Affinage

MDM2

E3 ubiquitin-protein ligase Mdm2 · UniProt Q00987

Length
491 aa
Mass
55.2 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MDM2 is the principal negative regulator of the tumor suppressor p53, functioning as a p53-specific E3 ubiquitin ligase that constitutively monoubiquitinates p53 in unstressed cells to drive its proteasomal degradation (PMID:9153396, PMID:14707283). Efficient degradation requires MDM2 to shuttle between nucleus and cytoplasm via its own NLS and NES, co-compartmentalizing with p53 so that ubiquitinated substrate is delivered to nuclear and cytoplasmic proteasomes (PMID:10077639, PMID:11597128). Its E3 output is dictated by heterodimerization with MDMX/HdmX through reciprocal RING-RING interactions: MDMX stimulates MDM2 ligase activity and converts MDM2 from a monoubiquitination to a polyubiquitination enzyme, with MDMX itself serving as both activator and substrate of the holoenzyme (PMID:14507994, PMID:22673503, PMID:12860999). MDM2 activity is tuned by phosphorylation — Akt at Ser186 and AURKA both enhance MDM2-mediated p53 ubiquitination (PMID:11923280, PMID:24240108) — and by an upstream PTEN-controlled transcriptional input that restrains MDM2 expression through the P1 promoter (PMID:15090541). A major regulatory axis couples ribosome biogenesis and nucleolar stress to p53: ribosomal proteins L11, L23, and L6, together with nucleophosmin, bind MDM2 and inhibit its ligase activity to stabilize and activate p53, while additional partners such as gankyrin and MTBP promote, and RYBP inhibits, MDM2-driven p53 turnover (PMID:12842086, PMID:15144954, PMID:15314174, PMID:24174547, PMID:16023600, PMID:15632057, PMID:19098711). Beyond p53, MDM2 ubiquitinates MDMX, FOXO factors, and Ku70, stabilizes E2F1 by displacing its SCF(SKP2) ligase, binds and inhibits p73, and delays DNA double-strand break repair through interaction with Nbs1 — establishing p53-independent oncogenic functions (PMID:12860999, PMID:18665269, PMID:19247369, PMID:16170383, PMID:17700533, PMID:18541670, PMID:7791904). The RING domain also confers RNA-binding activity: MDM2 binds p53 mRNA to stimulate its translation and binds the XIAP IRES to enhance XIAP translation, with RNA engagement reciprocally suppressing its E3 ligase activity (PMID:19106616, PMID:27666947). MDM2 further cooperates with polycomb proteins EZH2 and RING1B to enforce repressive chromatin marks at target promoters independently of p53 (PMID:27927750).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1995 High

    Established that MDM2 has oncogenic activity beyond p53 by physically engaging and inactivating the retinoblastoma protein, broadening MDM2 from a p53 regulator to a multi-target growth controller.

    Evidence Co-immunoprecipitation and growth assays with pRB

    PMID:7791904

    Open questions at the time
    • Domain of MDM2 mediating pRB binding not defined here
    • Physiological contexts where this dominates over p53 regulation unclear
  2. 1997 High

    Answered how MDM2 controls p53 abundance by showing the interaction promotes proteasome-dependent p53 degradation at endogenous MDM2 levels, defining the core feedback brake on p53.

    Evidence Overexpression and proteasome-inhibitor studies with endogenous protein readouts

    PMID:9153396

    Open questions at the time
    • Did not establish MDM2 as the direct ligase versus an adaptor
    • Subcellular site of degradation not resolved
  3. 1999 High

    Determined that MDM2 must shuttle nucleocytoplasmically to degrade p53, linking its NLS/NES to substrate clearance.

    Evidence NLS/NES mutagenesis in p53/mdm2 double-null cells

    PMID:10077639

    Open questions at the time
    • Whether export is strictly required was later contested (see 2001)
  4. 2001 High

    Refined the shuttling model, showing degradation can occur in either compartment once MDM2 and p53 co-localize, so nuclear export is facilitating rather than absolutely required.

    Evidence NES mutants, leptomycin B and proteasome inhibition with fractionation

    PMID:11597128

    Open questions at the time
    • Relative contribution of nuclear versus cytoplasmic proteasomes in vivo not quantified
  5. 2001 Medium

    Identified MDMX/Hdmx as a RING-RING partner that stabilizes both MDM2 and p53 by inhibiting MDM2 self-ubiquitination, introducing the heterodimer as a key regulatory node.

    Evidence Transfection and RING-finger deletion mutant stability assays

    PMID:10827196 PMID:11606419

    Open questions at the time
    • Single-lab models; reconciled only later with stimulatory role
    • Trimeric complex proposed but not structurally confirmed
  6. 2003 High

    Established MDM2 as the principal p53-specific E3 ligase that constitutively monoubiquitinates p53, defining the molecular activity behind p53 turnover.

    Evidence In vitro ubiquitination and cell-based degradation assays

    PMID:14707283

    Open questions at the time
    • Mono- versus poly-ubiquitination determinants not yet resolved
  7. 2003 High

    Resolved MDMX's role as a stimulator rather than inhibitor of MDM2 E3 activity and a substrate of the complex, clarifying conflicting earlier stabilization data.

    Evidence In vitro E3 assays and siRNA knockdown

    PMID:14507994

    Open questions at the time
    • Stimulatory versus stabilizing roles context-dependent and not fully reconciled
  8. 2003 High

    Showed MDM2 ubiquitinates MDMX itself, with ARF redirecting MDM2 activity from p53 toward MDMX, revealing reciprocal regulation within the MDM2/MDMX module.

    Evidence Ubiquitination assays with ARF expression and DNA damage

    PMID:12860999

    Open questions at the time
    • Switch determinants controlling substrate choice not defined
  9. 2003 Medium

    Connected MDM2 to p53 sumoylation by nucleolar targeting, expanding its post-translational control of p53 beyond ubiquitination.

    Evidence In vivo sumoylation assay with MDM2 deletion mutants and ARF

    PMID:12917636

    Open questions at the time
    • Functional consequence of p53 sumoylation here not established
    • Single lab
  10. 2002 High

    Demonstrated kinase control of MDM2: Akt phosphorylation at Ser186 enhances p53 ubiquitination, linking PI3K/Akt signaling to p53 suppression.

    Evidence S186A mutagenesis, kinase and ubiquitination assays, LY294002

    PMID:11923280

    Open questions at the time
    • Mechanism by which Ser186 phosphorylation alters ligase activity unresolved
  11. 2002 High

    Showed MDM2's two E3 activities (p53 ubiquitination versus autoubiquitination) are pharmacologically separable, establishing the ligase as a druggable target.

    Evidence In vitro E3 assays with multiple noncompetitive inhibitor classes and kinetics

    PMID:12407176

    Open questions at the time
    • Common inhibitor binding site not structurally mapped
  12. 2004 High

    Defined the nucleolar/ribosomal stress axis: L11, L23, and nucleophosmin bind MDM2 and inhibit its ligase to stabilize p53, coupling ribosome biogenesis surveillance to p53.

    Evidence Co-IP, domain mapping, ubiquitination and siRNA assays with actinomycin D/UV

    PMID:12842086 PMID:15144954 PMID:15314174

    Open questions at the time
    • Hierarchy and stoichiometry among ribosomal protein partners unclear
    • Stress-specific selectivity not fully defined
  13. 2004 Medium

    Identified PTEN as a p53-independent transcriptional brake on MDM2 via the P1 promoter, placing MDM2 expression downstream of lipid-phosphatase signaling.

    Evidence Promoter reporter assays in Pten-null cells with phosphatase-dead mutant

    PMID:15090541

    Open questions at the time
    • Intermediate transcription factors linking PTEN to P1 not identified
    • Single lab
  14. 2005 Medium

    Expanded the partner network with gankyrin and MTBP as positive regulators of MDM2-mediated p53 degradation, and an alternatively spliced isoform that sequesters MDM2 to activate p53.

    Evidence Co-IP, ubiquitination, siRNA, proteasome-association and localization assays

    PMID:11494132 PMID:15632057 PMID:16023600

    Open questions at the time
    • Relative contributions in physiological settings unquantified
    • Mostly single-lab
  15. 2005 Medium

    Revealed p53-independent substrate range: MDM2 stabilizes E2F1 by displacing its ligase and promotes ubiquitin-independent degradation of TCAP.

    Evidence Co-IP, ubiquitination competition, half-life and proteasome inhibitor assays

    PMID:16170383 PMID:16678796

    Open questions at the time
    • Physiological significance of TCAP and E2F1 regulation unclear
    • Single-lab findings
  16. 2007 Medium

    Showed MDM2 binds and inhibits the p53 family member p73, with Nutlin-3 relieving this to drive p73-dependent apoptosis in p53-null cells.

    Evidence Endogenous co-IP, half-life, siRNA and target-gene analysis

    PMID:17700533

    Open questions at the time
    • Whether inhibition involves ubiquitination or binding alone not resolved
  17. 2008 High

    Established additional E3 substrates (FOXO factors) and a non-catalytic role in DNA repair, where MDM2-Nbs1 binding delays double-strand break repair and promotes transformation independent of ligase activity.

    Evidence In vitro/in vivo ubiquitination, reciprocal domain mutagenesis, γH2AX and chromosome break assays

    PMID:18541670 PMID:18665269

    Open questions at the time
    • FOXO ubiquitination physiology single-lab
    • How MDM2 mechanistically delays repair at Nbs1 unresolved
  18. 2008 Medium

    Added RYBP as a negative regulator of MDM2-mediated p53 ubiquitination acting in the DNA damage response.

    Evidence Co-IP, ubiquitination, cell cycle and DNA damage assays

    PMID:19098711

    Open questions at the time
    • Mechanism of ligase inhibition not defined
    • Single lab
  19. 2009 Medium

    Uncovered a dual function of the RING domain as an RNA-binding module: MDM2 binds p53 mRNA to stimulate translation, with RNA engagement suppressing its own E3 activity, and ubiquitinates Ku70 to suppress apoptosis under Akt control.

    Evidence RNA-protein interaction, translation and E3 activity assays; ubiquitination with Akt mutants

    PMID:19106616 PMID:19247369

    Open questions at the time
    • RNA-binding versus catalytic switch quantitatively undefined
    • Single-lab studies
  20. 2012 High

    Defined the mono-to-poly ubiquitination switch mechanism: MDMX RING interaction converts MDM2 into a polyubiquitin ligase required for p53 degradation, with MDM2 catalytic and MDMX activating/substrate.

    Evidence In vitro ubiquitination with RING mutants and knock-in mouse models

    PMID:22673503

    Open questions at the time
    • Structural basis of the chain-length switch not resolved
  21. 2013 Medium

    Extended kinase and ribosomal control: AURKA phosphorylates and stabilizes MDM2 to enhance p53 ubiquitination, while RPL6 inhibits MDM2 ligase activity in an autoregulatory ubiquitination loop.

    Evidence In vitro kinase, co-IP, ubiquitination and fractionation assays

    PMID:24174547 PMID:24240108

    Open questions at the time
    • Both single-lab; integration with other ribosomal-protein partners unclear
  22. 2016 Medium

    Identified MDM2 as an XIAP IRES-binding protein that enhances XIAP translation and is itself stabilized by RNA binding, defining a druggable p53-independent pro-survival function.

    Evidence Fluorescence polarization RNA binding, HTS screen, stability and expression assays

    PMID:27666947

    Open questions at the time
    • RNA-binding determinants on MDM2 not mapped here
    • Single study
  23. 2017 Medium

    Revealed a chromatin-repressive function: MDM2 is recruited by EZH2 to promoters where it augments H3K27me3 and H2AK119ub1 marks, supporting stemness independently of p53.

    Evidence Co-IP, ChIP, histone modification and expression profiling

    PMID:27927750

    Open questions at the time
    • Whether MDM2 catalytic activity contributes to histone marks unclear
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MDM2's catalytic, RNA-binding, and chromatin-associated functions are coordinately switched between substrates and contexts, and the structural basis of its ubiquitin chain-length control, remain unresolved.
  • No integrated structural model of MDM2/MDMX holoenzyme substrate selection
  • Physiological weighting of p53-independent functions unquantified
  • Regulatory logic coupling RNA binding and E3 activity undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 6 GO:0140096 catalytic activity, acting on a protein 5 GO:0003723 RNA binding 2 GO:0098772 molecular function regulator activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 2 GO:0005730 nucleolus 2
Pathway
R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-4839726 Chromatin organization 1 R-HSA-73894 DNA Repair 1
Partners
E2F1EZH2MDM4NBNNPM1RPL11RPL23TP53
Complex memberships
MDM2-L11-L23 ribosomal protein complexMDM2/MDMX E3 ligase heterodimerpolycomb repressive complex (with EZH2/RING1B)

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 MDM2 interaction with p53 promotes proteasome-dependent degradation of p53, reducing p53 protein levels. Endogenous levels of MDM2 are sufficient to regulate p53 stability, and overexpression of MDM2 reduces endogenous p53 protein. Transfection/overexpression assays, proteasome inhibitor studies, endogenous protein level analysis Nature High 9153396
1995 MDM2 physically interacts with the retinoblastoma protein pRB and inhibits pRB growth-regulatory function, demonstrating a p53-independent oncogenic mechanism. Co-immunoprecipitation, functional growth assays Nature High 7791904
2003 MDM2 functions as the principal p53-specific E3 ubiquitin ligase in unstressed cells, constitutively monoubiquitinating p53 to mediate its degradation by nuclear and cytoplasmic proteasomes. In vitro ubiquitination assays, cell-based degradation assays Molecular cancer research : MCR High 14707283
1999 HDM2/MDM2 must shuttle between nucleus and cytoplasm to target p53 for degradation; MDM2 mutants lacking NLS (nuclear entry) or NES (nuclear export) individually, or in combination, fail to promote p53 degradation, establishing that MDM2 shuttles p53 from nucleus to cytoplasm for proteasomal degradation. Site-directed mutagenesis of NLS/NES, cotransfection in p53/mdm2 double-null cells, p53 protein level assays Proceedings of the National Academy of Sciences of the United States of America High 10077639
2003 The ribosomal protein L11 binds HDM2 and inhibits its function, leading to stabilization and activation of p53. This interaction is enhanced by low-dose actinomycin D, linking ribosome biogenesis stress to p53 activation through HDM2 inhibition. Co-immunoprecipitation, functional p53 activity assays, actinomycin D treatment Cancer cell High 12842086
2004 Nucleophosmin (NPM/B23) binds HDM2 and acts as a negative regulator of the p53-HDM2 interaction, protecting p53 from HDM2-mediated degradation. UV damage induces nucleoplasmic redistribution of NPM which facilitates this binding. RNAi knockdown, co-immunoprecipitation of endogenous and ectopic proteins, subcellular fractionation Cancer cell High 15144954
2004 Ribosomal protein L23 interacts with HDM2 via the central acidic domain of HDM2 and an N-terminal domain of L23, forming a ternary complex with L11. L23 overexpression inhibits HDM2-induced p53 polyubiquitination and degradation, causing p53-dependent cell cycle arrest. L23 knockdown triggers nucleolar stress and p53 stabilization. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, cell cycle analysis Molecular and cellular biology High 15314174
2003 HdmX stimulates Hdm2-mediated ubiquitination of p53 in vitro, and also facilitates mutual ubiquitination between HdmX and Hdm2. Downregulation of HdmX in cells causes accumulation of both p53 and Hdm2, indicating that HdmX acts as a stimulator of Hdm2 E3 activity rather than an inhibitor. In vitro E3 ubiquitin ligase assay, siRNA knockdown, cell-based protein level analysis Proceedings of the National Academy of Sciences of the United States of America High 14507994
2001 Hdmx stabilizes both p53 and Mdm2. Hdmx does not target p53 for degradation but stabilizes Mdm2 by inhibiting its self-ubiquitination, likely through heterodimerization of the RING fingers of Mdm2 and Hdmx. Transfection, protein stability assays, RING finger deletion mutants EMBO reports Medium 11606419
2000 Hdmx stabilizes both p53 and Mdm2; the RING finger of Hdmx is necessary and sufficient for this stabilization, and likely involves hetero-oligomerization with the RING finger of Mdm2, inhibiting Mdm2 ubiquitin ligase activity. A trimeric Hdmx-Mdm2-p53 complex is proposed. Transfection, RING finger domain mutants, protein stability assays The Journal of biological chemistry Medium 10827196
2003 MDM2 promotes MDMX ubiquitination and proteasomal degradation via its RING domain E3 ligase activity. ARF stimulates MDM2-mediated MDMX ubiquitination (while inhibiting MDM2 ubiquitination of p53) and both MDM2 and ARF levels are increased by DNA damage leading to MDMX downregulation. Ubiquitination assay, proteasome inhibitor experiments, ARF adenovirus expression, inducible MDM2 expression Molecular and cellular biology High 12860999
2001 MDM2 can promote proteasomal degradation of p53 in both the nucleus and cytoplasm, provided they are co-compartmentalized. Nuclear export of p53 is not an absolute requirement for MDM2-mediated p53 degradation; ubiquitinated p53 accumulates in the nucleus when proteasome activity is inhibited. LMB inhibits MDM2-mediated ubiquitination of p53 by preventing MDM2 nuclear export. NES mutants of Mdm2 and p53, leptomycin B treatment, proteasome inhibition, subcellular fractionation Experimental cell research High 11597128
2002 Akt phosphorylates MDM2 at Ser186, enhancing MDM2-mediated ubiquitination and degradation of p53. Mutation of Ser186 to Ala renders MDM2 resistant to Akt-mediated enhancement of p53 ubiquitination and degradation. In vivo ubiquitination assay, site-directed mutagenesis (S186A), kinase assays, LY294002 inhibitor The Journal of biological chemistry High 11923280
2002 Small molecule inhibitors selectively block HDM2 E3 ligase-mediated ubiquitination of p53 without inhibiting HDM2 autoubiquitination, demonstrating that these two E3 activities of HDM2 can be pharmacologically separated. All three inhibitor classes were noncompetitive with respect to both substrates and bind at a common site on HDM2. In vitro E3 ubiquitin ligase assay, steady-state kinetic analysis, combinatorial inhibitor binding studies Proceedings of the National Academy of Sciences of the United States of America High 12407176
2005 Gankyrin binds MDM2/HDM2 and facilitates p53-MDM2 binding, increasing ubiquitylation and degradation of p53. Gankyrin also enhances MDM2 autoubiquitylation. Downregulation of gankyrin reduced amounts of MDM2 and p53 associated with the 26S proteasome. In vitro and in vivo ubiquitination assays, co-immunoprecipitation, siRNA knockdown, proteasome association assay Cancer cell High 16023600
2005 MDM2 stabilizes E2F1 protein by inhibiting its ubiquitination; MDM2 directly binds E2F1 and displaces SCF(SKP2), the E2F1 E3 ligase, thereby prolonging E2F1 half-life independent of p53 and pRB/p14ARF. Co-immunoprecipitation, ubiquitination assay, half-life measurement, MDM2 NLS deletion mutant Oncogene Medium 16170383
2001 An alternatively spliced HDM2 isoform (HDM2ALT1) lacking the p53-binding domain sequesters full-length HDM2 in the cytoplasm and inhibits HDM2-p53 interaction, thereby enhancing p53 transcriptional activity. Transient transfection, co-immunoprecipitation, subcellular localization, p53 transcriptional activity assay Oncogene Medium 11494132
2008 MDM2 acts as an E3 ubiquitin ligase for FOXO transcription factors, inducing ATP-dependent (multi)mono-ubiquitination of FOXO in vitro and in vivo. Mdm2-FOXO co-immunoprecipitate and Mdm2-mediated ubiquitination regulates FOXO transcriptional activity. In vitro ubiquitination assay, co-immunoprecipitation, siRNA knockdown, in vivo co-expression PloS one Medium 18665269
2003 MDM2, together with ARF, regulates p53 sumoylation by targeting p53 to the nucleolus. MDM2 overexpression increases p53 SUMO-1 conjugation, further stimulated by ARF; nucleolar targeting of p53 is required for efficient sumoylation in an MDM2- and ARF-dependent manner. Co-immunoprecipitation, sumoylation assay, subcellular localization studies, MDM2 deletion mutants Oncogene Medium 12917636
2005 MTBP (MDM2 binding protein) promotes MDM2-mediated ubiquitination and degradation of p53 and also MDM2 stabilization, both in an MDM2 RING finger-dependent manner. siRNA knockdown of endogenous MTBP reduces MDM2-mediated p53 regulation; UV (but not gamma-irradiation) destabilizes MTBP as part of the damage response. siRNA knockdown, ubiquitination assay, MDM2 RING mutants, UV/gamma irradiation Molecular and cellular biology Medium 15632057
2008 MDM2 interacts with Nbs1 (a component of the Mre11/Rad50/Nbs1 DNA repair complex) through a defined 31-amino-acid region; this interaction delays DNA double-strand break repair and phosphorylation of H2AX and ATM substrates, leading to chromosome instability and transformation independent of p53. Both Nbs1 and ATM (but not MDM2 ubiquitin ligase activity) are required for this effect. Co-immunoprecipitation, site-directed mutagenesis of MDM2 and Nbs1 binding domains, γH2AX foci analysis, chromosome break assay, transformation assay Molecular and cellular biology High 18541670
2009 HDM2 functions as a ubiquitin E3 ligase for Ku70, ubiquitinating and destabilizing Ku70 protein. Akt-mediated phosphorylation of HDM2 promotes its nuclear translocation, which inhibits cytosolic Ku70 degradation and thereby suppresses Bax-mediated apoptosis. Co-immunoprecipitation, ubiquitination assay, constitutively active/kinase-dead Akt, siRNA knockdown, subcellular fractionation Cell death and differentiation Medium 19247369
2004 PTEN negatively regulates MDM2 transcription through the MDM2 P1 promoter via its lipid phosphatase activity, independent of p53. In Pten-null cells, MDM2 P1 promoter activity is up-regulated, increasing L-Mdm2 expression. Promoter reporter assay, Pten-null cell lines and prostate cancer tissues, lipid phosphatase-dead PTEN mutant The Journal of biological chemistry Medium 15090541
2013 Ribosomal protein L6 (RPL6) binds HDM2, suppresses its E3 ubiquitin ligase activity, and attenuates HDM2-mediated p53 polyubiquitination and degradation. RPL6 translocates from nucleolus to nucleoplasm under ribosomal stress, facilitating HDM2 binding. The HDM2-RPL6 interaction leads to HDM2-mediated RPL6 polyubiquitination and degradation, forming an autoregulatory feedback loop. Co-immunoprecipitation, ubiquitination assay, subcellular fractionation, actinomycin D treatment, siRNA knockdown Nucleic acids research Medium 24174547
2013 Aurora kinase A (AURKA) directly interacts with and phosphorylates HDM2 protein in vitro; AURKA overexpression enhances HDM2 protein level and HDM2-mediated p53 ubiquitination; AURKA inhibition decreases HDM2 and induces p53 activity. Dual co-immunoprecipitation, in vitro kinase assay with recombinant proteins, AURKA knockdown/overexpression, p53 ubiquitination assay Clinical cancer research Medium 24240108
2008 RYBP (RING1- and YY1-binding protein) interacts with MDM2 and decreases MDM2-mediated p53 ubiquitination, leading to stabilization and increased p53 activity. RYBP is involved in the p53 DNA damage response. Co-immunoprecipitation, ubiquitination assay, cell cycle analysis, DNA damage assay EMBO reports Medium 19098711
2009 MDM2 interacts with p53 mRNA and stimulates its translation; this RNA binding is mediated through the RING domain, which overlaps with the E3 ligase domain, such that the p53 mRNA-MDM2 interaction suppresses MDM2's ability to promote p53 polyubiquitination and degradation. RNA-protein interaction assay, p53 protein synthesis measurement, E3 ligase activity assay Cell cycle (Georgetown, Tex.) Medium 19106616
2005 MDM2 interacts with the sarcomeric protein TCAP (telethonin/T-cap), co-localizes with it in the nucleus, and promotes its ubiquitin-independent proteasomal degradation. Elevated MDM2 alters TCAP subcellular localization, and p14ARF inhibits MDM2-mediated TCAP degradation. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, confocal microscopy, proteasome inhibitor experiments Biochemical and biophysical research communications Medium 16678796
2016 MDM2 protein binds the IRES region of XIAP mRNA; this protein-RNA interaction results in MDM2 protein stabilization and enhanced XIAP translation. Small molecule inhibitors blocking MDM2-XIAP RNA interaction cause MDM2 degradation and p53 activation. Fluorescence polarization protein-RNA binding assay, HTS compound screen, MDM2 protein stability assay, XIAP expression analysis Cancer cell Medium 27666947
2012 MdmX converts Mdm2 from a mono-ubiquitination E3 ligase into a p53 polyubiquitination E3 ligase necessary for p53 proteasomal degradation through RING-RING domain interactions. While Mdm2 is the catalytic component, MdmX is both the activating component and a substrate of the Mdm2/MdmX holoenzyme. In vitro ubiquitination assay, RING domain mutants, knock-in mouse models FEBS letters High 22673503
2007 HDM2 binds p73 and inhibits its function; Nutlin-3, by disrupting the HDM2-p73 interaction, increases p73 transcriptional activity, p73 protein half-life, and p73-dependent apoptosis in p53-null cells. Co-immunoprecipitation of endogenous proteins, p73 half-life assay, siRNA knockdown of p73, p73 target gene analysis Oncogene Medium 17700533
2017 Mdm2 interacts with polycomb group (PcG) proteins, including EZH2 and RING1B; EZH2 recruits Mdm2 to target gene promoters where it enhances repressive chromatin modifications (H3K27me3 and H2AK119ub1), supporting gene repression and stem cell phenotype in a p53-independent manner. Co-immunoprecipitation, chromatin immunoprecipitation, histone modification analysis, gene expression profiling Journal of molecular cell biology Medium 27927750

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Regulation of p53 stability by Mdm2. Nature 2903 9153396
1998 The MDM2 gene amplification database. Nucleic acids research 827 9671804
2003 The MDM2-p53 interaction. Molecular cancer research : MCR 734 14707283
2006 p53 ubiquitination: Mdm2 and beyond. Molecular cell 733 16455486
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 552 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 493 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
2004 Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. Cancer cell 355 15144954
2014 Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment. Journal of medicinal chemistry 353 25396320
2013 The MDM2-p53 pathway revisited. Journal of biomedical research 321 23885265
2004 Inhibition of HDM2 and activation of p53 by ribosomal protein L23. Molecular and cellular biology 308 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 Mdm2: keeping p53 under control. Oncogene 235 9285554
2003 MDM2 promotes ubiquitination and degradation of MDMX. Molecular and cellular biology 204 12860999
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
2002 p53-Mdm2--the affair that never ends. Carcinogenesis 179 11960904
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
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 156 35831864
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 123 16170383
2001 An alternatively spliced HDM2 product increases p53 activity by inhibiting HDM2. Oncogene 121 11494132
2008 Mdm2 induces mono-ubiquitination of FOXO4. PloS one 112 18665269
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
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
2003 MDM2-ARF complex regulates p53 sumoylation. Oncogene 103 12917636
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
2015 Transcription factors that interact with p53 and Mdm2. International journal of cancer 87 26132471
1995 MDM2 and CDK4 gene amplification in Ewing's sarcoma. The Journal of pathology 87 7738717
2012 Mdm2 and MdmX partner to regulate p53. FEBS letters 86 22673503
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 85 15090541
2001 MDM2: life without p53. Trends in genetics : TIG 84 11485818
2014 p53-independent effects of Mdm2. Sub-cellular biochemistry 82 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 80 24096477
2021 MDM2 Amplified Sarcomas: A Literature Review. Diagnostics (Basel, Switzerland) 73 33799733
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
2016 Discovery of Dual Inhibitors of MDM2 and XIAP for Cancer Treatment. Cancer cell 69 27666947
2013 Podocyte loss involves MDM2-driven mitotic catastrophe. The Journal of pathology 69 23749457
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2003 p53 Mutation and MDM2 amplification in inflammatory myofibroblastic tumours. Histopathology 64 12713619
2005 Regulation of p53 and MDM2 activity by MTBP. Molecular and cellular biology 62 15632057
2009 Mdm2 affects genome stability independent of p53. Cancer research 61 19244108
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
2019 MDM2 and MDM4 Are Therapeutic Vulnerabilities in Malignant Rhabdoid Tumors. Cancer research 57 30755442
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 55 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
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2011 Mdm2 promotes systemic lupus erythematosus and lupus nephritis. Journal of the American Society of Nephrology : JASN 48 21949095
2022 Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma. Frontiers in oncology 47 36439412
2005 Mdm2 in growth signaling and cancer. Growth factors (Chur, Switzerland) 46 16243710
2007 The p53-MDM2 network: from oscillations to apoptosis. Journal of biosciences 44 17914240
2011 p53 regulation: teamwork between RING domains of Mdm2 and MdmX. Cell cycle (Georgetown, Tex.) 42 22134240
2015 Regulation of MDM2 Stability After DNA Damage. Journal of cellular physiology 41 25808808
2010 MDM2 as a modifier gene in retinoblastoma. Journal of the National Cancer Institute 41 21051655
2009 Recent advances in validating MDM2 as a cancer target. Anti-cancer agents in medicinal chemistry 41 19538162
1996 The organization and expression of the mdm2 gene. Genomics 41 8660994
2006 Excess HDM2 impacts cell cycle and apoptosis and has a selective effect on p53-dependent transcription. The Journal of biological chemistry 40 16624812
2009 Hdm2 is a ubiquitin ligase of Ku70-Akt promotes cell survival by inhibiting Hdm2-dependent Ku70 destabilization. Cell death and differentiation 39 19247369
2017 Role of Mdm2 and Mdmx in DNA repair. Journal of molecular cell biology 38 27932484
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
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2017 Unbalancing p53/Mdm2/IGF-1R axis by Mdm2 activation restrains the IGF-1-dependent invasive phenotype of skin melanoma. Oncogene 35 28092675
2012 Mdm2 in evolution. Genes & cancer 35 23150765
2007 Mdm2: p53's lifesaver? Molecular cell 35 17386256
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
2017 Anatomy of Mdm2 and Mdm4 in evolution. Journal of molecular cell biology 34 28077607
2012 Mdm2 and tumorigenesis: evolving theories and unsolved mysteries. Genes & cancer 34 23150752
2019 Helping the Released Guardian: Drug Combinations for Supporting the Anticancer Activity of HDM2 (MDM2) Antagonists. Cancers 33 31331108
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2011 MDM2 and MDMX in cancer and development. Current topics in developmental biology 33 21295684

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