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Cited by 1,279Cancer-related Molecular PathwaysHeat shock proteins researchPI3K/AKT/mTOR signaling in cancer

MDM2, MDMX and p53 in oncogenesis and cancer therapy

Open access
Wade, Mark, Li, Yao-Cheng, Wahl, Geoffrey M.·2013·Nature Reviews Cancer
DOI 10.1038/nrc3430PMC PMC4161369
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Abstract

The MDM2 and MDMX (also known as HDMX and MDM4) proteins are deregulated in many human cancers and exert their oncogenic activity predominantly by inhibiting the p53 tumour suppressor. However, the MDM proteins modulate and respond to many other signalling networks in which they are embedded. Recent mechanistic studies and animal models have demonstrated how functional interactions in these networks are crucial for maintaining normal tissue homeostasis, and for determining responses to oncogenic and therapeutic challenges. This Review highlights the progress made and pitfalls encountered as the field continues to search for MDM-targeted antitumour agents.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that MDM2 and MDMX are major negative regulators of p53 whose deregulation contributes to many cancers, but their full oncogenic potential generally requires cooperating lesions. It surveys mechanisms, mouse models, and drug development, concluding that p53 reactivation via MDM2/MDMX antagonists is promising but context-dependent and still limited by lack of selective MDMX inhibitors and clinical challenges.

Key findings

  • MDM2 and MDMX inhibit p53 transactivation by binding its N-terminal domain; MDM2 homo-oligomers have E3 ubiquitin ligase activity via an intact C-terminal RING domain, whereas MDMX lacks intrinsic ligase activity but hetero-oligomerizes with MDM2, and this hetero-oligomerization is crucial for p53 suppression during embryonic development.
  • In vivo evidence shows context dependence: MDM2 overexpression can induce carcinoma and lymphomas or sarcomas, and an MDM2 SNP knock-in accelerates tumorigenesis at a rate similar to Trp53-hemizygous animals; MDMX overexpression alone has yielded conflicting tumorigenicity results, while MDMX3SA mice are radioresistant and more prone to Myc-induced tumors, and MDM2-Ser394Ala mice show increased spontaneous tumors.
  • In a Phase I proof-of-mechanism study of RG7112 in 20 patients with MDM2-amplified liposarcoma, the drug reached its target and increased MIC1/GDF15, but increases in p53 and p21 and decreased proliferation did not reach significance; at least one adverse event occurred in each patient, most frequently haematological toxicities.
  • Nutlin 3a is 500-fold less potent against MDMX than MDM2; the dual inhibitor RO-5963 had better in vitro MDM2 binding affinity than nutlin 3a (IC50 17.3 nM versus 18.7 nM) but poorer pharmacological properties, and the stapled peptide SAH-p53-8 had tenfold better MDM2 IC50 than nutlin 3a and also disrupts p53–MDMX interactions.

Methods

  • Design: narrative review of MDM2, MDMX, and p53 biology, oncogenesis, and therapeutic targeting.
  • Data: published mechanistic studies, cell-based assays, mouse genetic models, and clinical trial data; no new primary data are reported.
  • Analysis: qualitative synthesis of the core pathway, transcriptional/post-transcriptional regulation, oncogenic evidence, and small-molecule/peptidic inhibitor strategies.

Limitations

  • The paper states that much remains unknown about MDM2 and MDMX transcriptional regulation, that in vivo mutation of p53 response elements in Mdm2 and Mdmx promoters is needed, that the biological importance of the p53–miRNA network remains to be clarified, and that the identity of the relevant E2 ubiquitin-conjugating enzymes is unknown.
  • The paper states that no selective MDMX small-molecule inhibitor currently exists, that the RG7112 trial was preliminary with only 20 patients and heterogeneous tumour tissue, and that relying on MDM gene amplification alone for patient selection is inadequate.
  • Evident from the text: as a narrative review, it does not perform a systematic search or quantitative meta-analysis, and it reports conflicting mouse-model results for MDMX overexpression, so conclusions depend on context and cited study designs.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/nrc3430

Cites

174 of 174 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 131 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    A major oncogenic role of MDM proteins is to block p53 transcriptional activity.

    “Taken together, these observations indicate that a major oncogenic role of MDM proteins is to block p53 transcriptional activity.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Both MDM2 and MDMX can inhibit p53 transactivation by engaging its N-terminal transactivation domain via related hydrophobic pockets.

    “Although both MDM2 and MDMX can inhibit p53 transactivation function by engaging its amino-terminal transactivation domain via related N-terminal hydrophobic pockets2,11,12”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [2] Momand, J., Zambetti, G. P., Olson, D. C., George, D. & Levine, A. J. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69, 1237–1245 (1992). The first demonstration that MDM2 could inhibit p53 activity. source

      Not checked in the free run.

    • cites [11] Kussie, P. H. et al. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274, 948–953 (1996). The structure that described the hydrophobic p53-binding pocket of MDM2, on which many drug discovery efforts are now based. source

      Not checked in the free run.

    • cites [12] Laurie, N. A. et al. Inactivation of the p53 pathway in retinoblastoma. Nature 444, 61–66 (2006). source

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  • Premisenone given

    The frequency of MDM protein deregulation is higher in tumours that retain wild-type p53.

    “In many cases, the frequency of MDM protein deregulation is higher in tumours that retain wild-type p53.”
    Quote in the paperSubstantial claim
  • Interpretationnone given

    MDM2 and MDMX are druggable using a variety of strategies.

    “which now seem to be ‘druggable’ using a variety of strategies.”
    Quote in the paperSubstantial claim
  • Premisecitation

    MDM2 and MDMX are the two major negative regulators of p53.

    “Mouse genetic models strongly suggest that MDM2 and MDMX are the two major p53 antagonists in vivo107,108”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [107] Montes de Oca Luna, R., Wagner, D. S. & Lozano, G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378, 203–206 (1995). source

      Not checked in the free run.

    • cites [108] Parant, J. et al. Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53. Nature Genet. 29, 92–95 (2001). References 107 and 108 demonstrate that deletions of Mdm2 and Mdmx cause embryonic lethality that can be rescued by Trp53 deletion, thus providing genetic evidence that MDM2 and MDM4 are crucial p53 repressors with non-overlapping functions. source

      Not checked in the free run.

  • May combine two claims. 42
  • Classified as probably not a substantial claim. 3

  • May combine two claims.

    Premisecitation

    MDM2 and MDMX are deregulated in many human cancers and act oncogenically mainly by inhibiting p53.

    “The MDM2 and MDMX (also known as HDMX and MDM4) proteins are deregulated in many human cancers and exert their oncogenic activity predominantly by inhibiting the p53 tumour suppressor.”
    • Also stated in: § The core pathway · hedged
      “Taken together, these observations indicate that a major oncogenic role of MDM proteins is to block p53 transcriptional activity.”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [3] Shibagaki, I. et al. p53 mutation, murine double minute 2 amplification, and human papillomavirus infection are frequently involved but not associated with each other in esophageal squamous cell carcinoma. Clin. Cancer Res. 1, 769–773 (1995).

      Not checked in the free run.

    • cites [4] Forslund, A. et al. MDM2 gene amplification is correlated to tumor progression but not to the presence of SNP309 or TP53 mutational status in primary colorectal cancers. Mol. Cancer Res. 6, 205–211 (2008). source

      Not checked in the free run.

    • cites [5] Ito, M. et al. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008). source

      Not checked in the free run.

    • cites [6] Lam, S. et al. Role of Mdm4 in drug sensitivity of breast cancer cells. Oncogene 29, 2415–2426 (2010). source

      Not checked in the free run.

    • cites [7] Mejia-Guerrero, S. et al. Characterization of the 12q15 MDM2 and 12q13-14 CDK4 amplicons and clinical correlations in osteosarcoma. Genes Chromosomes Cancer 49, 518–525 (2010). source

      Not checked in the free run.

    • cites [8] Ito, M. et al. Comprehensive mapping of p53 pathway alterations reveals an apparent role for both SNP309 and MDM2 amplification in sarcomagenesis. Clin. Cancer Res. 17, 416–426 (2011). source

      Not checked in the free run.

    • cites [9] Gilkes, D. M. et al. Regulation of MDMX expression by mitogenic signaling. Mol. Cell. Biol. 28, 1999–2010 (2008). source

      Not checked in the free run.

    • cites [10] Gembarska, A. et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nature Med. 18, 1239–1247 (2012). The first report showing that MDMX is associated with aggressive melanoma in vivo and can be targeted with a dual MDM2 and MDMX inhibitor peptide. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Amplification of MDM genes or altered expression of MDM proteins is a feature of many tumours.

    “Amplification of MDM genes or altered expression of MDM proteins is a feature of many tumours3–10 (Table 1).”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [3] Shibagaki, I. et al. p53 mutation, murine double minute 2 amplification, and human papillomavirus infection are frequently involved but not associated with each other in esophageal squamous cell carcinoma. Clin. Cancer Res. 1, 769–773 (1995).

      Not checked in the free run.

    • cites [4] Forslund, A. et al. MDM2 gene amplification is correlated to tumor progression but not to the presence of SNP309 or TP53 mutational status in primary colorectal cancers. Mol. Cancer Res. 6, 205–211 (2008). source

      Not checked in the free run.

    • cites [5] Ito, M. et al. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008). source

      Not checked in the free run.

    • cites [6] Lam, S. et al. Role of Mdm4 in drug sensitivity of breast cancer cells. Oncogene 29, 2415–2426 (2010). source

      Not checked in the free run.

    • cites [7] Mejia-Guerrero, S. et al. Characterization of the 12q15 MDM2 and 12q13-14 CDK4 amplicons and clinical correlations in osteosarcoma. Genes Chromosomes Cancer 49, 518–525 (2010). source

      Not checked in the free run.

    • cites [8] Ito, M. et al. Comprehensive mapping of p53 pathway alterations reveals an apparent role for both SNP309 and MDM2 amplification in sarcomagenesis. Clin. Cancer Res. 17, 416–426 (2011). source

      Not checked in the free run.

    • cites [9] Gilkes, D. M. et al. Regulation of MDMX expression by mitogenic signaling. Mol. Cell. Biol. 28, 1999–2010 (2008). source

      Not checked in the free run.

    • cites [10] Gembarska, A. et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nature Med. 18, 1239–1247 (2012). The first report showing that MDMX is associated with aggressive melanoma in vivo and can be targeted with a dual MDM2 and MDMX inhibitor peptide. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most p53 mutants in human tumours are transactivation-deficient, suggesting that blocking p53-dependent transcription is a crucial event in tumorigenesis.

    “Most p53 mutants in human tumours are transactivation-deficient, suggesting that blocking p53-dependent transcription is a crucial event in tumorigenesis1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Bieging, K. T. & Attardi, L. D. Deconstructing p53 transcriptional networks in tumor suppression. Trends Cell Biol. 22, 97–106 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RAS signalling converges on activation of ETS transcription factors, and overexpression of RAS leads to ETS-dependent upregulation of both MDM2 and MDMX expression.

    “The RAS signalling pathway converges on the activation of ETS transcription factors, and overexpression of RAS leads to ETS-dependent upregulation of both MDM2 and MDMX expression9,25.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Gilkes, D. M. et al. Regulation of MDMX expression by mitogenic signaling. Mol. Cell. Biol. 28, 1999–2010 (2008). source

      Not checked in the free run.

    • cites [25] Ries, S. et al. Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF. Cell 103, 321–330 (2000). source

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  • May combine two claims.

    Premisecitation

    MDMX does not homo-oligomerize and has no intrinsic ubiquitin ligase function, but can increase or decrease MDM2 ubiquitin ligase activity depending on MDMX abundance.

    “By contrast, MDMX does not homo-oligomerize and has no intrinsic ubiquitin ligase function, although it can increase or decrease MDM2 ubiquitin ligase activity depending on MDMX abundance16.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Linares, L. K., Hengstermann, A., Ciechanover, A., Muller, S. & Scheffner, M. HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53. Proc. Natl Acad. Sci. USA 100, 12009–12014 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutation of Ser394 to alanine in mouse MDM2 in vivo removes an ATM phosphorylation site, engenders radioresistance and increases the rate of spontaneous tumorigenesis to that observed in Trp53-hemizygous animals.

    “By contrast, the mutation of Ser394 to alanine (Ser394Ala) in mouse MDM2 in vivo removes an ATM phosphorylation site, engenders radioresistance and increases the rate of spontaneous tumorigenesis to that observed in Trp53-hemizygous animals47.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Gannon, H. S., Woda, B. A. & Jones, S. N. ATM phosphorylation of Mdm2 Ser394 regulates the amplitude and duration of the DNA damage response in mice. Cancer Cell 21, 668–679 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although there was no increase in spontaneous tumour formation in MDMX3SA animals, these mice were more prone to Myc-induced tumorigenesis.

    “Surprisingly, although there was no increase in spontaneous tumour formation in MDMX3SA animals, these mice were more prone to Myc-induced tumorigenesis69 (discussed below).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Park, S. S. et al. Insertion of Myc into Igh accelerates peritoneal plasmacytomas in mice. Cancer Res. 65, 7644–7652 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MDMX can immortalize primary mouse embryonic fibroblasts and accelerate growth of human fibroblasts.

    “MDMX can immortalize primary mouse embryonic fibroblasts and can accelerate the growth of human fibroblasts63,64.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [63] Danovi, D. et al. Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity. Mol. Cell. Biol. 24, 5835–5843 (2004). source

      Not checked in the free run.

    • cites [64] Lenos, K. et al. Oncogenic functions of hMDMX in in vitro transformation of primary human fibroblasts and embryonic retinoblasts. Mol. Cancer 10, 111 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A recent mir-34-knockout mouse model suggests caution; the mir-34 family does not have a substantial effect on p53 tumour suppressor functions in vivo.

    “These studies have revealed that the mir-34 family does not have a substantial effect on p53 tumour suppressor functions in vivo54.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Concepcion, C. P. et al. Intact p53-dependent responses in miR-34-deficient mice. PLoS Genet. 8, e1002797 (2012). This article forces a re-evaluation of the contexts in which miR-34 contributes to the p53 response in vivo. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MDM2 overexpression at supraphysiological levels is toxic to many normal cells, suggesting it may have other cellular targets.

    “This is probably because MDM2 overexpression at supraphysiological levels is toxic to many normal cells, suggesting that it may have other cellular targets61.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Marine, J. C. & Lozano, G. Mdm2-mediated ubiquitylation: p53 and beyond. Cell Death Differ. 17, 93–102 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    KSHV expresses vIRF4, a factor that binds MDM2 and seems to switch its ubiquitin ligase activity to p53 degradation.

    “Kaposi's sarcoma-associated herpes virus (KSHV) expresses vIRF4, a factor that binds MDM2 and that seems to switch its ubiquitin ligase activity to p53 degradation57.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Lee, H. R. et al. Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor 4 targets MDM2 to deregulate the p53 tumor suppressor pathway. J. Virol. 83, 6739–6747 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activated p53 was thought to exclusively upregulate MDM2, but new data reveal p53-dependent increases in MDMX expression under certain conditions.

    “Although activated p53 was thought to exclusively upregulate MDM2, new data have revealed p53-dependent increases in MDMX expression under certain conditions14.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Phillips, A. et al. 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. J. Biol. Chem. 285, 29111–29127 (2010). source

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  • May combine two claims.

    Premisereasoning

    Multiple kinases modify both MDM proteins, and downstream effects cluster into those that inhibit and those that activate p53.

    “Multiple kinases are known to modify both MDM proteins and (perhaps unsurprisingly) the downstream effects cluster into those that inhibit and those that activate p53.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PPM1D can dephosphorylate both MDM2 and MDMX, thereby contributing to its oncogenic function.

    “Indeed, protein phosphatase 1D (PPM1D) can dephosphorylate both MDM2 and MDMX, thereby contributing to its oncogenic function43,44.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [43] Lu, X., Nguyen, T. A., Zhang, X. & Donehower, L. A. The Wip1 phosphatase and Mdm2: cracking the “Wip” on p53 stability. Cell Cycle 7, 164–168 (2008). source

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    • cites [44] Zhang, X. et al. Phosphorylation and degradation of MdmX is inhibited by Wip1 phosphatase in the DNA damage response. Cancer Res. 69, 7960–7968 (2009). source

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  • May combine two claims.

    Premisecitation

    Phosphorylation of MDM2 at Ser166 and Ser186, and of MDMX at Ser367, leads to their stabilization and is associated with p53 inhibition.

    “Phosphorylation of MDM2 at Ser166 and Ser186 (Ref. 32), and of MDMX at Ser367 (Ref. 33), leads to their stabilization, and is associated with p53 inhibition.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] Mayo, L. D. & Donner, D. B. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc. Natl Acad. Sci. USA 98, 11598–11603 (2001). source

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    • cites [33] Lopez-Pajares, V., Kim, M. M. & Yuan, Z. M. Phosphorylation of MDMX mediated by Akt leads to stabilization and induces 14-3-3 binding. J. Biol. Chem. 283, 13707–13713 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Co-expression of MDMX leads to cellular transformation in vitro, and this requires the p53-binding domain of MDMX.

    “However, co-expression of MDMX leads to cellular transformation in vitro63,64,70. Importantly, this requires the p53-binding domain of MDMX, suggesting that p53-inhibitory activity of MDMX is crucial for transformation63.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [63] Danovi, D. et al. Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity. Mol. Cell. Biol. 24, 5835–5843 (2004). source

      Not checked in the free run.

    • cites [64] Lenos, K. et al. Oncogenic functions of hMDMX in in vitro transformation of primary human fibroblasts and embryonic retinoblasts. Mol. Cancer 10, 111 (2011). source

      Not checked in the free run.

    • cites [70] Miller, K. R., Kelley, K., Tuttle, R. & Berberich, S. J. HdmX overexpression inhibits oncogene induced cellular senescence. Cell Cycle 9, 3376–3382 (2010).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Following genotoxic stress, DNA-PK phosphorylates Ser17 of MDM2 and ABL phosphorylates Tyr99 of MDMX, leading to dissociation of p53 from its negative regulators.

    “Following genotoxic stress, DNA-dependent protein kinase (DNA-PK) phosphorylates Ser17 of MDM2 (Ref. 35), and ABL (also known as ABL1) phosphorylates Tyr99 of MDMX36. In each case, this leads to the dissociation of p53 from its negative regulators.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] Mayo, L. D., Turchi, J. J. & Berberich, S. J. Mdm-2 phosphorylation by DNA-dependent protein kinase prevents interaction with p53. Cancer Res. 57, 5013–5016 (1997).

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    • cites [36] Zuckerman, V. et al. c-Abl phosphorylates Hdmx and regulates its interaction with p53. J. Biol. Chem. 284, 4031–4039 (2009). source

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  • May combine two claims.

    Premisecitation

    MDM2 ubiquitylates p53 and leads to its proteasomal degradation, keeping p53 levels and activity low in unstressed cells.

    “On binding, MDM2 ubiquitylates p53 and leads to its proteasomal degradation; this keeps p53 levels and activity low in unstressed cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Fang, S., Jensen, J. P., Ludwig, R. L., Vousden, K. H. & Weissman, A. M. Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J. Biol. Chem. 275, 8945–8951 (2000). This paper revealed that MDM2 controls the stability of both itself and p53, and that the RING domain was required for these functions. source

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  • May combine two claims.

    Premisecitation

    A more recent mouse model used a knock-in of a human tumour-associated MDM2 SNP at the endogenous Mdm2 locus, and data confirm that a subtle increase in MDM2 levels engenders tumorigenesis at a rate similar to Trp53-hemizygous animals.

    “However, a more recent mouse model used a knock-in of a human tumour-associated MDM2 SNP at the endogenous Mdm2 locus. Data from this model confirm that a subtle increase in MDM2 levels engenders tumorigenesis at a rate that is similar to that observed in Trp53-hemizygous animals67.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Post, S. M. et al. A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development. Cancer Cell 18, 220–230 (2010). In vivo evidence that an MDM2 SNP is associated with increased cancer incidence in women is causally associated with tumorigenesis. source

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  • May combine two claims.

    Interpretationreasoning

    Differences in transgene introduction strategies and mouse genetic backgrounds may contribute to disparate results, underscoring that the context in which MDMX is overexpressed is probably a major determinant of its oncogenic activity.

    “Differences in transgene introduction strategies and mouse genetic backgrounds may contribute to these disparate results, which underscores the idea that the context in which MDMX is overexpressed is probably a major determinant of its oncogenic activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In Mdm2+/− and Mdmx+/− heterozygous mice, the threshold for p53 activation in response to MYC is lowered, resulting in lower rates of MYC-induced lymphoma.

    “In Mdm2+/−- and Mdmx+/−-heterozygous mice, the threshold for p53 activation in response to MYC is lowered, resulting in lower rates of MYC-induced lymphoma26,27.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] Alt, J. R., Greiner, T. C., Cleveland, J. L. & Eischen, C. M. Mdm2 haplo-insufficiency profoundly inhibits Myc-induced lymphomagenesis. EMBO J. 22, 1442–1450 (2003). source

      Not checked in the free run.

    • cites [27] Terzian, T. et al. Haploinsufficiency of Mdm2 and Mdm4 in tumorigenesis and development. Mol. Cell. Biol. 27, 5479–5485 (2007). source

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  • May combine two claims.

    Interpretationreasoning

    MDM2 and MDMX have oncogenic properties in vitro, but this is only manifest in the context of other oncogenic lesions.

    “MDM2 and MDMX have oncogenic properties in vitro, but this is only manifest in the context of other oncogenic lesions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Although RG7112 treatment generally correlated with increased p53 and p21 levels, and decreased proliferation, the data did not reach significance.

    “Interestingly, although RG7112 treatment generally correlated with increased p53 and p21 levels, and decreased proliferation, the data did not reach significance.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Ray-Coquard, I. et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol. 13, 1133–1140 (2012). source

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    Premisecitation

    siRNA therapy is still hampered by delivery and cellular uptake issues, making this approach currently unrealistic.

    “Unfortunately, siRNA therapy is still hampered by delivery and cellular uptake issues87, making this approach currently unrealistic.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Kole, R., Krainer, A. R. & Altman, S. RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nature Rev. Drug Discov. 11, 125–140 (2012). source

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  • May combine two claims.

    Premisereasoning

    Exposing cells to these ligase inhibitors increased p53 and MDM2 levels and then activated p53.

    “Treating cells with these compounds stabilized p53 and MDM2 and subsequently led to p53 activation.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Mouse models clearly demonstrate that inactivation of p53 promotes tumorigenesis, whereas restoration of p53 causes regression of established tumours.

    “Mouse models clearly demonstrate that the inactivation of p53 promotes tumorigenesis, whereas restoration of p53 causes the regression of established tumours78–80.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [78] Martins, C. P., Brown-Swigart, L. & Evan, G. I. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 127, 1323–1334 (2006). source

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    • cites [79] Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo. Nature 445, 661–665 (2007). source

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    • cites [80] Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007). source

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  • May combine two claims.

    Premisecitation

    Nutlin 3a and MI-219 robustly activate p53 in cancer cells with overexpressed MDM2, but do not consistently elicit p53-dependent effects in cancer cells that overexpress MDMX.

    “Although nutlin 3a and MI-219 robustly activate p53 in cancer cells with overexpressed MDM2, they do not consistently elicit p53-dependent effects in cancer cells that overexpress MDMX99–102.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [99] Patton, J. T. et al. Levels of HdmX expression dictate the sensitivity of normal and transformed cells to Nutlin-3. Cancer Res. 66, 3169–3176 (2006). source

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    • cites [100] Wade, M., Rodewald, L. W., Espinosa, J. M. & Wahl, G. M. BH3 activation blocks Hdmx suppression of apoptosis and cooperates with Nutlin to induce cell death. Cell Cycle 7, 1973–1982 (2008). source

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    • cites [101] Hu, B., Gilkes, D. M., Farooqi, B., Sebti, S. M. & Chen, J. MDMX overexpression prevents p53 activation by the MDM2 inhibitor Nutlin. J. Biol. Chem. 281, 33030–33035 (2006). source

      Not checked in the free run.

    • cites [102] Wade, M., Wong, E. T., Tang, M., Stommel, J. M. & Wahl, G. M. Hdmx modulates the outcome of p53 activation in human tumor cells. J. Biol. Chem. 281, 33036–33044 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of the PTEN tumour suppressor leads to activation of the AKT kinases and increases the level of MDM2.

    “Loss of the PTEN tumour suppressor leads to the activation of the AKT kinases and increases the level of MDM2 (Ref. 74).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Mayo, L. D., Dixon, J. E., Durden, D. L., Tonks, N. K. & Donner, D. B. PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J. Biol. Chem. 277, 5484–5489 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Following melanocyte-specific expression of MDMX and RAS, the time to onset of melanomas was reduced and the tumours that developed were more aggressive.

    “Following melanocyte-specific expression of MDMX and RAS, the time to onset of melanomas was reduced and the tumours that developed were more aggressive10.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Gembarska, A. et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nature Med. 18, 1239–1247 (2012). The first report showing that MDMX is associated with aggressive melanoma in vivo and can be targeted with a dual MDM2 and MDMX inhibitor peptide. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p53 pathway reactivation resulted in at least one adverse event in each patient, the most frequent being related to haematological toxicities.

    “Notably, p53 pathway reactivation resulted in at least one adverse event in each patient, the most frequent being related to haematological toxicities.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Ray-Coquard, I. et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol. 13, 1133–1140 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mouse genetic models strongly suggest that MDM2 and MDMX are the two major p53 antagonists in vivo and that they exert non-overlapping inhibitory activities towards p53.

    “Mouse genetic models strongly suggest that MDM2 and MDMX are the two major p53 antagonists in vivo107,108 and that they exert non-overlapping inhibitory activities towards p53 (Refs 24,109).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [107] Montes de Oca Luna, R., Wagner, D. S. & Lozano, G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378, 203–206 (1995). source

      Not checked in the free run.

    • cites [108] Parant, J. et al. Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53. Nature Genet. 29, 92–95 (2001). References 107 and 108 demonstrate that deletions of Mdm2 and Mdmx cause embryonic lethality that can be rescued by Trp53 deletion, thus providing genetic evidence that MDM2 and MDM4 are crucial p53 repressors with non-overlapping functions. source

      Not checked in the free run.

    • cites [24] Francoz, S. et al. Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo. Proc. Natl Acad. Sci. USA 103, 3232–3237 (2006). source

      Not checked in the free run.

    • cites [109] Xiong, S., Van Pelt, C. S., Elizondo-Fraire, A. C., Liu, G. & Lozano, G. Synergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development. Proc. Natl Acad. Sci. USA 103, 3226–3231 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The data indicate that RG7112 reaches its target in a solid tumour, and increases the level of MIC1/GDF15, a secreted protein product of a p53 target gene.

    “However, the data indicate that RG7112 reaches its target in a solid tumour, and increases the level of macrophage inhibitory cytokine 1 (MIC1; also known as GDF15), which is a secreted protein product of a p53 target gene.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Ray-Coquard, I. et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol. 13, 1133–1140 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These data indicate that wild-type p53 is a valid therapeutic target, and that reactivation of p53 via selective targeting of either MDM2 or MDMX is a viable strategy for cancer therapy.

    “These data indicate that wild-type p53 is a valid therapeutic target, and that reactivation of p53 via selective targeting of either MDM2 or MDMX is a viable strategy for cancer therapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Subtle structural differences in the MDMX N-terminal p53-binding pocket dramatically reduce the binding affinity of both nutlin 3a and MI-219 for MDMX; nutlin 3a is 500-fold less potent against MDMX compared with MDM2.

    “However, subtle structural differences in the MDMX N-terminal p53-binding pocket dramatically reduce the binding affinity of both nutlin 3a and MI-219 for MDMX; this is supported by in vitro binding studies showing that nutlin 3a is 500-fold less potent against MDMX compared with MDM2 (Ref. 103).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Graves, B. et al. Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization. Proc. Natl Acad. Sci. USA 109, 11788–11793 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    SAH-p53-8 is far less efficient at disrupting the p53-MDM2 interaction in cells and it requires nutlin 3a for optimal activity in cells that overexpress both MDM2 and MDMX.

    “However, SAH-p53-8 is far less efficient at disrupting the p53–MDM2 interaction in cells and it requires nutlin 3a for optimal activity in cells that overexpress both MDM2 and MDMX.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Although AKT has multiple downstream targets in addition to MDM2, tumour cells with activated AKT pathways are sensitive to MDM2 antagonists.

    “Although AKT has multiple downstream targets in addition to MDM2, tumour cells with activated AKT pathways are sensitive to MDM2 antagonists75,76.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [75] Cipriano, R., Patton, J. T., Mayo, L. D. & Jackson, M. W. Inactivation of p53 signaling by p73 or PTEN ablation results in a transformed phenotype that remains susceptible to Nutlin-3 mediated apoptosis. Cell Cycle 9, 1373–1379 (2010). source

      Not checked in the free run.

    • cites [76] Tabe, Y. et al. MDM2 antagonist nutlin-3 displays antiproliferative and proapoptotic activity in mantle cell lymphoma. Clin. Cancer Res. 15, 933–942 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Co-treatment of cancer cells with 17-AAG to downregulate MDMX and nutlin 3a to antagonize the MDM2-p53 interaction yielded synergistic cytotoxic effects, probably owing to enhanced p53 activation.

    “Co-treatment of such cancer cells with 17-AAG to downregulate MDMX, and nutlin 3a to antagonize the MDM2–p53 interaction, yielded synergistic cytotoxic effects, probably owing to enhanced p53 activation92.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Vaseva, A. V., Yallowitz, A. R., Marchenko, N. D., Xu, S. & Moll, U. M. Blockade of Hsp90 by 17AAG antagonizes MDMX and synergizes with Nutlin to induce p53-mediated apoptosis in solid tumors. Cell Death Dis. 2, e156 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The small molecule SJ-172550 was identified as an MDMX-p53-selective antagonist, but subsequent analyses showed that it forms covalent adducts with cysteine residues in the p53-binding domain of both MDM2 and MDMX.

    “The small molecule SJ-172550 was identified as an MDMX–p53-selective antagonist105 that exhibited additive cytotoxicity with nutlin 3a in MDMX-amplified retinoblastoma cells. However, subsequent analyses showed that SJ-172550 forms covalent adducts with cysteine residues in the p53-binding domain of both MDM2 and MDMX.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [105] Reed, D. et al. Identification and characterization of the first small molecule inhibitor of MDMX. J. Biol. Chem. 285, 10786–10796 (2010). source

      Not checked in the free run.

    • cites [106] Bista, M. et al. On the mechanism of action of SJ-172550 in inhibiting the interaction of MDM4 and p53. PLoS ONE 7, e37518 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Retinoblastomas retain wild-type TP53 and may therefore benefit from treatment with MDM2 and/or MDMX antagonists.

    “This is important from a clinical perspective because retinoblastomas retain wild-type TP53 and may therefore benefit from treatment with MDM2 and/or MDMX antagonists.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    RG7112, a derivative of nutlin 3a with better potency and pharmacological properties, is in Phase I clinical trials.

    “RG7112 (also known as RO5045337), a derivative of nutlin 3a with better potency and pharmacological properties, is in Phase I clinical trials”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    SAH-p53-8 is effective at high concentrations in a mouse model of melanoma in which MDMX is overexpressed, increasing cytotoxicity and sensitizing melanomas to cisplatin and vemurafenib.

    “Despite these issues, it is noteworthy that SAH-p53-8 is effective at high concentrations in a mouse model of melanoma in which MDMX is overexpressed10. In this model, SAH-p53-8 treatment increased cytotoxicity and sensitized melanomas to the chemotherapeutic agent cisplatin and the BRAF-V600E inhibitor vemurafenib (also known as PLX4032).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Gembarska, A. et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nature Med. 18, 1239–1247 (2012). The first report showing that MDMX is associated with aggressive melanoma in vivo and can be targeted with a dual MDM2 and MDMX inhibitor peptide. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Around 22 million cancer patients have defects in p53 signalling.

    “Around 22 million cancer patients have defects in p53 signalling77.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Brown, C. J., Lain, S., Verma, C. S., Fersht, A. R. & Lane, D. P. Awakening guardian angels: drugging the p53 pathway. Nature Rev. Cancer 9, 862–873 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A benzofuroxan derivative (NSC207895) selectively inhibits MDMX expression, downregulates MDMX levels and causes p53-dependent transactivation of proapoptotic genes in several cancer cell lines.

    “A benzofuroxan derivative (NSC207895) that selectively inhibits MDMX expression has been identified88. This molecule downregulates MDMX levels and causes p53-dependent transactivation of proapoptotic genes in several cancer cell lines.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Wang, H., Ma, X., Ren, S., Buolamwini, J. K. & Yan, C. A small-molecule inhibitor of MDMX activates p53 and induces apoptosis. Mol. Cancer Ther. 10, 69–79 (2011). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    As MDMX3SA mice have an attenuated response to DNA damage, and because MYC is known to induce genotoxic stress, disruption of the MYC-DNA damage-MDMX circuit might contribute to increased tumorigenesis in MDMX3SA mice.

    “As MDMX3SA mice have an attenuated response to DNA damage, and because MYC is known to induce genotoxic stress, disruption of the MYC–DNA damage–MDMX circuit might contribute to increased tumorigenesis in MDMX3SA mice.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Using only MDM gene amplification to choose patients for MDM2- and MDMX-targeted trials is insufficient.

    “A reliance simply on MDM gene amplification is inadequate.”
    Quote in the paperSubstantial claim
45 of 45

  • The paper relies on this without support.

    p53 is mutated or functionally inactivated in most human cancers.

    “Thirty years of research have shown that the tumour suppressor p53 has a crucial role in many physiological processes, and that it is mutated or functionally inactivated in most human cancers.”

  • The paper relies on this without support.

    In a substantial proportion of cancers, TP53 is wild type but the p53 protein is inactivated.

    “In a substantial proportion of cancers TP53 (which encodes p53) is wild type but the protein is inactivated; this offers an attractive strategy for cancer therapy based on p53 reactivation.”

  • The paper relies on this without support.

    Single-agent cancer therapy makes resistance more likely.

    “Conventional single-agent cancer therapy increases the likelihood of resistance.”

  • The paper relies on this without support.

    The PI3K–AKT pathway generally promotes cancer cell survival by opposing apoptosis.

    “The PI3K–AKT pathway usually has an anti-apoptotic role to promote cancer cell survival.”

  • The paper relies on this without support.

    Resistance to MDM2 antagonists can result from several mechanisms, such as p53 mutation, dominant survival pathways, or blocked death pathways.

    “Insensitivity to MDM2 antagonists can arise from a variety of mechanisms, including p53 mutation, the presence of dominant survival pathways or the inhibition of death-inducing pathways.”

  • The paper relies on this without support.

    ATM kinase activates p53 after DNA damage.

    “ATM kinase activates p53 in response to DNA damage.”

  • The paper relies on this without support.

    The intracellular E2 enzymes needed for p53 ubiquitylation in vivo remain unidentified.

    “the intracellular E2s that are required for p53 ubiquitylation have not been identified.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • MDM2 encodes a nuclear-localized E3 ubiquitin ligase that mediates the degradation of p53 and RB1 in a proteasome-dependent and ubiquitin-independent manner.

    “MDM2 encodes a nuclear-localized E3 ubiquitin ligase that mediates the degradation of p53 and RB162 in a proteasome-dependent and ubiquitin-independent manner64.”

    From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [62]

    The core pathway section says MDM2 is an E3 ubiquitin ligase and leads to proteasomal degradation of p53, but it explicitly says MDM2 first ubiquitylates p53—the opposite of the claimed ubiquitin-independent mechanism. The passages found do not establish the asserted degradation of RB1. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • MDM2 and UIMC1 are highly expressed in the testis and have been implicated in cancer.

    “Both genes are highly expressed in the testis (http://www.gtexportal.org/) and have been implicated in cancer62, 63.”

    From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [62]

  • Mdm2 is an E3 ubiquitin ligase and a negative regulator of p53 that is frequently overexpressed in human malignancies.

    “The E3 ubiquitin ligase Mdm2, a negative regulator of the p53 tumor suppressor, is frequently overexpressed in many human malignancies.1–3”

    From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [3]

  • Mdmx is overexpressed in many human malignancies and, together with Mdm2, negatively regulates the p53 tumor suppressor.

    “The oncogene Mdmx is overexpressed in many human malignancies, and together with Mdm2, negatively regulates the p53 tumor suppressor.”

    From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [3]

  • Human tumors with MDMX overexpression may also have inactivated p53, indicating a potential oncogenic benefit from Mdmx overexpression in addition to p53 inhibition.

    “Moreover, human tumors with MDMX overexpression may also have inactivated p53,3,19,30,31 which indicates a potential oncogenic benefit to the cancer cells from Mdmx overexpression in addition to its inhibition of p53.”

    From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [3]

Cites

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Related

Authors
Wade, M., Li, Y.-C., & Wahl, G. M.
Affiliations
  • Center for Genomic Science (IT)
  • Salk Institute for Biological Studies (US)
Corresponding author
Wahl, Geoffrey M.
ORCID
Venue
Nature Reviews Cancer
Publisher
Springer Science and Business Media LLC
Published
2013-01-10
Volume
13
Issue
2
Pages
83-96
ISSN
  • 1474-175X (ISSN-L)
  • 1474-1768
DOI
10.1038/nrc3430
PMC
PMC4161369
OpenAlex
W1976295398
Semantic Scholar
934adde696496e55f90e9c60fcd0c09e3d18b3cb
Cited by
1,279
References
174
Citations by year
2026: 76 · 2025: 81 · 2024: 73 · 2023: 83 · 2022: 92 · 2021: 104 · 2020: 109 · 2019: 117 · 2018: 89 · 2017: 98 · 2016: 100 · 2015: 90 · 2014: 118 · 2013: 49
FWCI
12.77
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature reviews. Cancer (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Sanofi
  • National Institutes of Health
  • National Institute of Mental Health (R03MH089489, R03‑MH089489‑01)
  • National Cancer Institute (CA014195, R01CA061449, R01‑CA61449, P30CA014195)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
MDM2, MDMX, p53, p53 reactivation, MDM2 inhibitors, HDMX, MDM4, carcinogenesis, cancer therapy, signaling networks, tissue homeostasis, anticancer agents
MeSH terms
Animals, Cell Transformation, Neoplastic, Humans, Neoplasms, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-mdm2

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

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