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Cited by 450Cancer-related Molecular PathwaysHeat shock proteins researchCell death mechanisms and regulation

The p53 orchestra: Mdm2 and Mdmx set the tone

Open access
Wade, Mark, Wang, Yunyuan V., Wahl, Geoffrey M.·2010·Trends in Cell Biology
DOI 10.1016/j.tcb.2010.01.009PMC PMC2910097
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Abstract

The activities of p53 cover diverse aspects of cell biology, including cell cycle control, apoptosis, metabolism, fertility, differentiation and cellular reprogramming. Although loss of p53 function engenders tumor susceptibility, hyperactivation of p53 is lethal. Therefore, p53 activity must be strictly regulated to maintain normal tissue homeostasis. Critical for the control of p53 function are its two main negative regulators: Mdm2 and Mdmx. Recent reports have provided insight into the complex mechanisms that regulate these two proteins and have revealed novel functions for each. Here, we review and evaluate models of Mdm2- and Mdmx-dependent regulation of p53 activity. Both Mdm2 and Mdmx receive input from numerous signaling pathways and interact with many proteins in addition to p53. Therefore, we also consider roles for Mdm2 and Mdmx in additional cancer-related networks, including Notch signaling and the epithelial-to-mesenchymal transition.

AI snapshot

Written from the paper’s full text.

TL;DR

This review evaluates how Mdm2 and Mdmx negatively regulate p53 through complex post-translational mechanisms and stoichiometric control, and it considers additional cancer-related roles for these proteins. It argues that Mdm2 and Mdmx are critical nodes integrating stress and growth signals into p53 activity.

Key findings

  • Mdm2 and Mdmx are critical negative regulators of p53: deletion of either gene is lethal in a p53-dependent manner, while p53 is mutated in ~50% of human cancers and functionally inactivated in many more.
  • Mdm2 has intrinsic E3 ubiquitin ligase activity via its RING domain, whereas Mdmx shows little intrinsic ubiquitin ligase activity toward p53; the Mdm2–Mdmx hetero-oligomer is a more effective ligase for p53 in vitro than Mdm2 alone.
  • DNA damage–induced phosphorylation of Mdm2 and Mdmx promotes their degradation/destabilization and p53 stabilization; Mdmx3SA mice show an approximately 50% reduction in basal p53 activity, are remarkably radio-resistant, and are predisposed to c-Myc-induced tumorigenesis.
  • Stoichiometry is crucial: a two-fold increase in Mdm2 expression due to a polymorphism reduces p53 activation and significantly increases risk and decreases age of onset for hormone-dependent breast cancer in women.

Methods

  • This is a review article; the authors state they “review and evaluate models of Mdm2- and Mdmx-dependent regulation of p53 activity.”
  • The paper synthesizes genetic, biochemical, structural, mouse-model, and clinical studies rather than reporting primary experimental data, sample, or statistical analysis.
  • No primary data or main analysis are reported in the paper.

Limitations

  • The authors state that the field lacks a complete understanding of the modification status and composition of Mdm2–Mdmx hetero-oligomers, and they highlight the unresolved question of how phosphorylation prevents Mdm2 self-oligomerization while permitting oligomerization with Mdmx.
  • The authors state that there are no published data addressing deletion of Mdmx in adult thymus or spleen to compare with Mdm2 knockout in these tissues, so a direct comparison of functional redundancy between Mdm2 and Mdmx cannot be made and the generality of the co-operation model remains to be determined.
  • The text makes evident that many conclusions rely on in vitro studies and mouse models, and the authors note technical challenges in identifying bona fide E2/E3 pairs and determining which ubiquitin-like modifications are physiologically relevant.

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

Integrity signals

Registry

Crossref · 10.1016/j.tcb.2010.01.009

Cites

129 of 129 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 187 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Mdm2 mediates diverse non-ubiquitin modifications of p53.

    “There is also evidence to suggest that Mdm2 mediates diverse non-ubiquitin modifications of p53 (Box 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Box 2

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  • Premisecitation

    The C termini of both Mdm2 and Mdmx contain a RING domain of the C2H2C4 type.

    “The C termini of both Mdm2 and Mdmx contain a RING (really interesting new gene) domain of the ‘rare’ C2H2C4 type [8].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Kostic, 2006, Solution structure of the Hdm2 C2H2C4 RING, a domain critical for ubiquitination of p53, J. Mol. Biol. source

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  • Premisecitation

    Mdm2 can transcriptionally inactivate some p53 target genes by direct ubiquitylation of histones.

    “For example, Mdm2 can transcriptionally inactivate some p53 target genes by direct ubiquitylation of histones [109].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Minsky, 2004, The RING domain of Mdm2 mediates histone ubiquitylation and transcriptional repression, Mol. Cell source

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  • Premisecitation

    Mono-ubiquitination of p53 can facilitate export of p53 from the nucleus to the cytoplasm, thereby inhibiting its role as a transcription factor.

    “Additionally, mono-ubiquitination of p53 can facilitate export of p53 from the nucleus to the cytoplasm, thereby inhibiting its role as a transcription factor [110,111].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [110] Carter, 2007, C-terminal modifications regulate MDM2 dissociation and nuclear export of p53, Nat. Cell Biol. source

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    • cites [111] Li, 2003, Mono- Versus Polyubiquitination: Differential Control of p53 Fate by Mdm2, Science source

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  • Premisecitation

    Mdm2 facilitates polyubiquitylation and proteasome-dependent degradation of p53.

    “Consistent with this, Mdm2 facilitates the polyubiquitylation and proteasome-dependent degradation of p53 [11].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Brooks, 2006, p53 ubiquitination: Mdm2 and beyond, Mol. Cell source

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  • May combine two claims. 55
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Premisecitation

    Under certain conditions, Mdm2 can promote monoubiquitylation of p53; this does not directly cause p53 degradation but can induce changes in Mdm2 localization and function.

    “Under certain conditions, Mdm2 can also promote monoubiquitylation of p53; this does not directly cause p53 degradation, but can induce changes in Mdm2 localization and function (Box 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Box 1

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  • May combine two claims.

    Premisecitation

    p53 function is inhibited by Mdm2-dependent degradation, which occurs in both the nucleus and cytoplasm, perhaps linked to nuclear export.

    “p53 function is also inhibited by Mdm2 dependent degradation (see below), which occurs in both the nucleus and cytoplasm, perhaps linked to nuclear export [5].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Moll, 2003, The MDM2-p53 interaction, Mol. Cancer Res.

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  • May combine two claims.

    Premisecitation

    Mdm2-dependent mono-ubiquitination induces translocation of p53 to the mitochondria, where it can activate transcription-independent apoptosis.

    “Consistent with this, recent data suggest that Mdm2-dependent mono-ubiquitination induces translocation of p53 to the mitochondria [113], where it can activate transcription-independent apoptosis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Marchenko, 2007, Monoubiquitylation promotes mitochondrial p53 translocation, EMBO J. source

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  • May combine two claims.

    Premisecitation

    Over-expression of either Mdm2 or Mdmx inactivates p53 and is oncogenic, as shown by their frequently elevated levels in human cancers expressing wild-type p53.

    “Conversely, inactivation of p53 by over-expression of either Mdm2 or Mdmx is oncogenic, as revealed by their frequently elevated levels in human cancers expressing wild type p53 (for a review, see Ref [1]).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ref [1] Marine, 2006, Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4, Cell Death Differ. source

      Not checked in the free run.

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    Premisecitation

    p53 activation can be enhanced by reduced nuclear export and increased nuclear import.

    “Conversely, p53 activation can be enhanced by reduced nuclear export and increased nuclear import [6,7].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Stommel, 1999, A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking, EMBO J. source

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    • cites [7] Marchenko, 2009, Stress-mediated nuclear stabilization of p53 is regulated by ubiquitination and importin-alpha3 binding, Cell Death Differ. source

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  • May combine two claims.

    Premisecitation

    Mdm2 and Mdmx are most abundant in the cytosol in many cell lines, suggesting that cytoplasmic localization is important for their function.

    “However, Mdm2 and Mdmx are most abundant in the cytosol in many cell lines, suggesting cytoplasmic localization is important for their function [3].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Wang, 2007, Quantitative analyses reveal the importance of regulated Hdmx degradation for p53 activation, Proc. Natl. Acad. Sci. U. S. A. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Mdm2 negatively regulates p53 by both suppressing transactivation and promoting post-translational destabilization.

    “Thus, Mdm2 negatively regulates p53 by both suppression of transactivation and post-translational destabilization.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mdm2 and Mdmx are critical negative regulators of p53, and deletion of either gene is lethal in a p53-dependent manner.

    “Mdm2 and Mdmx (for mouse double minute, Mdmx is also known as Mdm4) are critical negative regulators of p53, as revealed by models in which deletion of either gene is lethal in a p53-dependent manner (Table 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 1

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    Premisecitation

    The Mdm2 RING domain has intrinsic E3 ubiquitin ligase activity, promoting transfer of ubiquitin from an E2 enzyme to lysine residues of target substrates.

    “In common with many other RING domain proteins, the Mdm2 RING has intrinsic E3 ubiquitin ligase activity, in that it can promote the transfer of ubiquitin molecules from an E2 conjugating enzyme directly to lysine residues of target substrates (Figure 1 and Ref. [9] for review).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Deshaies, 2009, RING Domain E3 Ubiquitin Ligases, Annual Review of Biochemistry source

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

    Premisecitation

    p53 is a tumor suppressor that is mutated in about half of human cancers and functionally inactivated in many additional cancers.

    “Clinical studies and mouse models have shown that p53 is a tumor suppressor that is mutated in ~50% of human cancers, and functionally inactivated in many more.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mdm2 undergoes auto-degradation and targets Mdmx for degradation, which is critical for optimal p53 activation after stress.

    “However, in addition to degrading p53, Mdm2 also undergoes auto-degradation [12,13] and targets Mdmx for degradation [14–16], which is critical for optimal p53 activation after stress.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [12] Stommel, 2004, Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation, EMBO J. source

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    • cites [13] Fang, 2000, Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53, J. Biol. Chem. source

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    • cites [14] de Graaf, 2003, Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2, J. Biol. Chem. source

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    • cites [15] Kawai, 2003, DNA damage-induced MDMX degradation is mediated by MDM2, J. Biol. Chem. source

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    • cites [16] Pan, 2003, MDM2 promotes ubiquitination and degradation of MDMX, Mol. Cell Biol. source

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  • May combine two claims.

    Premisecitation

    Proteasome-dependent degradation of nuclear p53 can also effectively prevent its transactivation function, suggesting that monoubiquitylation of cytoplasmic p53 is required for other processes.

    “However, proteasome-dependent degradation of nuclear p53 can also effectively prevent its transactivation function [111,112], suggesting monoubiquitylation of cytoplasmic p53 is required for other processes.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [111] Li, 2003, Mono- Versus Polyubiquitination: Differential Control of p53 Fate by Mdm2, Science source

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    • cites [112] Joseph, 2003, Nuclear and cytoplasmic degradation of endogenous p53 and HDM2 occurs during down-regulation of the p53 response after multiple types of DNA damage, Faseb. J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mdm2 promotes translocation of p53 from the nucleus to the cytoplasm, and Mdmx may modulate this process.

    “Interestingly, Mdm2 has been reported to promote translocation of p53 from the nucleus to the cytoplasm, and Mdmx may modulate this process [4].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Ohtsubo, 2009, Cytoplasmic tethering is involved in synergistic inhibition of p53 by Mdmx and Mdm2, Cancer Sci. source

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    Premisecitation

    In Mdmx3SA mice, damage-induced Mdmx degradation is attenuated and p53 stabilization is significantly reduced compared with wild-type mice.

    “When these serines are mutated to alanine in vivo (Mdmx3SA mice), damage-induced Mdmx degradation is attenuated. Furthermore, p53 stabilization is significantly reduced in Mdmx3SA compared with wild type mice [30].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Wang, 2009, Increased Radioresistance and Accelerated B Cell Lymphomas in Mice with Mdmx Mutations that Prevent Modifications by DNA-Damage-Activated Kinases, Cancer Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice in which these lysines are mutated to arginine are viable and have a normal lifespan, although p53 regulation is subtly altered in some cell types.

    “Furthermore, mice in which these lysines are mutated to arginine are viable and have a normal lifespan, although p53 regulation is subtly altered in some cell types [128,129].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [128] Krummel, 2005, The C-terminal lysines fine-tune p53 stress responses in a mouse model, but are not required for stability control or transactivation, Proc. Natl. Acad. Sci. U. S. A. source

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    • cites [129] Feng, 2005, Functional analysis of the roles of posttranslational modifications at the p53C terminus in regulating p53 stability and activity, Mol. Cell Biol. source

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  • May combine two claims.

    Premisecitation

    K386 can also be ubiquitylated and acetylated.

    “For example, K386 can also be ubiquitylated and acetylated [126].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Tang, 2008, Acetylation is indispensable for p53 activation, Cell source

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  • May combine two claims.

    Interpretationreasoning

    The viability of mice with these lysine-to-arginine mutations suggests either that the lysine residues fine-tune the p53 response or that compensatory mechanisms are present in their absence.

    “This suggests that either the lysine residues fine-tune the p53 response or that compensatory mechanisms are present in their absence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Replacing these lysines with arginine leads to increased p53 transcriptional activity in vitro, suggesting that NEDDylation of p53 inhibits its function.

    “Replacing these lysines with arginine leads to increased p53 transcriptional activity in vitro, suggesting that NEDDylation of p53 inhibits its function.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Xirodimas, 2004, Mdm2-Mediated NEDD8 Conjugation of p53 Inhibits Its Transcriptional Activity, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A knock-in mouse Mdm2 mutant with a C462A mutation in the RING domain was embryonic lethal in a p53-dependent manner, providing evidence that the Mdm2 RING domain is required for correct regulation of p53 activity in vivo.

    “Recently, a knock-in mouse Mdm2 mutant was described in which one of the critical cysteines in the Mdm2 RING domain was mutated to alanine (C462A) [31]. The homozygous mutation was embryonic lethal in a p53-dependent manner, providing compelling evidence that the Mdm2 RING domain is required for correct regulation of p53 activity in vivo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Itahana, 2007, Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation, Cancer Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Brca1-Bard1 complex recruits only a subset of E2 enzymes, and only some of these are capable of transferring ubiquitin to target lysines.

    “Moreover, the Brca1–Bard1 complex recruits only a subset of E2 enzymes, and only some of these are actually capable of transferring ubiquitin to target lysines [21].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Christensen, 2007, E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages, Nat. Struct. Mol. Biol. source

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  • May combine two claims.

    Premisecitation

    Arf can stimulate Mdm2-dependent SUMOylation of itself and of p53 at K386, and SUMOylation is associated with relocalization of p53 to subnuclear structures.

    “There is some consensus that Arf can stimulate the Mdm2-dependent SUMOylation of both itself and of p53 at K386 [119,120] and that SUMOylation is associated with relocalization of p53 to subnuclear structures [121,122].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [119] Chen, 2003, MDM2-ARF complex regulates p53 sumoylation, Oncogene source

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    • cites [120] Xirodimas, 2002, P14ARF promotes accumulation of SUMO-1 conjugated (H)Mdm2, FEBS Lett source

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    • cites [121] Di Ventura, 2008, Reconstitution of Mdm2-dependent post-translational modifications of p53 in yeast, PLoS ONE source

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    • cites [122] Mauri, 2008, Modification of Drosophila p53 by SUMO Modulates Its Transactivation and Pro-apoptotic Functions, J. Biol. Chem. source

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  • May combine two claims.

    Premisecitation

    Aromatic residues are conserved in the Mdmx C-terminal tail and can act in trans to reactivate E3 ligase function in Mdm2 C-terminal mutants.

    “Aromatic residues are conserved in the Mdmx C-terminal tail, and can also act in trans to reactivate E3 ligase function in Mdm2 C-terminal mutants [27,28].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Uldrijan, 2007, An essential function of the extreme C-terminus of MDM2 can be provided by MDMX, EMBO J. source

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    • cites [28] Poyurovsky, 2007, The Mdm2 RING domain C-terminus is required for supramolecular assembly and ubiquitin ligase activity, EMBO J. source

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  • May combine two claims.

    Premisecitation

    In Mdmx3SA, Mdm2 remains bound to Mdmx, but degradation of Mdmx is significantly reduced.

    “In Mdmx3SA, Mdm2 remains bound to Mdmx, but degradation of Mdmx is significantly reduced.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Wang, 2009, Increased Radioresistance and Accelerated B Cell Lymphomas in Mice with Mdmx Mutations that Prevent Modifications by DNA-Damage-Activated Kinases, Cancer Cell source

      Not checked in the free run.

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

    Premisecitation

    Brca1 RING domain activity is enhanced via hetero-oligomerization with its non-catalytic partner Bard1.

    “Although the Brca1 RING domain is a different (C3HC4) subtype, functional studies have shown that its activity is enhanced via hetero-oligomerization with its non-catalytic partner, Bard1 [18].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Hashizume, 2001, The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation, J. Biol. Chem. source

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  • May combine two claims.

    Premisecitation

    Mdm2 can homo-oligomerize or hetero-oligomerize with Mdmx via RING/RING interaction, whereas Mdmx alone is monomeric.

    “Although Mdm2 can homo-oligomerizea, or hetero-oligomerize with Mdmx via RING/RING interaction, it appears that Mdmx alone is monomeric [17].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Tanimura, 1999, MDM2 interacts with MDMX through their RING finger domains, FEBS Lett. source

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  • May combine two claims.

    Premisecitation

    Mdm2 promotes conjugation of NEDD8 to itself and to p53.

    “Mdm2 also promotes the conjugation of NEDD8 (another Ubl molecule), to itself and to p53 [124].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Xirodimas, 2004, Mdm2-Mediated NEDD8 Conjugation of p53 Inhibits Its Transcriptional Activity, Cell source

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  • May combine two claims.

    Interpretationreasoning

    Both disruption of Mdm2 oligomers and functional inactivation of Mdm2-Mdmx oligomers via Mdmx degradation contribute to maximal p53 stabilization after stress.

    “Together, these results suggest that both disruption of Mdm2 oligomers, and the functional inactivation of Mdm2–Mdmx oligomers via Mdmx degradation, contribute to maximal p53 stabilization after stress (Figure 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The C462A mutation does not directly test whether Mdm2 and Mdmx co-operate as an E3 ligase complex, because it profoundly alters RING structure and likely prevents Mdmx binding.

    “This is an important finding, but it does not directly test whether Mdm2 and Mdmx co-operate as an E3 ligase complex to regulate p53, because the C462A mutation profoundly alters the structure of the RING domain, most likely rendering it unable to bind to Mdmx.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    HAUSP-dependent stabilization of Mdm2 and Mdmx might enhance degradation of p53 by the Mdm2-Mdmx heterodimer.

    “In addition, HAUSP-dependent stabilization of Mdm2 and Mdmx might enhance degradation of p53 by the Mdm2–Mdmx heterodimer.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Most DUBs, including HAUSP, have additional cellular targets, raising the possibility that DUB inhibition could lead to mechanism-based toxicity in normal tissues.

    “However, most DUBs, including HAUSP, have additional cellular targets, raising the possibility that DUB inhibition could lead to mechanism-based toxicity in normal tissues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mdmx is relatively stable compared with Mdm2 and p53, presumably due to preferential ubiquitylation of the latter proteins.

    “It appears that Mdmx is relatively stable compared with Mdm2 and p53 [41], presumably due to preferential ubiquitylation of the latter proteins.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Pereg, 2005, Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage, Proc. Natl. Acad. Sci. U. S. A. source

      Not checked in the free run.

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

    Premisecitation

    Loss of Mdm2 E3 ubiquitin ligase activity is likely responsible for the C462A phenotype, since the mutant could still bind p53 and block p53-dependent transactivation.

    “The authors concluded that loss of Mdm2 E3 ubiquitin ligase activity is likely responsible for the observed phenotype, since the mutant could still bind to p53 and block p53-dependent transactivation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Itahana, 2007, Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation, Cancer Cell source

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  • May combine two claims.

    Premisecitation

    Reversal of Mdm2 and Mdmx phosphorylation should inhibit p53 function, and studies of the Wip1 phosphatase suggest this is the case.

    “A corollary from the above is that reversal of Mdm2 and Mdmx phosphorylation should inhibit p53 function, and studies of the Wip1 phosphatase suggest this is the case [59,60].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [59] Zhang, 2009, Phosphorylation and Degradation of MdmX Is Inhibited by Wip1 Phosphatase in the DNA Damage Response, Cancer Res. source

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    • cites [60] Lu, 2008, The Wip1 phosphatase and Mdm2: cracking the “Wip” on p53 stability, Cell Cycle source

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

    Premisecitation

    Other ligases are also proposed to target p53 for ubiquitin-dependent proteolysis under certain circumstances.

    “Other ligases are also proposed to target p53 for ubiquitin dependent proteolysis under certain circumstances, as recently reviewed by Lee and Gu [44].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Lee, 2010, The multiple levels of regulation by p53 ubiquitination, Cell Death Differ. source

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  • May combine two claims.

    Premisecitation

    The switch between target substrate ubiquitylation and autoubiquitylation following changes in binding partner might be a general feature of RING E3 ligases, since ligand binding to IAP stimulates IAP auto-destruction.

    “This switch between target substrate ubiquitylation and autoubiquitylation following changes in binding partner might be a general feature of RING E3 ligases, since ligand binding to IAP (a member of the RING E3 inhibitor of apoptosis proteins) stimulates IAP auto-destruction [43].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Varfolomeev, 2007, IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis, Cell source

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  • May combine two claims.

    Premisecitation

    Phosphorylation of Mdm2 and Mdmx at serine residues close to the RING domain by ATM or ATM-dependent kinases leads to accelerated auto-degradation of both Mdm2 and Mdmx, with consequent p53 accumulation and activation.

    “Additionally, phosphorylation of Mdm2 and Mdmx at serine residues close to the RING domain by ATM or ATM-dependent kinases leads to accelerated auto-degradation of both Mdm2 [54] and Mdmx [41,55–58], with consequent p53 accumulation and activation.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [54] Maya, 2001, ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage, Genes Dev. source

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    • cites [41] Pereg, 2005, Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage, Proc. Natl. Acad. Sci. U. S. A. source

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    • cites [55] Chen, 2005, ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage, EMBO J. source

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    • cites [56] LeBron, 2006, Regulation of MDMX nuclear import and degradation by Chk2 and 14-3-3, EMBO J. source

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    • cites [57] Okamoto, 2005, DNA Damage-Induced Phosphorylation of MdmX at Serine 367 Activates p53 by Targeting MdmX for Mdm2-Dependent Degradation, Mol. Cell Biol. source

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    • cites [58] Pereg, 2006, Differential Roles of ATM- and Chk2-Mediated Phosphorylations of Hdmx in Response to DNA Damage, Mol. Cell. Biol. source

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  • May combine two claims.

    Premisecitation

    Usp2a has been reported to deubiquitylate both Mdm2 and Mdmx and lead to p53 destabilization.

    “More recently a second DUB, Usp2a, has been reported to deubiquitylate both Mdm2 and Mdmx [47,48] and lead to p53 destabilization.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [47] Allende-Vega, 2010, MdmX is a substrate for the deubiquitinating enzyme USP2a, Oncogene source

      Not checked in the free run.

    • cites [48] Stevenson, 2007, The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2, EMBO J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Following growth factor stimulation, Akt phosphorylates Mdm2 at Ser166 and Ser186, which increases Mdm2 half-life and stimulates Mdm2-dependent p53 degradation.

    “Following growth factor stimulation, Akt phosphorylates Mdm2 at Ser166 and Ser186 [62], which increases Mdm2 half-life and stimulates Mdm2-dependent p53 degradation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Mayo, 2001, A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus, Proc. Natl. Acad. Sci. U. S. A. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HAUSP is a deubiquitylase that binds to and stabilizes Mdm2 and Mdmx preferentially under normal growth conditions.

    “For example, HAUSP is a deubiquitylase (DUB) that binds to and stabilizes Mdm2 and Mdmx preferentially under normal growth conditions [45,46].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Li, 2004, A dynamic role of HAUSP in the p53-Mdm2 pathway, Mol. Cell source

      Not checked in the free run.

    • cites [46] Meulmeester, 2005, Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2, Mol. Cell source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    A general conclusion from the available data is that Mdm2 loss is almost invariably lethal, whereas Mdmx loss can be tolerated in some cases.

    “A general conclusion from the available data is that Mdm2 loss is almost invariably lethal, whereas Mdmx loss can be tolerated in some cases.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Wip1 can specifically dephosphorylate Mdm2 at Ser395 and Mdmx at Ser403 and indirectly at Ser342 and Ser367, which increases their stability in order to inhibit p53 function.

    “In addition to dephosphorylating p53, Wip1 can specifically dephosphorylate Mdm2 at Ser395 and Mdmx at Ser403 and indirectly at Ser342 and Ser367, which increases their stability in order to inhibit p53 function [59,60].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [59] Zhang, 2009, Phosphorylation and Degradation of MdmX Is Inhibited by Wip1 Phosphatase in the DNA Damage Response, Cancer Res. source

      Not checked in the free run.

    • cites [60] Lu, 2008, The Wip1 phosphatase and Mdm2: cracking the “Wip” on p53 stability, Cell Cycle source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Phosphorylation is an important regulator of E3 ligase function and Mdm2/Mdmx stability.

    “Together with the observation that ATM can inhibit Mdm2 oligomerization and p53 degradation (see above and [29]) these data indicate phosphorylation is an important regulator of E3 ligase function and Mdm2/Mdmx stability [9].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Deshaies, 2009, RING Domain E3 Ubiquitin Ligases, Annual Review of Biochemistry source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Loss of Mdm2 appears to exhibit more profound effects than loss of Mdmx in classically radiosensitive tissues, suggesting that Mdmx cannot compensate for lack of Mdm2.

    “Importantly, loss of Mdm2 appears to exhibit more profound effects than loss of Mdmx (at least in classically radiosensitive tissues), suggesting that Mdmx cannot compensate for lack of Mdm2 (Table 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 1

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Altering how Mdmx is regulated disturbs the balance of the p53 pathway and has strong effects in living animals.

    “Perturbing the stoichiometry of the p53 pathway by altering Mdmx regulation also has profound effects in vivo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Modifications of Mdm2 and Mdmx triggered by damage make these proteins less stable and cause their breakdown, which lowers their capacity to oppose p53.

    “In vitro and in vivo studies show that damage-induced modifications of Mdm2 and Mdmx lead to their destabilization and degradation, reducing their ability to antagonize p53 [49,50].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [49] Marine, 2007, MDMX: from bench to bedside, J. Cell Sci. source

      Not checked in the free run.

    • cites [50] Meek, 2003, Posttranslational Modification of MDM2, Molecular Cancer Research

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CK1-α increases the interaction between Mdmx and p53, which should inactivate p53.

    “By contrast, CK1-α increases the interaction between Mdmx and p53, which should inactivate p53 [67].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Chen, 2005, Regulation of p53-MDMX interaction by casein kinase 1 alpha, Mol. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Akt phosphorylates Mdmx at Ser367, and both DNA damage and Akt-induced Ser367 phosphorylation stimulate binding of Mdmx to 14-3-3 proteins.

    “Interestingly, one of the damage kinase target residues (Ser367) of Mdmx is also phosphorylated by Akt [65]. Furthermore, DNA damage and Akt-induced Ser367 phosphorylation both stimulate binding of Mdmx to 14-3-3 proteins [57,64].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [65] Winter, 2004, Protein kinase CK1delta phosphorylates key sites in the acidic domain of murine double-minute clone 2 protein (MDM2) that regulate p53 turnover, Biochemistry source

      Not checked in the free run.

    • cites [57] Okamoto, 2005, DNA Damage-Induced Phosphorylation of MdmX at Serine 367 Activates p53 by Targeting MdmX for Mdm2-Dependent Degradation, Mol. Cell Biol. source

      Not checked in the free run.

    • cites [64] Lopez-Pajares, 2008, Phosphorylation of MDMX Mediated by Akt Leads to Stabilization and Induces 14-3-3 Binding, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CK1-δ can also phosphorylate Thr18 of p53, which may reduce the affinity of Mdm2 for p53.

    “CK1-δ can also phosphorylate Thr18 of p53, which may reduce the affinity of Mdm2 for p53 [66].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Sakaguchi, 2000, Damage-mediated phosphorylation of human p53 threonine 18 through a cascade mediated by a casein 1-like kinase. Effect on Mdm2 binding, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Modifications caused by damage help activate p53 by shifting the balance of the pathway and changing how tightly Mdm2 and Mdmx bind p53.

    “The increasing ratio between p53 and its negative regulators, concomitant with the onset of p53 transcriptional activity, suggests that damage-induced modifications contribute to p53 activation by changing the stoichiometry of the pathway, and altering the affinity of Mdm2 and Mdmx for p53 [3].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Wang, 2007, Quantitative analyses reveal the importance of regulated Hdmx degradation for p53 activation, Proc. Natl. Acad. Sci. U. S. A. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Biochemical analysis indicates that DNA damage-induced phosphorylation of p53 at Ser15 and Ser20 does not completely prevent Mdm2 binding, and mutation at these phosphorylation sites does not abrogate p53 stabilization after DNA damage in vivo.

    “However, biochemical analysis indicates that these phosphorylation events do not completely prevent Mdm2 binding, and mutation at these phosphorylation sites does not abrogate p53 stabilization after DNA damage in vivo (see [69] for review).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Toledo, 2006, Regulating the p53 pathway: in vitro hypotheses, in vivo veritas, Nat. Rev. Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Numb binds to Mdm2 and inhibits it, which stabilizes p53.

    “Numb was recently reported to bind and inhibit Mdm2, leading to stabilization of p53, which is consistent with reports of a Numb tumor suppressor function [93].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Colaluca, 2008, NUMB controls p53 tumour suppressor activity, Nature source

      Not checked in the free run.

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

    Premisecitation

    Numb acts as a tumor suppressor.

    “Numb was recently reported to bind and inhibit Mdm2, leading to stabilization of p53, which is consistent with reports of a Numb tumor suppressor function [93].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Colaluca, 2008, NUMB controls p53 tumour suppressor activity, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Notch1 and Numb are both thought to take part in controlling Mdm2 activity.

    “For example, Notch1 and its negative regulator Numb are both implicated in the regulation of Mdm2 activity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Women carrying an Mdm2 polymorphism that doubles Mdm2 expression have less p53 activation, which raises their risk of hormone-dependent breast cancer and makes it appear earlier.

    “For example, a two-fold increase in Mdm2 expression due to a polymorphism in the Mdm2 gene reduces p53 activation enough to significantly increase the risk and decrease the age of onset for hormone-dependent breast cancer in women [74,75].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [74] Bond, 2006, MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner, Cancer Res. source

      Not checked in the free run.

    • cites [75] Bond, 2004, A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Mdmx3SA mice show strong resistance to radiation and can survive a dose of ionizing radiation that is normally lethal.

    “This renders the mice remarkably radio-resistant, as they survive an ordinarily lethal dose of ionizing radiation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Wang, 2009, Increased Radioresistance and Accelerated B Cell Lymphomas in Mice with Mdmx Mutations that Prevent Modifications by DNA-Damage-Activated Kinases, Cancer Cell source

      Not checked in the free run.

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

    Premisecitation

    Notch1 functions as an oncogene.

    “This is in agreement with the role of Notch1 as an oncogene.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Beverly, 2005, Suppression of p53 by Notch in lymphomagenesis: implications for initiation and regression, Cancer Res. source

      Not checked in the free run.

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

    Interpretationcitation

    The ability of Mdm2 to lower Slug and raise E-cadherin would presumably make cells less invasive.

    “Furthermore, Mdm2 was recently reported to downregulate Slug and increase E-cadherin in cell culture, which would presumably prevent invasiveness [101].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Wang, 2009, p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug, Nat. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tumor cells with more Slug and less E-cadherin become more invasive, acquire cancer stem-cell-like traits, and resist certain chemotherapy drugs.

    “In tumor cells, upregulation of Slug and decreased E-cadherin promotes invasiveness of tumor cells as well as acquisition of a ‘cancer stem- cell’ like phenotype and resistance to some chemotherapeutic agents [97].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Polyak, 2009, Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits, Nat. Rev. Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cancer is uncommon during the years of peak reproduction and becomes much more common late in life.

    “Finally, it is unlikely that p53 was selected for as a tumor suppressor in humans, as the frequency of cancer onset is low during peak reproductive years, and increases sharply in old age [105].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Aranda-Anzaldo, 2007, Reassessing the role of p53 in cancer and ageing from an evolutionary perspective, Mechanisms of Ageing and Development source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The ubiquitin ligase activity of Mdm2 can also act in ways that do not degrade proteins, and these actions may either suppress or stimulate p53.

    “Adding to the complexity, Mdm2 ubiquitin ligase activity can perform non-degradative functions that either inhibit or activate p53 function (Box 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Box 1

      Not checked in the free run.

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

    Premisecitation

    In cell culture, Mdm2 lowers Slug and raises E-cadherin.

    “Furthermore, Mdm2 was recently reported to downregulate Slug and increase E-cadherin in cell culture, which would presumably prevent invasiveness [101].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Wang, 2009, p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug, Nat. Cell Biol. source

      Not checked in the free run.

61 of 61

  • The paper relies on this without support.

    p53 is a transcription factor that induces expression of many downstream targets in response to intra- and extracellular cues.

    “p53 is a transcription factor that induces expression of numerous downstream targets in response to intra- and extracellular cues.”

  • The paper relies on this without support.

    Mdm2 and Mdmx bind to p53 via an N-terminal hydrophobic pocket, and this domain contains the highest amino acid identity between the two proteins.

    “Both proteins bind to p53 via an N-terminal hydrophobic pocket, and this domain contains the highest identity at the amino acid level.”

  • The paper relies on this without support.

    The Mdm2 and Mdmx p53-binding domains occlude an N-terminal alpha-helix of p53, preventing recruitment of transcriptional co-activators and thereby inhibiting p53 transactivation function.

    “The Mdm2 and Mdmx p53-binding domains occlude an N-terminal alpha-helix of p53. This prevents the recruitment of transcriptional co-activators and thereby inhibits p53 transactivation function.”

  • The paper relies on this without support.

    Mdm2 is itself a p53 target gene.

    “For example, because Mdm2 itself is a p53 target gene, it is involved in attenuation of the p53 response.”

  • The paper relies on this without support.

    Degradation of Mdmx is required for full activation of p53.

    “This is important, because degradation of Mdmx is required for full activation of p53.”

  • The paper relies on this without support.

    In the absence of exogenous stress, there is balanced turnover of Mdm2, Mdmx and p53.

    “In the absence of exogenous stress, there is balanced turnover of Mdm2, Mdmx and p53.”

  • The paper relies on this without support.

    Mdm2 and Mdmx are subjected to phosphorylation at several sites.

    “In addition to ubiquitylation, Mdm2 and Mdmx are also subjected to phosphorylation at several sites.”

  • The paper relies on this without support.

    Two classes of kinases mediate Mdm2 and Mdmx phosphorylations: those activated by DNA damage and those involved in cell growth and survival signals.

    “To date, two classes of kinases are known to mediate Mdm2 and Mdmx phosphorylations: those activated by DNA damage, and others involved in mediation of cell growth and survival signals.”

  • The paper relies on this without support.

    Normal tissue function depends on the presence of both Mdm2 and Mdmx.

    “However, as both Mdm2 and Mdmx are required for normal tissue function, the challenge will be to provide maximal therapeutic benefit with minimal mechanism-based toxicity.”
9 of 9

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Authors
Wade, M., Wang, Y. V., & Wahl, G. M.
Affiliations
Salk Institute for Biological Studies (US)
Corresponding author
Wahl, Geoffrey M.
ORCID
Venue
Trends in Cell Biology
Publisher
Elsevier BV
Published
2010-05
Volume
20
Issue
5
Pages
299-309
ISSN
0962-8924 (ISSN-L)
DOI
10.1016/j.tcb.2010.01.009
PMC
PMC2910097
OpenAlex
W2003971548
Semantic Scholar
f58cb2163cb8f7f7a4ae4ce8b6689e0f7e5b36ce
Cited by
450
References
129
Citations by year
2026: 15 · 2025: 19 · 2024: 15 · 2023: 11 · 2022: 21 · 2021: 22 · 2020: 21 · 2019: 11 · 2018: 17 · 2017: 30 · 2016: 21 · 2015: 23 · 2014: 60 · 2013: 41 · 2012: 48
FWCI
5.75
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Trends in Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (R01CA061449, CA 061449)
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 › Cell death mechanisms and regulation
Keywords
p53, MDM2, MDMX, p53 regulation, cell cycle regulation, apoptosis, Notch signaling, epithelial-mesenchymal transition, cancer susceptibility
MeSH terms
Animals, Humans, Models, Biological, Nuclear Proteins, Phosphorylation, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Tumor Suppressor Protein p53, Cell Cycle Proteins, Proto-Oncogene Proteins c-mdm2, Ubiquitination

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

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