRC-dependent repressive chromatin modifications (H3K27me3 and H2AK119ub1), regulating gene expression independently of p53 and promoting stem cell pluripotency. Co-immunoprecipitation, chromatin immunoprecipitation, gene expression profiling, stem cell assays Journal of molecular cell biology Medium 27927750
2016 MDM2 RING protein binds the IRES region of XIAP mRNA, resulting in MDM2 protein stabilization and enhanced XIAP translation; small-molecule inhibitors blocking the MDM2 protein-XIAP RNA interaction lead to MDM2 degradation, reduced XIAP expression, and p53 activation. Fluorescence polarization protein-RNA binding assay, high-throughput screening, RNA co-immunoprecipitation, MDM2 stability assay Cancer cell Medium 27666947
2009 Mdm2 binds p53 mRNA (via the Mdm2 RING domain, which overlaps with the E3 ligase domain) and stimulates p53 mRNA translation; this mRNA interaction also suppresses Mdm2-promoted p53 polyubiquitination and degradation, revealing that RNA binding and E3 ligase functions of Mdm2 are mutually regulated. RNA co-immunoprecipitation, translation assay, Phe19Ala p53 mutant analysis Cell cycle Medium 19106616

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science (New York, N.Y.) 3869 14704432
1997 Mdm2 promotes the rapid degradation of p53. Nature 3855 9153395
1992 The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 3013 1535557
1997 Regulation of p53 stability by Mdm2. Nature 2898 9153396
1992 Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature 1933 1614537
1996 Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science (New York, N.Y.) 1841 8875929
1997 DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 1783 9363941
1997 Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS letters 1655 9450543
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1998 ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 1365 9529249
1998 The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell 1309 9529248
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2004 A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 1065 15550242
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
1998 The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. The EMBO journal 1012 9724636
2013 MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nature reviews. Cancer 989 23303139
2001 A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proceedings of the National Academy of Sciences of the United States of America 964 11504915
2000 Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes & development 949 10640274
2000 Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. The Journal of biological chemistry 890 10722742
1998 The MDM2 gene amplification database. Nucleic acids research 826 9671804
1999 Nucleolar Arf sequesters Mdm2 and activates p53. Nature cell biology 782 10559859
2001 HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nature cell biology 775 11715018
1998 Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proceedings of the National Academy of Sciences of the United States of America 755 9653180
2003 The MDM2-p53 interaction. Molecular cancer research : MCR 729 14707283
2006 p53 ubiquitination: Mdm2 and beyond. Molecular cell 726 16455486
2004 Dynamics of the p53-Mdm2 feedback loop in individual cells. Nature genetics 726 14730303
2017 Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate. Clinical cancer research : an official journal of the American Association for Cancer Research 719 28351930
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2008 Acetylation is indispensable for p53 activation. Cell 697 18485870
2001 Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin. Science (New York, N.Y.) 695 11588219
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1993 Mapping of the p53 and mdm-2 interaction domains. Molecular and cellular biology 644 7686617
2004 Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nature medicine 642 15558054
2003 Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science (New York, N.Y.) 642 14671306
1995 Interaction between the retinoblastoma protein and the oncoprotein MDM2. Nature 560 7791904
2003 Regulation of HDM2 activity by the ribosomal protein L11. Cancer cell 550 12842086
2002 Akt enhances Mdm2-mediated ubiquitination and degradation of p53. The Journal of biological chemistry 501 11923280
1999 Functions of the MDM2 oncoprotein. Cellular and molecular life sciences : CMLS 491 10065155
2003 MDM2, an introduction. Molecular cancer research : MCR 369 14707282
2010 The p53 orchestra: Mdm2 and Mdmx set the tone. Trends in cell biology 366 20172729
1993 Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. Cancer research 362 8221695
2013 The MDM2-p53 pathway revisited. Journal of biomedical research 316 23885265
2004 Inhibition of HDM2 and activation of p53 by ribosomal protein L23. Molecular and cellular biology 307 15314174
1999 Nucleocytoplasmic shuttling of oncoprotein Hdm2 is required for Hdm2-mediated degradation of p53. Proceedings of the National Academy of Sciences of the United States of America 298 10077639
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
2002 The p53 and Mdm2 families in cancer. Current opinion in genetics & development 236 11790555
1997 Molecular characterization of the hdm2-p53 interaction. Journal of molecular biology 205 9223638
2003 MDM2 promotes ubiquitination and degradation of MDMX. Molecular and cellular biology 204 12860999
2006 Critical role for Daxx in regulating Mdm2. Nature cell biology 195 16845383
2005 The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53. Cancer cell 194 16023600
2001 Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms. EMBO reports 190 11606419
2000 MdmX protects p53 from Mdm2-mediated degradation. Molecular and cellular biology 183 10629057
2003 Posttranslational modification of MDM2. Molecular cancer research : MCR 174 14707285
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
2007 HDM2 antagonist Nutlin-3 disrupts p73-HDM2 binding and enhances p73 function. Oncogene 158 17700533
2022 Targeting p53-MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials. Journal of hematology & oncology 152 35831864
2001 Inhibition of MDM2 by hsp90 contributes to mutant p53 stabilization. The Journal of biological chemistry 151 11507088
2009 Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry? Molecular cancer research : MCR 149 19147532
2003 p53-independent functions of MDM2. Molecular cancer research : MCR 128 14707286
2000 Hdmx stabilizes Mdm2 and p53. The Journal of biological chemistry 125 10827196
2005 Stabilization of E2F1 protein by MDM2 through the E2F1 ubiquitination pathway. Oncogene 122 16170383
2001 An alternatively spliced HDM2 product increases p53 activity by inhibiting HDM2. Oncogene 121 11494132
2002 Hypophosphorylation of Mdm2 augments p53 stability. Molecular and cellular biology 119 12167711
2001 Cocompartmentalization of p53 and Mdm2 is a major determinant for Mdm2-mediated degradation of p53. Experimental cell research 110 11597128
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
2005 A chromatin-associated and transcriptionally inactive p53-Mdm2 complex occurs in mdm2 SNP309 homozygous cells. The Journal of biological chemistry 106 15908423
2001 HDM2 protein overexpression, but not gene amplification, is related to tumorigenesis of cutaneous melanoma. Cancer research 105 11606406
2015 Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas. Clinical cancer research : an official journal of the American Association for Cancer Research 103 26482041
2011 Novel targeted therapeutics: inhibitors of MDM2, ALK and PARP. Journal of hematology & oncology 98 21504625
1997 Induction of Mdm2 and enhancement of cell survival by bFGF. Oncogene 96 9400998
2017 Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas. Journal of hematology & oncology 89 28629371
2008 Mdm2 promotes genetic instability and transformation independent of p53. Molecular and cellular biology 89 18541670
2001 Abnormal expression of MDM2 in prostate carcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 88 11353053
1995 MDM2 and CDK4 gene amplification in Ewing's sarcoma. The Journal of pathology 87 7738717
2015 Transcription factors that interact with p53 and Mdm2. International journal of cancer 86 26132471
2002 Differentiation of Hdm2-mediated p53 ubiquitination and Hdm2 autoubiquitination activity by small molecular weight inhibitors. Proceedings of the National Academy of Sciences of the United States of America 86 12407176
2004 PTEN regulates Mdm2 expression through the P1 promoter. The Journal of biological chemistry 84 15090541
2014 p53-independent effects of Mdm2. Sub-cellular biochemistry 81 25201198
2013 miR-661 downregulates both Mdm2 and Mdm4 to activate p53. Cell death and differentiation 81 24141721
2017 Modulation of the p53/MDM2 interplay by HAUSP inhibitors. Journal of molecular cell biology 80 27927749
2013 MDM2's social network. Oncogene 79 24096477
2016 TP53 mutations emerge with HDM2 inhibitor SAR405838 treatment in de-differentiated liposarcoma. Nature communications 78 27576846
2002 Novel targets of Akt, p21(Cipl/WAF1), and MDM2. Seminars in oncology 76 12138399
2008 RYBP stabilizes p53 by modulating MDM2. EMBO reports 72 19098711
2004 Mdmx and Mdm2: brothers in arms? Cell cycle (Georgetown, Tex.) 72 15254433
2014 The MDM2 gene family. Biomolecular concepts 71 25372739
2006 Nucleolin inhibits Hdm2 by multiple pathways leading to p53 stabilization. Oncogene 71 16751805
2001 The contribution of the acidic domain of MDM2 to p53 and MDM2 stability. Oncogene 70 11313871
2016 Discovery of Dual Inhibitors of MDM2 and XIAP for Cancer Treatment. Cancer cell 68 27666947
2013 Podocyte loss involves MDM2-driven mitotic catastrophe. The Journal of pathology 68 23749457
1996 Overexpression of the MDM2 oncogene in leukemia and lymphoma. Leukemia & lymphoma 66 9172803
2003 p53 Mutation and MDM2 amplification in inflammatory myofibroblastic tumours. Histopathology 63 12713619
2005 Regulation of p53 and MDM2 activity by MTBP. Molecular and cellular biology 62 15632057
2001 Regulation of p63 function by Mdm2 and MdmX. DNA and cell biology 61 11445003
2013 HDM2 regulation by AURKA promotes cell survival in gastric cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 60 24240108
2008 Oscillations by the p53-Mdm2 feedback loop. Advances in experimental medicine and biology 59 18783169
2007 Unlocking the Mdm2-p53 loop: ubiquitin is the key. Cell cycle (Georgetown, Tex.) 59 18235222
2014 Mdmx promotes genomic instability independent of p53 and Mdm2. Oncogene 56 24608433
2013 Regulation of the HDM2-p53 pathway by ribosomal protein L6 in response to ribosomal stress. Nucleic acids research 56 24174547
2004 Nucleophosmin, HDM2 and p53: players in UV damage incited nucleolar stress response. Cell cycle (Georgetown, Tex.) 55 15254398
2001 Expression of heparanase, Mdm2, and erbB2 in ovarian cancer. International journal of oncology 53 11351242
2015 Role of p14ARF-HDM2-p53 axis in SOX6-mediated tumor suppression. Oncogene 51 26119940
2009 The p53 mRNA-Mdm2 interaction. Cell cycle (Georgetown, Tex.) 51 19106616
1997 The mdm2 proto-oncogene. Leukemia & lymphoma 49 9322885
2011 Mdm2 promotes systemic lupus erythematosus and lupus nephritis. Journal of the American Society of Nephrology : JASN 48 21949095
2009 Chemotherapy induces NEDP1-mediated destabilization of MDM2. Oncogene 48 19784069
2005 HDM2 phosphorylation by MAPKAP kinase 2. Oncogene 48 15688025
2005 Mdm2 in growth signaling and cancer. Growth factors (Chur, Switzerland) 46 16243710
2022 Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma. Frontiers in oncology 44 36439412
2010 Hispolon promotes MDM2 downregulation through chaperone-mediated autophagy. Biochemical and biophysical research communications 44 20540933
2007 The p53-MDM2 network: from oscillations to apoptosis. Journal of biosciences 44 17914240
2015 Regulation of MDM2 Stability After DNA Damage. Journal of cellular physiology 41 25808808
2011 p53 regulation: teamwork between RING domains of Mdm2 and MdmX. Cell cycle (Georgetown, Tex.) 41 22134240
2010 MDM2 as a modifier gene in retinoblastoma. Journal of the National Cancer Institute 41 21051655
2012 Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma. Cancer 39 23165797
2009 Recent advances in validating MDM2 as a cancer target. Anti-cancer agents in medicinal chemistry 39 19538162
2008 The Wip1 phosphatase and Mdm2: cracking the "Wip" on p53 stability. Cell cycle (Georgetown, Tex.) 39 18333294
2017 Role of Mdm2 and Mdmx in DNA repair. Journal of molecular cell biology 38 27932484
2009 Hdm2 is a ubiquitin ligase of Ku70-Akt promotes cell survival by inhibiting Hdm2-dependent Ku70 destabilization. Cell death and differentiation 38 19247369
2007 Targeting MDM2 and MDMX in retinoblastoma. Current cancer drug targets 38 18045074
2006 MDM2 interacts with and downregulates a sarcomeric protein, TCAP. Biochemical and biophysical research communications 38 16678796
2009 p53 and MDM2: antagonists or partners in crime? Cancer cell 37 19249672
2005 Chemosensitization by antisense oligonucleotides targeting MDM2. Current cancer drug targets 37 15720189
1998 MDM2 expression during mouse embryogenesis and the requirement of p53. Mechanisms of development 36 9651526
2017 Unbalancing p53/Mdm2/IGF-1R axis by Mdm2 activation restrains the IGF-1-dependent invasive phenotype of skin melanoma. Oncogene 35 28092675
2006 Cyclooxygenase inhibitors modulate the p53/HDM2 pathway and enhance chemotherapy-induced apoptosis in neuroblastoma. Oncogene 35 16983334
2017 Mdm2 as a chromatin modifier. Journal of molecular cell biology 34 27927750
2012 Mdm2 and tumorigenesis: evolving theories and unsolved mysteries. Genes & cancer 34 23150752