The DOI matches its Crossref record; 45 of the 47 references it cites were found in a registry or an index; none of the 25 sources its claims cite is checked for support yet.
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.
Overview
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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.
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Claims the paper makes
24 Own result · 15 Not checked yet · 13 Own interpretation · 5 Own method · 1 No basis given
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Blocking MDM2 phosphorylation by alanine substitution of all six phosphorylation sites results in constitutive degradation of p53 after DNA damage.”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Alanine substitution at the six MDM2 phosphorylation sites prevents their phosphorylation.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, S386E and S429D phospho-mimic mutants were partially defective in p53 degradation (Figure 3A).”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Mimicry of MDM2 phosphorylation specifically blocks degradation of p53
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Phosphomimic substitutions with aspartate or glutamate at ATM target sites functionally mimic phosphorylation of MDM2.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Identification of novel MDM2 phosphorylation sites
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Inhibition of p53 stabilization by MDM2 phosphorylation mutant.”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Gel filtration chromatography
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Regulation of cell cycle and long-term survival after IR by MDM2 mutants.”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Gel filtration chromatography
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“DNA damage inhibits MDM2 RING domain oligomerization.”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Gel filtration chromatography
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Diagram shows MDM2 and relative positions of phosphorylation sites (underlined) identified by mass spectrometry.”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Gel filtration chromatography
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ATM-dependent phosphorylation of S386 and S429 after DNA damage.”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Gel filtration chromatography
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Regulation of cell cycle and long-term survival after IR by MDM2 mutants.”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Gel filtration chromatography
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Analysis of MDM2 in ATMdeficient human skin fibroblast Hs235 showed that ATM expression was needed for S386 and S429 phosphorylation after IR (Figure 2B).”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > ATM-dependent phosphorylation of S386 and S429
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- It may state two separate claims as one. 14
- Probably not a substantial claim. 10
- The quote only partly states this claim. 2
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“MDM2 phosphorylation was induced rapidly after IR before significant accumulation of p53, and peaked about 2.5 h in SJSA cells (Figure 2A).”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > ATM-dependent phosphorylation of S386 and S429
plaincorrelational- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Gel filtration chromatography
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > ATM-dependent phosphorylation of S386 and S429
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Effects of MDM2 phosphorylation site mutation on p53 and MDMX degradation.”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Gel filtration chromatography
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > ATM-dependent phosphorylation of S386 and S429
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“Furthermore, Chk1 and Chk2 failed to phosphorylate S386 and S429 in vitro, but phosphorylated the positive control site MDMX S367 (Chen et al, 2005).”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > ATM-dependent phosphorylation of S386 and S429
What the sources say
- Not checked yetcites Chen et al, 2005 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Phosphorylation by ATM inhibits RING domain oligomerization, specifically suppressing p53 poly ubiquitination.”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Introduction
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“However, biochemical analysis using phosphorylated p53 peptide indicated that S15 and S20 phosphorylation do not prevent MDM2 binding in vitro (Bottger et al, 1999).”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Introduction
What the sources say
- Not checked yetcites Bottger et al, 1999 source
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“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).”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Introduction
What the sources say
- Not checked yetcites Zhang and Xiong, 2001
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“His6-MDM2 produced in E. coli was used to rule out cross reactivity.”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Gel filtration chromatography
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the absence of DNA damage, MDM2 RING domain forms oligomers that recruit multiple E2s, increasing the processivity of ubiquitin chain elongation.”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Gel filtration chromatography
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: High-order E3 structures help expose multiple E2 active sites to the substrate and speed up the reaction.
None of the sources cited for this claim have been checked yet.
In the paper
“Formation of high-order oligomers is a common feature of RING domains (Kentsis et al, 2002;Poyurovsky et al, 2007).”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Discussion
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The sizes of RING fragment complexes were determined by comparing the elution profile to a molecular weight standard fractionated under identical conditions.”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Gel filtration chromatography
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Identification of novel MDM2 phosphorylation sites
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Discussion
What the sources say
- Not checked yetcites Tang et al, 2007 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Dephosphorylation by CIP was performed on immobilized MDM2 before p53 capture.”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Gel filtration chromatography
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“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).”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Discussion
What the sources say
- Not checked yetcites Barbash et al, 2008 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“GST-MDMX-280-490 was used as a positive control for Chk2 phosphorylation of S367.”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Gel filtration chromatography
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Introduction
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“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).”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Introduction
What the sources say
- Not checked yetcites Chao et al, 2006 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Caspase 3 cleaves MDM2 at a single site (361) and releases the C-terminal fragment 362-491 containing the phosphorylation sites and RING domain.”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Gel filtration chromatography
What the sources say
- Not checked yetcites Chen et al, 1997 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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?
In the citing paper
“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 the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Gel filtration chromatography
“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”
§ ATM activates p53 by regulating MDM2 oligomerization and E3 processivity > Gel filtration chromatography
“irradiated with 10 Gy IR for 1 h, immunoprecipitated using MDM2 antibody 4B2, and cleaved with Caspase 3.”
Citations
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
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
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
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 1,769
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
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
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Substrate Specificities and Identification of Putative Substrates of ATM Kinase Family Members
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ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage
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“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).”
Background
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Metadata
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-08, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-08 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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