ATM activates p53 by regulating MDM2 oligomerization and E3 processivity
Open accessAbstract
Rapid activation of p53 by ionizing irradiation is a classic DNA damage response mediated by the ATM kinase. However, the major signalling target and mechanism that lead to p53 stabilization are unknown. We show in this report that ATM induces p53 accumulation by phosphorylating the ubiquitin E3 ligase MDM2. Multiple ATM target sites near the MDM2 RING domain function in a redundant manner to provide robust DNA damage signalling. In the absence of DNA damage, the MDM2 RING domain forms oligomers that mediate p53 poly ubiquitination and proteasomal degradation. Phosphorylation by ATM inhibits RING domain oligomerization, specifically suppressing p53 poly ubiquitination. Blocking MDM2 phosphorylation by alanine substitution of all six phosphorylation sites results in constitutive degradation of p53 after DNA damage. These observations show that ATM controls p53 stability by regulating MDM2 RING domain oligomerization and E3 ligase processivity. Promoting or disrupting E3 oligomerization may be a general mechanism by which signalling kinases regulate ubiquitination reactions, and a potential target for therapeutic intervention.
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Written from the paper’s full text.
TL;DR
ATM phosphorylates multiple C-terminal sites on MDM2, inhibiting MDM2 RING-domain oligomerization and thereby blocking p53 polyubiquitination and degradation. This provides a mechanism for rapid p53 stabilization after DNA damage and suggests E3 oligomerization as a regulatory target.
Key findings
- Mass spectrometry identified six MDM2 phosphorylation sites near the RING domain—S386, S395, S407, T419, S425, and S429—with S386 and S429 induced by IR and other DNA-damaging agents; ATM was required for their phosphorylation, and ATM directly phosphorylated S386/S429 in vitro.
- Phospho-mimic MDM2 mutants were partially defective in p53 degradation, while MDM2-6A (all six sites mutated to alanine) increased p53 degradation; MDM2-6A blocked p53 accumulation for up to 8 h after IR and impaired p21 induction, but did not affect MDMX degradation.
- MDM2 phosphorylation specifically reduced p53 polyubiquitination while retaining substantial p53 mono/oligo-ubiquitination; in vitro, MDM2-6D mainly induced p53 mono-ubiquitination, whereas MDM2-6A was more active in p53 polyubiquitination.
- In nonirradiated cells, about 50% of the MDM2 RING domain migrated as oligomers (~200 kDa) and 50% as monomers (~15 kDa); IR inhibited RING oligomerization, and the ATM inhibitor KU55933 restored it. Non-phosphorylated RING bound MDM2 with much higher affinity than phosphorylated RING.
Methods
- Cell-based assays used 293T, SJSA, ATM-deficient Hs235, normal human foreskin fibroblast, H1299, and U2OS cells; MDM2 point mutants were generated by site-directed mutagenesis, and U2OS lines stably expressing MDM2 mutants were selected with G418.
- MDM2 phosphorylation sites were mapped by mass spectrometry after 10 Gy IR and MG132; phospho-specific antibodies, in vitro kinase reactions with FLAG-ATM/Chk1/Chk2, in vivo and in vitro ubiquitination assays, caspase-3 cleavage, and gel filtration chromatography were used.
- Functional consequences were assessed by western blot, immunoprecipitation, autoradiography, densitometry, 3H-thymidine incorporation after 10 Gy IR, and colony formation after 0–7.5 Gy IR over 15 days.
Limitations
- The paper does not state limitations.
- Evident from the text: all experiments are in cultured human cell lines, with no in vivo animal models or primary tumor data.
- Evident from the text: conclusions rely heavily on overexpression and phospho-mimic/alanine MDM2 mutants, and the proposed conformational/steric mechanism in Figure 9 is a model rather than a direct structural demonstration.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
Statistics
Claims the paper makes
0 of 25 cited sources checked · 0 supported · 0 flagged
- Findingown data
Alanine substitution of all six MDM2 phosphorylation sites causes constitutive p53 degradation after DNA damage.
“Blocking MDM2 phosphorylation by alanine substitution of all six phosphorylation sites results in constitutive degradation of p53 after DNA damage.”
Quote in the paperSubstantial claim- Rests on an assumption: Alanine substitution at the six MDM2 phosphorylation sites prevents their phosphorylation.
- Findingown data
S386E and S429D phospho-mimic mutants were partially defective in p53 degradation.
“However, S386E and S429D phospho-mimic mutants were partially defective in p53 degradation (Figure 3A).”
Quote in the paperSubstantial claim- Rests on an assumption: Phosphomimic substitutions with aspartate or glutamate at ATM target sites functionally mimic phosphorylation of MDM2.
- Findingown data
Mass spectrometry identified novel MDM2 phosphorylation sites near the C-terminal RING domain, including S386, T419, S425, and S429, in addition to S395 and S407.
“The results showed that in addition to previously reported S395 and S407 sites, several novel modifications sites were identified near the C-terminal RING domain, including S386, T419, S425, and S429 (Figure 1A).”
Quote in the paperSubstantial claim - Findingown data
The MDM2 phosphorylation mutant blocks p53 stabilization.
“Inhibition of p53 stabilization by MDM2 phosphorylation mutant.”
Quote in the paperSubstantial claim - Findingown data
MDM2 mutants affect long-term survival after IR.
“Regulation of cell cycle and long-term survival after IR by MDM2 mutants.”
Quote in the paperSubstantial claim
- Findingown data
DNA damage prevents oligomerization of the MDM2 RING domain.
“DNA damage inhibits MDM2 RING domain oligomerization.”
Quote in the paperSubstantial claim - Findingown data
Mass spectrometry identified phosphorylation sites on MDM2.
“Diagram shows MDM2 and relative positions of phosphorylation sites (underlined) identified by mass spectrometry.”
Quote in the paperSubstantial claim - Findingown data
After DNA damage, MDM2 is phosphorylated at S386 and S429 in an ATM-dependent manner.
“ATM-dependent phosphorylation of S386 and S429 after DNA damage.”
Quote in the paperSubstantial claim - Findingown data
MDM2 mutants affect cell cycle progression after IR.
“Regulation of cell cycle and long-term survival after IR by MDM2 mutants.”
Quote in the paperSubstantial claim - Findingown data
ATM expression is required for S386 and S429 phosphorylation after IR in Hs235 cells.
“Analysis of MDM2 in ATMdeficient human skin fibroblast Hs235 showed that ATM expression was needed for S386 and S429 phosphorylation after IR (Figure 2B).”
Quote in the paperSubstantial claim - Findingown data
Phosphorylation prevents interaction of the MDM2 RING domain.
“Phosphorylation alters MDM2 mobility and inhibits RING domain interaction.”
Quote in the paperSubstantial claim - Findingown data
The MDM2 RING monomer is hyper-phosphorylated.
“The result indicates that RING monomer is hyper-phosphorylated.”
Quote in the paperSubstantial claim - Findingown data
MDM2 phosphorylation site mutations change p53 degradation.
“Effects of MDM2 phosphorylation site mutation on p53 and MDMX degradation.”
Quote in the paperSubstantial claim - Findingown data
MDM2-6D was defective for p53 degradation.
“A compound MDM2 mutant (MDM2-6D) with aspartic acid substitution on all six phosphorylation sites was also defective for p53 degradation (Figure 3A).”
Quote in the paperSubstantial claim- Rests on an assumption: Phosphomimic substitutions with aspartate or glutamate at ATM target sites functionally mimic phosphorylation of MDM2.
- Findingown data
Phosphorylation changes MDM2 mobility.
“Phosphorylation alters MDM2 mobility and inhibits RING domain interaction.”
Quote in the paperSubstantial claim - Findingown data
MDM2 phosphorylation specifically blocks polyubiquitination of p53.
“Phosphorylation of MDM2 specifically inhibits p53 poly ubiquitination.”
- Also stated in: § Gel filtration chromatography · plain
“MDM2 phosphorylation inhibits poly ubiquitination of p53 in vitro.”
Quote in the paperSubstantial claim - Also stated in: § Gel filtration chromatography · plain
- Findingown data
Antibodies against PS386 and PS429 detected strong induction of MDM2 phosphorylation after gamma IR in SJSA cells overexpressing MDM2.
“Both antibodies detected strong induction of MDM2 phosphorylation after g IR of SJSA cells overexpressing MDM2 because of gene amplification (Figure 1B).”
Quote in the paperSubstantial claim - Findingown data
MDM2-6A significantly increased p53 degradation.
“Interestingly, substitution of all six phosphorylation sites with alanine (MDM2-6A) significantly increased p53 degradation (Figure 3B and C).”
Quote in the paperSubstantial claim- Rests on an assumption: Alanine substitution at the six MDM2 phosphorylation sites prevents their phosphorylation.
- Findingown data
ATM phosphorylates MDM2 at S386 and S429 in vitro.
“In vitro phosphorylation of S386 and S429 by ATM.”
Quote in the paperSubstantial claim - Findingown data
After IR, a subpopulation of MDM2 migrates faster.
“Arrow indicates faster migration of a subpopulation of MDM2.”
Quote in the paperSubstantial claim - Interpretationreasoning
p53 stability is mainly regulated by MDM2.
“Therefore, it seems that p53 stability is mainly regulated by MDM2.”
Quote in the paperSubstantial claim - Interpretationown data
Multiple ATM target sites near the MDM2 RING domain act redundantly to provide robust DNA damage signalling.
“Multiple ATM target sites near the MDM2 RING domain function in a redundant manner to provide robust DNA damage signalling.”
Quote in the paperSubstantial claim- Rests on an assumption: Phosphomimic substitutions with aspartate or glutamate at ATM target sites functionally mimic phosphorylation of MDM2.
- Rests on an assumption: Alanine substitution at the six MDM2 phosphorylation sites prevents their phosphorylation.
- Premisecitation
Mutation of multiple p53 phosphorylation sites including S15 and S20 did not abrogate p53 stabilization after DNA damage in cell culture.
“Mutation of multiple phosphorylation sites including S15 and S20 did not abrogate p53 stabilization after DNA damage in cell culture (Ashcroft et al, 1999;Blattner et al, 1999;Dumaz and Meek, 1999).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
MDMX regulates p53 mainly by forming inactive p53-MDMX complexes.
“it seems to regulate p53 mainly by formation of inactive p53-MDMX complexes (Francoz et al, 2006;Toledo et al, 2006).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationown data
ATM controls p53 stability by regulating MDM2 RING domain oligomerization and E3 ligase processivity.
“These observations show that ATM controls p53 stability by regulating MDM2 RING domain oligomerization and E3 ligase processivity.”
Quote in the paperSubstantial claim- Rests on an assumption: Phosphomimic substitutions with aspartate or glutamate at ATM target sites functionally mimic phosphorylation of MDM2.
- Rests on an assumption: The MDM2 RING domain oligomers observed in vitro correspond to the functional E3 complex that mediates p53 polyubiquitination in cells.
- Premisecitation
DNA double-strand breaks induce phosphorylation of p53 S15 by DNA-PK and ATM.
“Several landmark studies showed that DNA double strand breaks induce phosphorylation of p53 S15 by DNA-PK and ATM (Mayo et al, 1997;Shieh et al, 1997;Banin et al, 1998;Prives and Hall, 1999).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
MDMX lacks significant intrinsic E3 ligase activity.
“However, MDMX does not have significant intrinsic E3 ligase activity (Stad et al, 2001)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Stad et al, 2001 source
Not checked in the free run.
- Interpretationown data
ATM causes p53 accumulation by phosphorylating MDM2.
“We show in this report that ATM induces p53 accumulation by phosphorylating the ubiquitin E3 ligase MDM2.”
Quote in the paperSubstantial claim- Rests on an assumption: Phosphomimic substitutions with aspartate or glutamate at ATM target sites functionally mimic phosphorylation of MDM2.
- Rests on an assumption: Alanine substitution at the six MDM2 phosphorylation sites prevents their phosphorylation.
- Interpretationown data
In the absence of DNA damage, the MDM2 RING domain forms oligomers that mediate p53 polyubiquitination and proteasomal degradation.
“In the absence of DNA damage, the MDM2 RING domain forms oligomers that mediate p53 poly ubiquitination and proteasomal degradation.”
Quote in the paperSubstantial claim- Rests on an assumption: The MDM2 RING domain oligomers observed in vitro correspond to the functional E3 complex that mediates p53 polyubiquitination in cells.
- Interpretationreasoning
Monomeric RING domains carry out ubiquitination in a dissociative way, producing monoubiquitination at different p53 lysines.
“Monomeric RING domains catalyse ubiquitination in a dissociative manner, resulting in mono ubiquitination of different lysines on p53.”
Quote in the paperSubstantial claim- Rests on an assumption: High-order E3 structures help expose multiple E2 active sites to the substrate and speed up the reaction.
- Interpretationown data
Phosphorylation of a single site on MDM2 is sufficient to stabilize p53.
“These results suggest that phosphorylation of a single site on MDM2 is sufficient to stabilize p53.”
Quote in the paperSubstantial claim- Rests on an assumption: Phosphomimic substitutions with aspartate or glutamate at ATM target sites functionally mimic phosphorylation of MDM2.
- Interpretationown data
After DNA damage, MDM2 phosphorylation induces conformational changes that block RING domain oligomerization.
“After DNA damage, phosphorylation of MDM2 causes conformational changes that prevent RING domain oligomerization.”
Quote in the paperSubstantial claim- Rests on an assumption: High-order E3 structures help expose multiple E2 active sites to the substrate and speed up the reaction.
- Interpretationcitation
Robust p53 stabilization involves mechanisms besides p53 phosphorylation.
“However, these results also indicate that robust p53 stabilization involves mechanisms besides p53 phosphorylation.”
Quote in the paperSubstantial claim - Interpretationown data
ATM is responsible for directly phosphorylating S386 and S429 after DNA damage.
“These data indicate that ATM is responsible for directly phosphorylating S386 and S429 after DNA damage.”
Quote in the paperSubstantial claim - Premisecitation
The MDM2 RING domain has greater E3 ligase activity in vitro when it oligomerizes.
“Oligomerization of MDM2 RING domain increases its E3 ligase activity in vitro (Poyurovsky et al, 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Poyurovsky et al, 2007 source
Not checked in the free run.
- Interpretationown data
The findings in this report identify inhibition of RING domain self-assembly as a new way that ATM regulates MDM2.
“Results described in this report showed that inhibition of RING domain self-assembly is a novel mechanism of MDM2 regulation by ATM.”
Quote in the paperSubstantial claim- Rests on an assumption: High-order E3 structures help expose multiple E2 active sites to the substrate and speed up the reaction.
- May combine two claims. 14
- Classified as probably not a substantial claim. 10
- The quote only partly states this claim. 2
May combine two claims.
Findingown dataMDM2 phosphorylation was induced rapidly after IR before significant p53 accumulation and peaked about 2.5 h in SJSA cells.
“MDM2 phosphorylation was induced rapidly after IR before significant accumulation of p53, and peaked about 2.5 h in SJSA cells (Figure 2A).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingnone givenThe MDM2 RING fragment runs on SDS-PAGE at about 30 kDa, which is slower than its calculated 15 kDa.
“Note that the RING fragment migrates on SDS-PAGE as a B30 kDa band, which is slower than its calculated molecular weight of 15 kDa.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataATM-specific inhibitor KU55933 or ATM/ATR inhibitor caffeine blocked S386 and S429 phosphorylation after IR.
“Further, treatment of SJSA cells with ATM-specific inhibitor KU55933 (Figure 2C) or the less specific ATM/ATR inhibitor caffeine (not shown) also blocked phosphorylation of S386 and S429 after IR.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataMDM2 phosphorylation site mutations change MDMX degradation.
“Effects of MDM2 phosphorylation site mutation on p53 and MDMX degradation.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataS386 and S429 are directly phosphorylated by ATM in vitro, while kinase-inactive ATM-KD has no effect.
“The results showed that both S386 and S429 were phosphorylated by ATM in vitro, and the kinase-inactive ATM-KD had no effect (Figure 2D).”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationChk1 and Chk2 failed to phosphorylate S386 and S429 in vitro, but phosphorylated MDMX S367.
“Furthermore, Chk1 and Chk2 failed to phosphorylate S386 and S429 in vitro, but phosphorylated the positive control site MDMX S367 (Chen et al, 2005).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chen et al, 2005 source
Not checked in the free run.
May combine two claims.
Interpretationown dataATM phosphorylation inhibits MDM2 RING domain oligomerization and specifically suppresses p53 polyubiquitination.
“Phosphorylation by ATM inhibits RING domain oligomerization, specifically suppressing p53 poly ubiquitination.”
Quote in the paperSubstantial claim- Rests on an assumption: Phosphomimic substitutions with aspartate or glutamate at ATM target sites functionally mimic phosphorylation of MDM2.
- Rests on an assumption: The MDM2 RING domain oligomers observed in vitro correspond to the functional E3 complex that mediates p53 polyubiquitination in cells.
May combine two claims.
PremisecitationATM activates Chk2, which phosphorylates p53 S20, a residue in the MDM2-binding site.
“ATM also activates Chk2, which in turn phosphorylates p53 on S20, which is a part of the MDM2-binding site (Shieh et al, 1997(Shieh et al, , 2000;;Banin et al, 1998;Chehab et al, 2000).”
Quote in the paperNot a substantial claim0 of 3 sources checkedClassified as probably not a substantial claim.
PremisecitationS15 and S20 phosphorylation do not prevent MDM2 binding in vitro.
“However, biochemical analysis using phosphorylated p53 peptide indicated that S15 and S20 phosphorylation do not prevent MDM2 binding in vitro (Bottger et al, 1999).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bottger et al, 1999 source
Not checked in the free run.
May combine two claims.
PremisecitationMDM2 binds p53 and acts as an E3 ligase to promote p53 degradation by the proteasome.
“P53 turnover is regulated by MDM2, which binds p53 and functions as an ubiquitin E3 ligase to promote p53 degradation by the proteasome (Zhang and Xiong, 2001).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zhang and Xiong, 2001
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.
Study design and conductown dataE. coli-produced His6-MDM2 was used to rule out cross-reactivity of the phosphorylation-specific antibodies.
“His6-MDM2 produced in E. coli was used to rule out cross reactivity.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataWithout DNA damage, MDM2 RING domains oligomerize, recruit several E2s, and thereby make ubiquitin chain elongation more processive.
“In the absence of DNA damage, MDM2 RING domain forms oligomers that recruit multiple E2s, increasing the processivity of ubiquitin chain elongation.”
Quote in the paperSubstantial claim- Rests on an assumption: High-order E3 structures help expose multiple E2 active sites to the substrate and speed up the reaction.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRING domains commonly form high-order oligomers.
“Formation of high-order oligomers is a common feature of RING domains (Kentsis et al, 2002;Poyurovsky et al, 2007).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataRING fragment complex sizes were assigned by comparing their elution profile with a molecular weight standard run under the same conditions.
“The sizes of RING fragment complexes were determined by comparing the elution profile to a molecular weight standard fractionated under identical conditions.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown dataThe PS386 and PS429 antibodies did not react with non-phosphorylated His6-MDM2 or with S386A and S429A mutants after IR.
“The specificity of the antibodies was confirmed by lack of reactivity to non-phosphorylated His6-MDM2 purified from Escherichia coli (Figure 1B) or to transfected MDM2-S386A and S429A mutants after IR (Figure 1C).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationIn the SCFcdc4 E3 ligase, assembly of SCF protomers into dimers is required for adding ubiquitin chains to substrates; when dimerization fails, substrates receive only a single ubiquitin.
“In the multimeric SCFcdc4 E3 ligase complex, dimer formation by SCF protomers is important for poly ubiquitination of substrates, whereas failure to form E3 dimer results in substrate mono ubiquitination (Tang et al, 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Tang et al, 2007 source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown dataCIP dephosphorylation was done on immobilized MDM2 before capturing p53.
“Dephosphorylation by CIP was performed on immobilized MDM2 before p53 capture.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn cancer, failure of SCF(Fbx4) to dimerize blocks ubiquitination of cyclin D1, leading to cyclin D1 accumulation and transformation.
“Lack of SCF(Fbx4) dimerization in cancer prevents ubiquitination of its substrate cyclin D1, which contributes to cyclin D1 overexpression and transformation (Barbash et al, 2008).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Barbash et al, 2008 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenGST-MDMX-280-490 served as a positive control for Chk2 phosphorylation of S367.
“GST-MDMX-280-490 was used as a positive control for Chk2 phosphorylation of S367.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationMDM2 is phosphorylated by ATM, ATR, and C-Abl on sites near its C terminus.
“MDM2 is phosphorylated by ATM, ATR, and C-Abl on sites near the C terminus (Maya et al, 2001;Sionov et al, 2001;Shinozaki et al, 2003).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationBlocking mouse p53 phosphorylation on S18 and S23 only partially reduced p53 stabilization after DNA damage and caused partial defects in apoptosis and tumour suppression.
“Studies in mouse models showed that blocking mouse p53 phosphorylation on S18 and S23 (equivalents of human p53 S15 and S20) only partially reduced p53 stabilization after DNA damage, and causes partial defects in apoptosis and tumour suppression functions (Chao et al, 2006).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chao et al, 2006 source
Not checked in the free run.
May combine two claims.
Premiseown dataCaspase 3 cuts MDM2 at one site, residue 361, releasing a C-terminal fragment (362-491) that contains the phosphorylation sites and the RING domain.
“Caspase 3 cleaves MDM2 at a single site (361) and releases the C-terminal fragment 362-491 containing the phosphorylation sites and RING domain.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chen et al, 1997 source
Not checked in the free run.
The paper relies on this without support.
Phosphomimic substitutions with aspartate or glutamate at ATM target sites functionally mimic phosphorylation of MDM2.
“However, S386E and S429D phospho-mimic mutants were partially defective in p53 degradation (Figure 3A).”
The paper relies on this without support.
Alanine substitution at the six MDM2 phosphorylation sites prevents their phosphorylation.
“Interestingly, substitution of all six phosphorylation sites with alanine (MDM2-6A) significantly increased p53 degradation (Figure 3B and C).”
The paper relies on this without support.
The MDM2 RING domain oligomers observed in vitro correspond to the functional E3 complex that mediates p53 polyubiquitination in cells.
“In the absence of DNA damage, the MDM2 RING domain forms oligomers that mediate p53 poly ubiquitination and proteasomal degradation.”
The paper relies on this without support.
High-order E3 structures help expose multiple E2 active sites to the substrate and speed up the reaction.
“Mechanistically, formation of high-order structures by E3 helps to present multiple E2 active sites to the substrate and increase the reaction rate.”
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?
Phosphorylation of novel sites adjacent to the Mdm2 RING domain upon irradiation prevents Mdm2 oligomerization.
“The phosphorylation appears to prevent Mdm2 oligomerization, as the Mdm2 RING domain isolated from irradiated cells is unable to interact with non-phosphorylated Mdm2.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [29]
In cell lines expressing non-phosphorylatable Mdm2 mutants, p53 stabilization and activation after damage is markedly attenuated.
“In cell lines expressing non-phosphorylatable Mdm2 mutants, p53 stabilization and activation after damage is markedly attenuated.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [29]
Phosphorylated Mdm2 retains the capacity to bind and degrade Mdmx.
“Cheng et al. also show that phosphorylated Mdm2 retains the capacity to bind and degrade Mdmx.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [29]
Control of Mdm2 oligomerization is important for p53 stabilization following DNA damage.
“However, Cheng and colleagues recently found that control of Mdm2 oligomerization is important for p53 stabilization following DNA damage [29].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [29]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Figure 5C and Methods give different treatment times and antibodies
MinorFor the endogenous MDM2 gel-filtration experiment, the Figure 5C caption says cells were collected 2 h after irradiation and MDM2 was immunoprecipitated with 2A9. The Methods describe 1 h after irradiation and immunoprecipitation with 4B2.
“MDM2 was immunoprecipated with 2A9 after 2 h, cleaved with Caspase 3, and the C-terminal fragment (362-491) was analysed by gel filtration chromatography”
“irradiated with 10 Gy IR for 1 h, immunoprecipitated using MDM2 antibody 4B2, and cleaved with Caspase 3.”
Cites
DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2
Shieh, S.-Y., Ikeda, M., Taya, Y., & Prives, C. (1997) · Cell · doi:10.1016/s0092-8674(00)80416-x · Cited by 2,100 · see citing works
The p53 pathway: positive and negative feedback loops
Harris, S. L., & Levine, A. J. (2005) · Oncogene · doi:10.1038/sj.onc.1208615 · Cited by 1,967 · see citing works
Enhanced Phosphorylation of p53 by ATM in Response to DNA Damage
Banin, S., Moyal, L., Shieh, S.-Y., Taya, Y., Anderson, C. W., Chessa, L., Smorodinsky, N. I., Prives, C., Reiss, Y., Shiloh, Y., et al. (1998) · Science · doi:10.1126/science.281.5383.1674 · Cited by 1,797 · see citing works
Recognition of the polyubiquitin proteolytic signal
Thrower, J. S., Hoffman, L. M., Rechsteiner, M., & Pickart, C. M. (2000) · The EMBO Journal · doi:10.1093/emboj/19.1.94 · Cited by 1,718 · see citing works
Hickson, I., Zhao, Y., Richardson, C. J., Green, S. J., Martin, N. M. B., Orr, A. I., Reaper, P. M., Jackson, S. P., Curtin, N. J., & Smith, G. C. M. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-2727 · Cited by 1,220 · see citing works
Disruption of p53 in human cancer cells alters the responses to therapeutic agents.
Bunz, F., Hwang, P. M., Torrance, C., Waldman, T., Zhang, Y., Dillehay, L., Williams, J., Lengauer, C., Kinzler, K. W., & Vogelstein, B. (1999) · Journal of Clinical Investigation · doi:10.1172/jci6863 · Cited by 1,044 · see citing works
Shieh, S.-Y., Ahn, J., Tamai, K., Taya, Y., & Prives, C. (2000) · Genes & Development · doi:10.1101/gad.14.3.289 · Cited by 972 · see citing works
Substrate Specificities and Identification of Putative Substrates of ATM Kinase Family Members
Kim, S.-T., Lim, D.-S., Canman, C. E., & Kastan, M. B. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.53.37538 · Cited by 810 · see citing works
Chk2/hCds1 functions as a DNA damage checkpoint in G<sub>1</sub>by stabilizing p53
Chehab, N. H., Malikzay, A., Appel, M., & Halazonetis, T. D. (2000) · Genes & Development · doi:10.1101/gad.14.3.278 · Cited by 805 · see citing works
ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage
Maya, R., Balass, M., Kim, S.-T., Shkedy, D., Leal, J.-F. M., Shifman, O., Moas, M., Buschmann, T., Ronai, Z., Shiloh, Y., et al. (2001) · Genes & Development · doi:10.1101/gad.886901 · Cited by 716 · cited 2× · see citing works
“MDM2 is phosphorylated by ATM, ATR, and C-Abl on sites near the C terminus (Maya et al, 2001; Sionov et al, 2001; Shinozaki et al, 2003).”
BackgroundMapping of the p53 and mdm-2 Interaction Domains
Chen, J., Maréchal, V., & Levine, A. J. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.7.4107 · Cited by 689 · see citing works
Self-citationMDMX: a novel p53‐binding protein with some functional properties of MDM2.
Shvarts, A., Steegenga, W. T., Riteco, N., van Laar, T., Dekker, P., Bazuine, M., van Ham, R. C., van der Houven van Oordt, W., Hateboer, G., van der Eb, A. J., et al. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00919.x · Cited by 648 · see citing works
Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage
Khosravi, R., Maya, R., Gottlieb, T., Oren, M., Shiloh, Y., & Shkedy, D. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.26.14973 · Cited by 461 · see citing works
Dumaz, N., & Meek, D. W. (1999) · The EMBO Journal · doi:10.1093/emboj/18.24.7002 · Cited by 455 · see citing works
Regulation of p53 function and stability by phosphorylation.
Ashcroft, M., Kubbutat, M. H. G., & Vousden, K. H. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.3.1751 · Cited by 452 · see citing works
Accelerated MDM2 auto‐degradation induced by DNA‐damage kinases is required for p53 activation
Stommel, J. M., & Wahl, G. M. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600145 · Cited by 386 · see citing works
Targeting of substrates to the 26S proteasome
Pickart, C. M. (1997) · The FASEB Journal · doi:10.1096/fasebj.11.13.9367341 · Cited by 367 · see citing works
Celli, G. B., Denchi, E. L., & de Lange, T. (2006) · Nature Cell Biology · doi:10.1038/ncb1444 · Cited by 320 · see citing works
A UbcH5/Ubiquitin Noncovalent Complex Is Required for Processive BRCA1-Directed Ubiquitination
Brzović, P. S., Lissounov, A., Christensen, D. E., Hoyt, D. W., & Klevit, R. E. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.02.008 · Cited by 311 · see citing works
Monoubiquitylation promotes mitochondrial p53 translocation
Marchenko, N. D., Wolff, S., Erster, S., Becker, K., & Moll, U. M. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601560 · Cited by 286 · see citing works
Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells <i>in vivo</i>
Francoz, S., Froment, P., Bogaerts, S., De Clercq, S., Maetens, M., Doumont, G., Bellefroid, E., & Marine, J.-C. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508476103 · Cited by 260 · see citing works
ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage
Chen, L., Gilkes, D. M., Pan, Y., Lane, W. S., & Chen, J. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600812 · Cited by 260 · see citing works
Self-citationMDM2 promotes ubiquitination and degradation of MDMX
Pan, Y., & Chen, J. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.15.5113-5121.2003 · Cited by 246 · see citing works
Self-citation(1997) · PubMed · Cited by 243 · see citing works
Cam, L. L., Linares, L. K., Paul, C., Julien, E., Lacroix, M., Hatchi, E., Triboulet, R., Bossis, G., Shmueli, A., Rodríguez, M. S., et al. (2006) · Cell · doi:10.1016/j.cell.2006.09.031 · Cited by 241 · see citing works
Critical role for Daxx in regulating Mdm2
Tang, J., Qu, L., Zhang, J., Wang, W., Michaelson, J. S., Degenhardt, Y., El‐Deiry, W. S., & Yang, X. (2006) · Nature Cell Biology · doi:10.1038/ncb1442 · Cited by 239 · see citing works
Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms
Stad, R., Little, N. A., Xirodimas, D. P., Frenk, R., van der Eb, A. J., Lane, D. P., Saville, M. K., & Jochemsen, A. G. (2001) · The EMBO Reports · doi:10.1093/embo-reports/kve227 · Cited by 234 · see citing works
Tang, X., Orlicky, S., Lin, Z., Willems, A., Neculai, D., Ceccarelli, D., Mercurio, F., Shilton, B. H., Sicheri, F., & Tyers, M. (2007) · Cell · doi:10.1016/j.cell.2007.04.042 · Cited by 209 · see citing works
Poyurovsky, M. V., Priest, C., Kentsis, A., Borden, K. L., Pan, Z., Pavletich, N., & Prives, C. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601465 · Cited by 203 · see citing works
Toledo, F., Krummel, K. A., Lee, C. J., Liu, C.-W., Rodewald, L.-W., Tang, M., & Wahl, G. M. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.03.014 · Cited by 199 · cited 1× · see citing works
“However, MDMX does not have significant intrinsic E3 ligase activity (Stad et al, 2001), it seems to regulate p53 mainly by formation of inactive p53–MDMX complexes (Francoz et al, 2006; Toledo et al, 2006).”
BackgroundRegulation of Mdm2-Directed Degradation by the C Terminus of p53
Kubbutat, M. H. G., Ludwig, R. L., Ashcroft, M. A., & Vousden, K. H. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.10.5690 · Cited by 193 · see citing works
Comparative study of the p53-mdm2 and p53-MDMX interfaces
Böttger, V., Böttger, A., Garcia-Echeverria, C., Ramos, Y. F., van der Eb, A. J., Jochemsen, A. G., & Lane, D. P. (1999) · Oncogene · doi:10.1038/sj.onc.1202281 · Cited by 189 · see citing works
Control of p53 ubiquitination and nuclear export by MDM2 and ARF.
Zhang, Y., & Xiong, Y. (2001) · PubMed · Cited by 176 · see citing works
Ser18 and 23 phosphorylation is required for p53‐dependent apoptosis and tumor suppression
Chao, C., Herr, D., Chun, J., & Xu, Y. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601167 · Cited by 158 · see citing works
DNA damage induced p53 stabilization: no indication for an involvement of p53 phosphorylation
Blattner, C., Tobiasch, E., Litfen, M., Rahmsdorf, H. J., & Herrlich, P. (1999) · Oncogene · doi:10.1038/sj.onc.1202480 · Cited by 151 · see citing works
Cell Type- and Promoter-specific Roles of Ser18 Phosphorylation in Regulating p53 Responses
Chao, C., Hergenhahn, M., Kaeser, M. D., Wu, Z., Saito, S., Iggo, R., Hollstein, M., Appella, E., & Xu, Y. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306938200 · Cited by 141 · see citing works
Barbash, O., Zamfirova, P., Lin, D. I., Chen, X., Yang, K., Nakagawa, H., Lu, F., Rustgi, A. K., & Diehl, J. A. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.05.017 · Cited by 140 · see citing works
Oligomerization Is Required for p53 to be Efficiently Ubiquitinated by MDM2
Maki, C. G. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.23.16531 · Cited by 125 · see citing works
Defective apoptosis and B-cell lymphomas in mice with p53 point mutation at Ser 23
MacPherson, D., Kim, J., Kim, T., Rhee, B. K., van Oostrom, C. T., DiTullio, R. A., Venere, M., Halazonetis, T. D., Bronson, R., de Vries, A., et al. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600363 · Cited by 124 · see citing works
Proteolytic Cleavage of the mdm2 Oncoprotein during Apoptosis
Chen, L., Marechal, V., Moreau, J., Levine, A. J., & Chen, J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.36.22966 · Cited by 121 · see citing works
Self-citationControl of biochemical reactions through supramolecular RING domain self-assembly
Kentsis, A., Gordon, R. E., & Borden, K. L. B. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.202608799 · Cited by 112 · see citing works
Vogt Sionov, R., Coen, S., Goldberg, Z., Berger, M., Bercovich, B., Ben-Neriah, Y., Ciechanover, A., & Haupt, Y. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.17.5869-5878.2001 · Cited by 94 · see citing works
Functional role of Mdm2 phosphorylation by ATR in attenuation of p53 nuclear export
Shinozaki, T., Nota, A., Taya, Y., & Okamoto, K. (2003) · Oncogene · doi:10.1038/sj.onc.1207176 · Cited by 93 · see citing works
DNA Damage Induces MDMX Nuclear Translocation by p53-Dependent and -Independent Mechanisms
Li, C., Chen, L., & Chen, J. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.21.7562-7571.2002 · Cited by 82 · see citing works
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MDM2, MDMX and p53 in oncogenesis and cancer therapy
Wade, M., Li, Y.-C., & Wahl, G. M. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3430 · Cited by 1,279 · see citing works
Epigenetic and genetic features of 24 colon cancer cell lines
Ahmed, D., Eide, P. W., Eilertsen, I. A., Danielsen, S. A., Eknæs, M., Hektoen, M., Lind, G. E., & Lothe, R. A. (2013) · Oncogenesis · doi:10.1038/oncsis.2013.35 · Cited by 913 · see citing works
The p53 orchestra: Mdm2 and Mdmx set the tone
Wade, M., Wang, Y. V., & Wahl, G. M. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.01.009 · Cited by 450 · see citing works
Abiotic stress tolerance mediated by protein ubiquitination
Lyzenga, W. J., & Stone, S. L. (2011) · Journal of Experimental Botany · doi:10.1093/jxb/err310 · Cited by 429 · see citing works
The Mdm2–p53 relationship evolves: Mdm2 swings both ways as an oncogene and a tumor suppressor
Manfredi, J. J. (2010) · Genes & Development · doi:10.1101/gad.1941710 · Cited by 344 · see citing works
Patterns and functional implications of rare germline variants across 12 cancer types
Lu, C., Xie, M., Wendl, M. C., Wang, J., McLellan, M. D., Leiserson, M. D. M., Huang, K., Wyczalkowski, M. A., Jayasinghe, R. G., Banerjee, T., et al. (2015) · Nature Communications · doi:10.1038/ncomms10086 · Cited by 296 · see citing works
Regulation of the p53 response and its relationship to cancer
Meek, D. W. (2015) · Biochemical Journal · doi:10.1042/bj20150517 · Cited by 291 · see citing works
Mechanism of p53 stabilization by ATM after DNA damage
Cheng, Q., & Chen, J. (2010) · Cell Cycle · doi:10.4161/cc.9.3.10556 · Cited by 248 · see citing works
Self-citationThe Regulation of Multiple p53 Stress Responses is Mediated through MDM2
Hu, W., Feng, Z., & Levine, A. J. (2012) · Genes & Cancer · doi:10.1177/1947601912454734 · Cited by 176 · see citing works
The regulation of MDM2 oncogene and its impact on human cancers
Zhao, Y., Yu, H., & Hu, W. (2014) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmt147 · Cited by 173 · see citing works
Gajjar, M. K., Candeias, M. M., Malbert-Colas, L., Mazars, A., Fujita, J., Olivares‐Illana, V., & Fåhræus, R. (2012) · Cancer Cell · doi:10.1016/j.ccr.2011.11.016 · Cited by 168 · see citing works
Smac Mimetics Activate the E3 Ligase Activity of cIAP1 Protein by Promoting RING Domain Dimerization
Feltham, R., Bettjeman, B., Budhidarmo, R., Mace, P. D., Shirley, S., Condon, S. M., Chunduru, S. K., McKinlay, M. A., Vaux, D. L., Silke, J., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.222919 · Cited by 168 · see citing works
The role of ubiquitin modification in the regulation of p53
Hock, A. K., & Vousden, K. H. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.05.022 · Cited by 168 · see citing works
The role of DNA damage responses in p53 biology
Speidel, D. (2015) · Archives of Toxicology · doi:10.1007/s00204-015-1459-z · Cited by 165 · see citing works
Role of p53 in Neurodegenerative Diseases
Chang, J. R., Ghafouri, M., Mukerjee, R., Bagashev, A., Chabrashvili, T., & Sawaya, B. E. (2011) · Neurodegenerative Diseases · doi:10.1159/000329999 · Cited by 145 · see citing works
ATM kinase: Much more than a DNA damage responsive protein
Guleria, A., & Chandna, S. (2015) · DNA repair · doi:10.1016/j.dnarep.2015.12.009 · Cited by 145 · see citing works
Adaptor Protein Self-Assembly Drives the Control of a Cullin-RING Ubiquitin Ligase
Errington, W. J., Khan, M. Q., Bueler, S. A., Rubinstein, J. L., Chakrabartty, A., & Privé, G. G. (2012) · Structure · doi:10.1016/j.str.2012.04.009 · Cited by 139 · see citing works
Regulation of p53: a collaboration between Mdm2 and MdmX
Pei, D., Zhang, Y., & Zheng, J. (2012) · Oncotarget · doi:10.18632/oncotarget.443 · Cited by 140 · see citing works
Roles of COP9 signalosome in cancer
Lee, M., Zhao, R., Phan, L. M., & Yeung, S. J. (2011) · Cell Cycle · doi:10.4161/cc.10.18.17320 · Cited by 137 · see citing works
The DNA Damage Response in Neurons: Die by Apoptosis or Survive in a Senescence-Like State?
Fielder, E., von Zglinicki, T., & Jurk, D. (2017) · Journal of Alzheimer's Disease · doi:10.3233/jad-161221 · Cited by 126 · see citing works
Mdm2 and MdmX partner to regulate p53
Wang, X., & Jiang, X. (2012) · FEBS Letters · doi:10.1016/j.febslet.2012.02.049 · Cited by 111 · see citing works
LncRNA Meg3 protects endothelial function by regulating the DNA damage response
Ali, M. S. S. H., Cheng, X., Moran, M., Haemmig, S., Naldrett, M. J., Alvarez, S., Feinberg, M. W., & Sun, X. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky1190 · Cited by 113 · see citing works
Nucleolar stress: From development to cancer
Lafita‐Navarro, M. C., & Conacci‐Sorrell, M. (2022) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2022.04.001 · Cited by 109 · see citing works
Spliced MDM2 isoforms promote mutant p53 accumulation and gain-of-function in tumorigenesis
Zheng, T., Wang, J., Zhao, Y., Zhang, C., Lin, M., Wang, X., Yu, H., Liu, L., Feng, Z., & Hu, W. (2013) · Nature Communications · doi:10.1038/ncomms3996 · Cited by 108 · see citing works
Gannon, H. S., Woda, B. A., & Jones, S. N. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.04.011 · Cited by 105 · see citing works
Cheteh, E. H., Sarne, V., Ceder, S., Bianchi, J., Augsten, M., Rundqvist, H., Egevad, L., Östman, A., & Wiman, K. G. (2020) · Cell Death Discovery · doi:10.1038/s41420-020-0272-5 · Cited by 105 · see citing works
FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage
Chung, Y. M., Park, S., Tsai, W.-B., Wang, S., Ikeda, M.-A., Berek, J. S., Chen, D. J., & Hu, M. C. ‐. (2012) · Nature Communications · doi:10.1038/ncomms2008 · Cited by 100 · see citing works
DNA Damage Repair in Huntington's Disease and Other Neurodegenerative Diseases
Maiuri, T., Suart, C., Hung, C. L.-K., Graham, K. J., Bazan, C. B., & Truant, R. (2019) · Neurotherapeutics · doi:10.1007/s13311-019-00768-7 · Cited by 92 · see citing works
Regulation of Mutant p53 Protein Expression
Vijayakumaran, R., Tan, K. H., Miranda, P. J., Haupt, S., & Haupt, Y. (2015) · Frontiers in Oncology · doi:10.3389/fonc.2015.00284 · Cited by 87 · see citing works
Liu, B., Peng, Z., Zhang, H., Zhang, N., Liu, Z., Xia, Z., Huang, S., Luo, P., & Cheng, Q. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02284-z · Cited by 82 · see citing works
Self-citationA p53-independent role for the MDM2 antagonist Nutlin-3 in DNA damage response initiation
Valentine, J. M., Kumar, S., & Moumen, A. (2011) · BMC Cancer · doi:10.1186/1471-2407-11-79 · Cited by 77 · see citing works
Scission of the p53-MDM2 Loop by Ribosomal Proteins
Zhou, X. Y., Liao, J.-M., Liao, W.-J., & Lu, H. (2012) · Genes & Cancer · doi:10.1177/1947601912455200 · Cited by 78 · see citing works
Control of SUMO and Ubiquitin by ROS: Signaling and disease implications
Stankovic‐Valentin, N., & Melchior, F. (2018) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2018.07.002 · Cited by 76 · see citing works
Hypoxia Inactivates the VHL Tumor Suppressor through PIASy-Mediated SUMO Modification
Cai, Q., Verma, S. C., Kumar, P., Ma, M., & Robertson, E. S. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009720 · Cited by 76 · see citing works
Meyer, P., Maity, P., Burkovski, A., Schwab, J. D., Müssel, C., Singh, K., Ferreira, F. F., Krug, L., Maier, H. J., Wlaschek, M., et al. (2017) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1005741 · Cited by 73 · see citing works
P53 and its molecular basis to chemoresistance in breast cancer
Knappskog, S., & Lønning, P. E. (2012) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2011.640322 · Cited by 73 · see citing works
Regulation of MDM2 E3 Ligase Activity by Phosphorylation after DNA Damage
Cheng, Q., Cross, B. L., Li, B., Chen, L., Li, Z., & Chen, J. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.05553-11 · Cited by 73 · see citing works
Self-citationInhibition of p53 DNA Binding Function by the MDM2 Protein Acidic Domain
Cross, B. L., Chen, L., Cheng, Q., Li, B., Yuan, Z.-M., & Chen, J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.228981 · Cited by 69 · see citing works
Self-citationLacoursiere, R. E., Hadi, D., & Shaw, G. S. (2022) · Biomolecules · doi:10.3390/biom12030467 · Cited by 70 · see citing works
Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis
Carr, M. I., & Jones, S. N. (2016) · Translational Cancer Research · doi:10.21037/tcr.2016.11.75 · Cited by 70 · see citing works
Role of Dietary Antioxidants in p53‐Mediated Cancer Chemoprevention and Tumor Suppression
Merlin, J. P. J., Rupasinghe, H. P. V., Dellaire, G., & Murphy, K. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/9924328 · Cited by 68 · see citing works
Malonia, S. K., Dutta, P., Santra, M. K., & Green, M. R. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1510929112 · Cited by 66 · see citing works
p53 promotes repair of heterochromatin DNA by regulating JMJD2b and SUV39H1 expression
Zheng, H., Chen, L., Pledger, W. J., Fang, J., & Chen, J. (2013) · Oncogene · doi:10.1038/onc.2013.6 · Cited by 65 · see citing works
Self-citationMultitasking with ubiquitin through multivalent interactions
Liu, F., & Walters, K. J. (2010) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2010.01.002 · Cited by 66 · see citing works
The Many Faces of MDM2 Binding Partners
Riley, M. F., & Lozano, G. (2012) · Genes & Cancer · doi:10.1177/1947601912455322 · Cited by 64 · see citing works
Xiong, X., Zhao, Y., Tang, F., Wei, D., Thomas, D. G., Wang, X., Liu, Y., Zheng, P., & Sun, Y. (2014) · eLife · doi:10.7554/elife.02236 · Cited by 66 · see citing works
Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma
Traweek, R. S., Cope, B. M., Roland, C. L., Keung, E. Z.-Y., Nassif, E. F., & Erstad, D. J. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1006959 · Cited by 61 · see citing works
DNA damage responses in mammalian oocytes
Collins, J. K., & Jones, K. T. (2016) · Reproduction · doi:10.1530/rep-16-0069 · Cited by 59 · see citing works
Falcicchio, M., Ward, J. A., Macip, S., & Doveston, R. G. (2020) · Cell Death Discovery · doi:10.1038/s41420-020-00362-3 · Cited by 58 · see citing works
Restoring p53 Function in Head and Neck Squamous Cell Carcinoma to Improve Treatments
de Bakker, T., Journé, F., Descamps, G., Saussez, S., Dragan, T., Ghanem, G., Krayem, M., & Gestel, D. V. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2021.799993 · Cited by 61 · see citing works
Glucose-induced CRL4COP1-p53 axis amplifies glycometabolism to drive tumorigenesis
Su, Y., Luo, Y., Zhang, P., Lin, H., Pu, W., Zhang, H., Wang, H., Hao, Y., Xiao, Y., Zhang, X., et al. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.06.010 · Cited by 57 · see citing works
Unravelling mechanisms of cisplatin sensitivity and resistance in testicular cancer
Koster, R., van Vugt, M. A. T. M., Timmer‐Bosscha, H., Gietema, J. A., & de Jong, S. (2013) · Expert Reviews in Molecular Medicine · doi:10.1017/erm.2013.13 · Cited by 57 · see citing works
Systematic identification of phosphorylation-mediated protein interaction switches
Betts, M. J., Wichmann, O., Utz, M., André, T., Petsalaki, E., Mínguez, P., Parca, L., Roth, F. P., Gavin, A., Peer Bork, B., et al. (2017) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1005462 · Cited by 56 · see citing works
Enigma negatively regulates p53 through MDM2 and promotes tumor cell survival in mice
Jung, C., Lim, J. H., Choi, Y., Kim, D., Kang, K. J., Noh, S., & Im, D. (2010) · Journal of Clinical Investigation · doi:10.1172/jci42674 · Cited by 54 · see citing works
Kinase Signalling in Huntington's Disease
Bowles, K. R., & Jones, L. (2014) · Journal of Huntington s Disease · doi:10.3233/jhd-140106 · Cited by 52 · see citing works
Posttranslational modification of mammalian AP endonuclease (APE1)
Busso, C. S., Lake, M. W., & Izumi, T. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0487-3 · Cited by 50 · see citing works
Leslie, P. L., Ke, H., & Zhang, Y. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.644435 · Cited by 50 · see citing works
Regulation of MDM2 Stability After DNA Damage
Li, J., & Kurokawa, M. (2015) · Journal of Cellular Physiology · doi:10.1002/jcp.24994 · Cited by 48 · see citing works
Casein Kinase 1α Regulates an MDMX Intramolecular Interaction To Stimulate p53 Binding
Wu, S., Chen, L., Becker, A., Schönbrunn, E., & Chen, J. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00851-12 · Cited by 48 · see citing works
Self-citationYu, Z.-C., Huang, Y., & Shieh, S.-Y. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv1173 · Cited by 44 · see citing works
Is p53 Involved in Tissue‐Specific Insulin Resistance Formation?
Strycharz, J., Drzewoski, J., Szemraj, J., & Śliwińska, A. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/9270549 · Cited by 44 · see citing works
Mechanisms of Mutant p53 Stabilization in Cancer
Frum, R. A., & Grossman, S. R. (2014) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-017-9211-0_10 · Cited by 40 · see citing works
Structural basis for DNA damage-induced phosphoregulation of MDM2 RING domain
Magnussen, H., Ahmed, S. F., Sibbet, G. J., Hristova, V. A., Nomura, K., Hock, A. K., Archibald, L. J., Jamieson, A. G., Fushman, D., Vousden, K. H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15783-y · Cited by 37 · see citing works
Switching on p53: an essential role for protein phosphorylation?
Loughery, J., & Meek, D. W. (2013) · Biodiscovery · doi:10.7750/biodiscovery.2013.8.1 · Cited by 38 · see citing works
Chen, C., Lin, C., Pei, Y., Ma, D., Liao, L., Li, S., Fan, L., Di, G., Wu, S., Liu, X., et al. (2023) · Cell Discovery · doi:10.1038/s41421-023-00614-3 · Cited by 42 · see citing works
Probing the mechanisms underlying human diseases in making ribosomes
Farley‐Barnes, K. I., & Baserga, S. J. (2016) · Biochemical Society Transactions · doi:10.1042/bst20160064 · Cited by 37 · see citing works
Negative auto-regulators trap p53 in their web
Zhou, X. Y., Cao, B., & Lu, H. (2017) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjx001 · Cited by 36 · see citing works
Li, W., Peng, X., Lang, J., & Xu, C. S. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00631 · Cited by 36 · see citing works
DNA damage-induced activation of ATM promotes β-TRCP-mediated Mdm2 ubiquitination and destruction
Wang, Z. P., Inuzuka, H., Zhong, J., Fukushima, H., Wan, L., Liu, P., & Wei, W. (2012) · Oncotarget · doi:10.18632/oncotarget.640 · Cited by 36 · see citing works
Correction: Phosphorylation of Daxx by ATM Contributes to DNA Damage-Induced p53 Activation
Tang, J., Agrawal, T., Cheng, Q., Qu, L., Brewer, M. D., Chen, J., & Yang, X. (2013) · PLoS ONE · doi:10.1371/annotation/032b026d-5bcf-4c1b-aa15-65c226a53818 · Cited by 36 · see citing works
Self-citationThe p53-Mdm2 Loop: A Critical Juncture of Stress Response
Levav-Cohen, Y., Goldberg, Z., Tan, K. H., Alsheich-Bartok, O., Zuckerman, V., Haupt, S., & Haupt, Y. (2014) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-017-9211-0_9 · Cited by 36 · see citing works
Carr, M. I., Roderick, J. E., Gannon, H., Kelliher, M. A., & Jones, S. N. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.08.014 · Cited by 34 · see citing works
SMG7 is a critical regulator of p53 stability and function in DNA damage stress response
Luo, H., Cowen, L. E., Yu, G., Jiang, W. G., & Tang, Y. (2016) · Cell Discovery · doi:10.1038/celldisc.2015.42 · Cited by 33 · see citing works
The roles of MDM2 and MDMX phosphorylation in stress signaling to p53
Chen, J. (2012) · Genes & Cancer · doi:10.1177/1947601912454733 · Cited by 33 · see citing works
Self-citationChen, Z., Cao, Z., Zhang, W., Gu, M., Zhou, Z., Li, B., Li, J., Tan, E., & Zeng, L. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx337 · Cited by 32 · see citing works
Abnormal MDMX degradation in tumor cells due to ARF deficiency
Li, X., Gilkes, D., Li, B., Cheng, Q., Pernazza, D., Lawrence, H., Lawrence, N., & Chen, J. (2012) · Oncogene · doi:10.1038/onc.2011.534 · Cited by 32 · see citing works
Self-citationRegulation of E3 ubiquitin ligases by homotypic and heterotypic assembly
Balaji, V., & Hoppe, T. (2020) · F1000Research · doi:10.12688/f1000research.21253.1 · Cited by 32 · see citing works
Wu, B., Chu, X., Feng, C., Hou, J., Fan, H., Liu, N., Li, C., Kong, X., Ye, X., & Meng, S. (2015) · Cancer Letters · doi:10.1016/j.canlet.2015.01.034 · Cited by 32 · see citing works
c-Abl Phosphorylation of Mdm2 Facilitates Mdm2-Mdmx Complex Formation
Waning, D. L., Lehman, J. A., Batuello, C. N., & Mayo, L. D. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.183012 · Cited by 30 · see citing works
Controlling the Mdm2-Mdmx-p53 Circuit
Waning, D. L., Lehman, J. A., Batuello, C. N., & Mayo, L. D. (2010) · Pharmaceuticals · doi:10.3390/ph3051576 · Cited by 30 · see citing works
Phosphorylation of Daxx by ATM contributes to DNA damage-induced p53 activation.
Tang, J., Agrawal, T., Cheng, Q., Qu, L., Brewer, M. D., Chen, J., & Yang, X. (2013) · PLoS ONE · doi:10.1371/journal.pone.0055813 · Cited by 28 · see citing works
Self-citationMdm2 links genotoxic stress and metabolism to p53
Wang, Z., & Li, B. (2010) · Protein & Cell · doi:10.1007/s13238-010-0140-9 · Cited by 29 · see citing works
It Takes 15 to Tango: Making Sense of the Many Ubiquitin Ligases of p53
Love, I. M., & Grossman, S. R. (2012) · Genes & Cancer · doi:10.1177/1947601912455198 · Cited by 28 · see citing works
MDM2-Driven Ubiquitination Rapidly Removes p53 from Its Cognate Promoters
Henningsen, K. M., Manzini, V., Magerhans, A., Gerber, S., & Dobbelstein, M. (2021) · Biomolecules · doi:10.3390/biom12010022 · Cited by 27 · see citing works
Functional analysis and consequences of Mdm2 E3 ligase inhibition in human tumor cells
Wade, M. R., Li, Y. C., Matani, A. S., Braun, S. M. G., Milanesi, F., Rodewald, L. W., & Wahl, G. M. (2012) · Oncogene · doi:10.1038/onc.2011.625 · Cited by 25 · see citing works
Ubiquitination of human AP-endonuclease 1 (APE1) enhanced by T233E substitution and by CDK5
Busso, C. S., Wedgeworth, C. M., & Izumi, T. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr401 · Cited by 24 · see citing works
Structural basis of how stress-induced MDMX phosphorylation activates p53
Chen, X., Gohain, N., Zhan, C., Lu, W.-Y., Pazgier, M., & Lu, W. (2015) · Oncogene · doi:10.1038/onc.2015.255 · Cited by 22 · see citing works
Mdm2's Dilemma: To Degrade or To Translate p53?
Hamard, P.-J., & Manfredi, J. J. (2012) · Cancer Cell · doi:10.1016/j.ccr.2011.12.018 · Cited by 23 · see citing works
Autoactivation of the MDM2 E3 Ligase by Intramolecular Interaction
Cheng, Q., Song, T., Chen, L., & Chen, J. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.00246-14 · Cited by 24 · see citing works
Self-citationBTK blocks the inhibitory effects of MDM2 on p53 activity
Rada, M., Althubiti, M., Ekpenyong‐Akiba, A. E., Lee, K.-G., Lam, K., Fedorova, O., Barlev, N. A., & Macip, S. (2017) · Oncotarget · doi:10.18632/oncotarget.22543 · Cited by 23 · see citing works
Mutant p53 Sequestration of the MDM2 Acidic Domain Inhibits E3 Ligase Activity
Yang, L., Song, T., Cheng, Q., Chen, L., & Chen, J. (2018) · Molecular and Cellular Biology · doi:10.1128/mcb.00375-18 · Cited by 23 · see citing works
Self-citationThe roles of mouse double minute 2 (MDM2) oncoprotein in ocular diseases: A review
Jiang, H., Luo, J., & Lei, H. (2022) · Experimental Eye Research · doi:10.1016/j.exer.2021.108910 · Cited by 23 · see citing works
The phenotype of MDM2 auto-degradation after DNA damage is due to epitope masking by phosphorylation
Cheng, Q., & Chen, J. (2011) · Cell Cycle · doi:10.4161/cc.10.7.15249 · Cited by 21 · see citing works
Self-citationProtecting the genome from mdm2 and mdmx
Melo, A. N., & Eischen, C. M. (2012) · Genes & Cancer · doi:10.1177/1947601912454139 · Cited by 20 · see citing works
Wang, J., Zhao, B., Yi, Y., Zhang, W., Wu, X., Zhang, L., & Shen, Y. (2012) · Biochemical Pharmacology · doi:10.1016/j.bcp.2012.07.004 · Cited by 20 · see citing works
Mouse modelling of the MDM2/MDMX−p53 signalling axis
Tackmann, N. R., & Zhang, Y. (2017) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjx006 · Cited by 21 · see citing works
MDM2 oligomers: antagonizers of the guardian of the genome
Leslie, P. L., & Zhang, Y. (2016) · Oncogene · doi:10.1038/onc.2016.88 · Cited by 17 · see citing works
MDM2 Overexpression, Activation of Signaling Networks, and Cell Proliferation
Deb, S. P., Singh, S., & Deb, S. (2014) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-017-9211-0_12 · Cited by 17 · see citing works
Roszak, A., Misztal, M., Sowińska, A., & Jagodziński, P. P. (2015) · Molecular Diagnosis & Therapy · doi:10.1007/s40291-015-0153-4 · Cited by 16 · see citing works
Lin, L., Qin, Y., Wu, H., Chen, Y., Wu, S., Si, X., Wang, H., Wang, T., Zhong, X., Zhai, X., et al. (2014) · Virus Research · doi:10.1016/j.virusres.2014.10.012 · Cited by 16 · see citing works
- Authors
- Cheng, Q., Chen, L., Li, Z., Lane, W. S., & Chen, J.
- Affiliations
- Moffitt Cancer Center (US)
- Harvard University (US)
- Corresponding author
- Chen, Jiandong
- Venue
- The EMBO Journal
- Published
- 2009-10-08
- Volume
- 28
- Issue
- 24
- Pages
- 3857-3867
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC2797053
- OpenAlex
- W2052556036
- Semantic Scholar
- e88bddccda91d2be900f5ee68192e79d03ef8b2a
- Cited by
- 165
- References
- 47
- Citations by year
- 2026: 11 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 10 · 2021: 7 · 2020: 9 · 2019: 4 · 2018: 6 · 2017: 11 · 2016: 8 · 2015: 14 · 2014: 11 · 2013: 12 · 2012: 23
- FWCI
- 8.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA109636, CA 109636, CA118219)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- ATM kinase, p53 stabilization, MDM2, proteasomal degradation, DNA damage response, ionizing radiation, kinase phosphorylation
- MeSH terms
- Amino Acid Sequence, Cell Line, Chromatography, Gel, DNA Damage, DNA-Binding Proteins, Humans, Molecular Sequence Data, Phosphorylation, Signal Transduction, Tumor Suppressor Protein p53, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Tumor Suppressor Proteins, Ubiquitin, Ubiquitin-Protein Ligases, Cell Line, Tumor, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-mdm2, Ataxia Telangiectasia Mutated Proteins
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