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ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage
Open accessAbstract
The p53 tumor suppressor is activated after DNA damage to maintain genomic stability and prevent transformation. Rapid activation of p53 by ionizing radiation is dependent on signaling by the ATM kinase. MDM2 and MDMX are important p53 regulators and logical targets for stress signals. We found that DNA damage induces ATM-dependent phosphorylation and degradation of MDMX. Phosphorylated MDMX is selectively bound and degraded by MDM2 preceding p53 accumulation and activation. Reduction of MDMX level by RNAi enhances p53 response to DNA damage. Loss of ATM prevents MDMX degradation and p53 stabilization after DNA damage. Phosphorylation of MDMX on S342, S367, and S403 were detected by mass spectrometric analysis, with the first two sites confirmed by phosphopeptide-specific antibodies. Mutation of MDMX on S342, S367, and S403 each confers partial resistance to MDM2-mediated ubiquitination and degradation. Phosphorylation of S342 and S367 in vivo require the Chk2 kinase. Chk2 also stimulates MDMX ubiquitination and degradation by MDM2. Therefore, the E3 ligase activity of MDM2 is redirected to MDMX after DNA damage and contributes to p53 activation.
Overview
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Written from the paper’s full text.
TL;DR
DNA damage induces ATM- and Chk2-dependent phosphorylation of MDMX at C-terminal serines, promoting MDM2 binding, ubiquitination, and degradation of MDMX, which contributes to p53 activation. Reducing MDMX by RNAi enhances p53 response and cell-cycle arrest after ionizing radiation.
Key findings
- DNA damage induces MDMX phosphorylation and degradation; phosphorylated MDMX is selectively bound and degraded by MDM2, and ATM-deficient fibroblasts fail to induce MDMX mobility shift/degradation after radiation.
- Mass spectrometry mapped MDMX phosphorylation on S161 (post-IR), S342 (pre- and post-IR), S367 (pre- and post-IR), S391 (post-IR), and S403 (post-IR), with approximately 77% peptide coverage; S342 and S367 were confirmed by phosphopeptide-specific antibodies.
- Mutation of S342, S367, and S403 each reduced MDM2-mediated polyubiquitination, with S367 having the most significant effect; the triple alanine mutant MDMX-3A was resistant to degradation after DNA damage and inhibited p53 activation more efficiently than wild-type MDMX.
- Chk2 was required in vivo for S342 and S367 phosphorylation after irradiation; Chk2-null HCT116 cells showed less efficient MDMX degradation and reduced p53 stabilization, MDM2 induction, and p21 induction after 5 Gy. MDMX siRNA (200 nM) in U2OS cells increased p53 target induction after 10 Gy and made DNA synthesis inhibition after gamma irradiation significantly more efficient by BrdU ELISA (n=4).
Methods
- Cell lines included MCF7, U2OS, H1299, Saos2, HCT116 wild-type/p53-null/Chk2-null, ATM-deficient Hs235.Sk, and normal human skin fibroblasts; experiments used MDMX point mutants, MDMX siRNA, retrovirus, ionizing radiation, MG132, caffeine, cycloheximide, and MDM2 antisense oligonucleotide.
- Protein analysis used Western blot, gradient gel electrophoresis, immunoprecipitation, GST-MDM2 pull-down, calf intestinal phosphatase treatment, and BrdU incorporation ELISA; phosphorylation-specific antibodies against PS342 and PS367 were generated and validated.
- Phosphorylation site mapping used FLAG-MDMX affinity purification, trypsin digestion, and LCQ DECA XP Plus ion trap MS/MS with SEQUEST/MUQUEST/FUZZYIONS; 32P metabolic labeling with 2-D phospho-amino-acid analysis and in vitro kinase reactions with ATM, Chk1, Chk2, Akt1, and CK1α were also performed.
Limitations
- Stated in the paper: lack of a viable Chk1-null mammalian cell line and strong toxicity of Chk1 siRNA hampered investigation of Chk1’s role; lack of a PS403 antibody precluded testing direct ATM modification of S403; more rigorous testing of cooperative phosphorylation requires gene replacement to avoid MDMX overexpression; the Chk2-null result differed from a prior study, possibly due to experimental conditions.
- Evident from the text: many conclusions rely on transfected/overexpressed MDMX and single versus triple mutants, with single mutants showing only minor differences in U2OS p53 activation; no animal models are reported, and the authors note Chk2 effects may be subtle and cell-line/damage-dose dependent.
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Claims the paper makes
53 Own result · 28 Own interpretation · 26 Not checked yet · 2 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
“We found that DNA damage induces ATMdependent phosphorylation and degradation of MDMX.”
- Also stated in: § DNA damage induces degradation of MDMX · plain
“MDMX was stable before irradiation but was rapidly degraded after DNA damage (Figure 1C).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Abstract
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- Also stated in: § DNA damage induces degradation of MDMX · plain
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
“Loss of ATM prevents MDMX degradation and p53 stabilization after DNA damage.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Abstract
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In the paper
“Mutation of MDMX on S342, S367, and S403 each confers partial resistance to MDM2-mediated ubiquitination and degradation.”
- Also stated in: § Phosphorylation site mutations reduce ubiquitination and degradation by MDM2 · plain
“The results showed that mutating S342, S367, and S403 each resulted in reduced poly-ubiquitination by MDM2, with S367 having the most significant effect (Figure 6C).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Abstract
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- Also stated in: § Phosphorylation site mutations reduce ubiquitination and degradation by MDM2 · plain
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In the paper
“Phosphorylation of MDMX on S342, S367, and S403 were detected by mass spectrometric analysis, with the first two sites confirmed by phosphopeptide-specific antibodies.”
- Also stated in: § Identification of phosphorylation sites on MDMX · plain
“Analysis of the MS results led to detection of phosphorylation on S161 (post-IR), S342 (preand post-IR), S367 (pre-and post-IR), S391 (post-IR), and S403 (post-IR).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Abstract
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- Also stated in: § Identification of phosphorylation sites on MDMX · plain
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In the paper
“Phosphorylation of S342 and S367 in vivo require the Chk2 kinase.”
- Also stated in: § Phosphorylation of MDMX by Chk2 · hedged
“Loss of Chk2 abrogated the induction of S342 and S367 phosphorylation after irradiation (Figure 8C), suggesting that Chk2 is required for the phosphorylation of both sites in vivo.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Abstract
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- Also stated in: § Phosphorylation of MDMX by Chk2 · hedged
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In the paper
“Inhibition of MDM2 expression led to the accumulation of slow migrating MDMX after radiation, similar to the effect of proteasome inhibition by MG132 (Figure 2C).”
- Also stated in: § Phosphorylation of MDMX promotes degradation by MDM2 · plain
“Therefore, MDM2 expression was required for the rapid degradation of phosphorylated MDMX after DNA damage.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX promotes degradation by MDM2
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- Also stated in: § Phosphorylation of MDMX promotes degradation by MDM2 · plain
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In the paper
“Chk2 also stimulates MDMX ubiquitination and degradation by MDM2.”
- Also stated in: § Phosphorylation of MDMX by Chk2 · boosted
“As expected, cotransfection of Chk2 strongly stimulated MDMX ubiquitination and degradation (Figure 9B).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Abstract
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- Also stated in: § Phosphorylation of MDMX by Chk2 · boosted
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In the paper
“with the first two sites confirmed by phosphopeptide-specific antibodies.”
- Also stated in: § Detection of MDMX phosphorylation by peptide-specific antibodies · plain
“The specificity of the antibodies was confirmed by the lack of binding to un-phosphorylated His6-MDMX produced in Escherichia coli (Figure 7A and B).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Abstract
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- Also stated in: § Detection of MDMX phosphorylation by peptide-specific antibodies · plain
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In the paper
“ATMdeficient fibroblasts failed to induce MDMX mobility shift and degradation after DNA damage (Figure 3C), demonstrating that ATM activity was required for this response.”
- Also stated in: § Phosphorylation of MDMX by Chk2 · plain
“Treatment of U2OS-MDMX cells with caffeine blocked induction of S342 and S367 phosphorylation after gamma irradiation (Figure 8B).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > ATM is required for stimulating MDMX phosphorylation
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- Also stated in: § Phosphorylation of MDMX by Chk2 · plain
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In the paper
“We found that DNA damage induces ATMdependent phosphorylation and degradation of MDMX.”
- Also stated in: § Phosphorylation of MDMX promotes degradation by MDM2 · hedged
“This treatment restored the mobility of the slow-migrating MDMX (Figure 2A), suggesting that DNA damage induced phosphorylation of MDMX.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Abstract
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- Also stated in: § Phosphorylation of MDMX promotes degradation by MDM2 · hedged
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In the paper
“The results showed that after irradiation, MDM2 co-precipitated more phosphorylated forms of MDMX than the unmodified form, despite both forms were present at comparable levels in the cell lysate (Figure 2D).”
- Also stated in: § Phosphorylation of MDMX promotes degradation by MDM2 · plain
“Incubation of GST-MDM2-loaded beads with HCT116 extract also selectively captured phosphorylated endogenous MDMX (Figure 2E).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX promotes degradation by MDM2
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- Also stated in: § Phosphorylation of MDMX promotes degradation by MDM2 · plain
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In the paper
“MDMX phosphorylation was detectable 15 min after IR in MCF7 cells (Figure 3A).”
- Also stated in: § ATM is required for stimulating MDMX phosphorylation · plain
“Significant stabilization of p53 was detected at the 2 and 4-h time points, correlating with the degradation of phosphorylated forms of MDMX.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > ATM is required for stimulating MDMX phosphorylation
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- Also stated in: § ATM is required for stimulating MDMX phosphorylation · plain
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In the paper
“Reduction of MDMX level by RNAi enhances p53 response to DNA damage.”
- Also stated in: § Reduction of MDMX level increases p53 response to DNA damage · plain
“However, higher expression levels of p53 target MDM2 and p21 were induced by gamma radiation compared to control siRNA-treated cells.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Abstract
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- Also stated in: § Reduction of MDMX level increases p53 response to DNA damage · plain
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In the paper
“The results showed that DNA synthesis inhibi- tion after gamma irradiation was significantly more efficient in MDMX knockdown cells compared to controls (Figure 4B).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Reduction of MDMX level increases p53 response to DNA damage
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“The casein kinase 1 alpha isoform that binds and phosphorylates MDMX in the central region in such reactions (Chen et al, 2005) did not target S342 and S367 (Figure 8A).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX by Chk2
What the sources say
- Not checked yetcites Chen et al, 2005 source
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In the paper
“Results described above showed that MDMX undergoes significant phosphorylation and degradation after DNA damage in an ATM and Chk2-dependent fashion.”
- Also stated in: § Discussion · boosted
“In summary, we have shown that DNA damage induces phosphorylation of MDMX through an ATM and Chk2dependent pathway, resulting in the degradation of MDMX by MDM2.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
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In the paper
“Although multiple phosphorylations are necessary for a complete phenotype, our results showed that knockout of Chk2 alone can have measurable effects on MDMX degradation and p53 activation under certain conditions such as gamma irradiation.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
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In the paper
“Gradient gel analysis of endogenous MDMX from MCF7 and SJSA cells treated with gamma radiation and MG132 revealed that a slower migrating form of MDMX accumulated 3-6 h after DNA damage (Figure 1D).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > DNA damage induces degradation of MDMX
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In the paper
“Phosphorylation signals were detectable in the nonirradiated MDMX sample for S342 and S367, suggesting the presence of basal phosphorylation.”
- Also stated in: § Detection of MDMX phosphorylation by peptide-specific antibodies · plain
“The results showed that low levels of MDMX phosphorylation on S342 and S367 were detected in the absence of DNA damage (Figure 7A and B), consistent with MS results.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Identification of phosphorylation sites on MDMX
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In the paper
“The results showed that mutation of S342, S367, and S403 significantly blocked mobility shift after DNA damage (Figure 6A), suggesting that phosphorylation of these serine residues contributed to the mobility shift.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation site mutations reduce ubiquitination and degradation by MDM2
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In the paper
“Although S367 is in an optimal sequence context for Akt1, it was not modified by Akt1 in vitro (Figure 8A).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX by Chk2
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In the paper
“Gamma irradiation significantly increased the phosphorylation levels of S342 and S367 in MCF7 cells in the presence of MG132 (Figure 7A and B).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Detection of MDMX phosphorylation by peptide-specific antibodies
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In the paper
“The results showed that within the sensitivity limit of this assay, the 367A mutant was significantly more resistant to degradation by MDM2 (Figure 6B), suggesting that phosphorylation of S367 may be critical for this function.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation site mutations reduce ubiquitination and degradation by MDM2
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In the paper
“The results showed that mutating the adjacent sites had no effect on the phosphorylation of S342 and S367 (Figure 7D).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Detection of MDMX phosphorylation by peptide-specific antibodies
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In the paper
“Most of the phosphorylation sites identified on MDMX are localized near the C-terminal RING domain, consistent with the observed impact on MDM2 binding and degradation.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
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In the paper
“Mutations on S161 and S391 had little effect on MDMX ubiquitination.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation site mutations reduce ubiquitination and degradation by MDM2
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“In vivo 32 P phosphate metabolic labeling and phosphopeptide analysis of MDMX revealed that S367 is the most heavily phosphorylated residue on MDMX after DNA damage (LeBron and Chen, unpublished observation).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
What the sources say
- Not checked yetcites LeBron and Chen, unpublished observation
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In the paper
“Irradiation dosage alone is probably not the cause, since the deficiency we observed in the HCT116-Chk2À/À cells were reproducible in a range between 5 and 20 Gy (data not shown).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX by Chk2
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In the paper
“Analysis of the cotransfected cells by MDM2 IP-MDMX Western blot showed that the 367A mutation did not prevent MDM2 binding (Figure 6B).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation site mutations reduce ubiquitination and degradation by MDM2
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In the paper
“ATMdeficient fibroblasts failed to induce MDMX mobility shift and degradation after DNA damage (Figure 3C), demonstrating that ATM activity was required for this response.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > ATM is required for stimulating MDMX phosphorylation
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In the paper
“Chk1 also efficiently modifies S342 in vitro, it is likely that Chk1 plays a role in the basal phosphorylation of MDMX in the absence of DNA damage.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
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In the paper
“In fact, mutation of S367 has the most dramatic effect on MDMX ubiquitination and stability (Figure 6).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
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In the paper
“When MDMX was ectopically expressed in p53-null H1299 or Saos2 cells with very low levels of MDM2, the accumulation of slow migrating MDMX was evident after gamma irradiation without MG132 treatment, possibly due to saturation of the MDM2 degradation system (Figure 1D).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > DNA damage induces degradation of MDMX
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In the paper
“In wild-type HCT116 cells, Chk2-A347 reduced S367 phosphorylation, possibly through dominant-negative effect (Figure 9A).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX by Chk2
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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
“However, DNA damage-induced phosphorylation of S342 and S367 strictly requires Chk2.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
boosteddirect- 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
“These results confirmed that the decrease in MDMX level was due to reduced stability.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > DNA damage induces degradation of MDMX
boosteddirect- 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
“Results described above showed that MDMX undergoes significant phosphorylation and degradation after DNA damage in an ATM and Chk2-dependent fashion.”
- Also stated in: § Discussion · boosted
“In summary, we have shown that DNA damage induces phosphorylation of MDMX through an ATM and Chk2dependent pathway, resulting in the degradation of MDMX by MDM2.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
boosteddirect- 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.
- Also stated in: § Discussion · boosted
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
“Transient knock-down of MDMX resulted in moderate increase of p53 level in the absence of DNA damage (Figure 4A).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Reduction of MDMX level increases p53 response to DNA damage
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether 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
“We show here that phosphorylation of MDMX S342 and S367 by Chk2 promote its ubiquitination and degradation by MDM2.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
boosteddirect- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“However, mutations of phosphorylation sites for these kinases on p53 and MDM2 or siRNA knockdown of Chk1 and Chk2 kinases lead to partial or no phenotypes (Wu et al, 2002;Ahn et al, 2003;Chao et al, 2003;Sluss et al, 2004), suggesting that additional targets and mechanisms may also contribute to activation of p53 after DNA damage.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Introduction
What the sources say
hedgeddirect- 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.
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
“This suggests that unlike MDM2, MDMX may not be directly modified by the c-Abl tyrosine kinase.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Chk1 also efficiently modifies S342 in vitro, it is likely that Chk1 plays a role in the basal phosphorylation of MDMX in the absence of DNA damage.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Therefore, the C-terminal region of MDMX contains sequence important for phosphorylation.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Identification of phosphorylation sites on MDMX
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“A recent study was able to demonstrate the phosphorylation of S403 by ATM using a phosphorylation-specific antibody (Pereg et al, 2005).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX by Chk2
What the sources say
- Not checked yetcites Pereg et al, 2005 source
boosteddirect- 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 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
“This result suggested that multiple phosphorylation events cooperate to regulate MDMX degradation after DNA damage.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation site mutations reduce ubiquitination and degradation by MDM2
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“S403 is in a favorable context for ATM and a recent study by Pereg et al (2005) provided direct evidence that it is an ATM target site.”
- Also stated in: § Discussion · plain
“Our results of S403 phosphorylation also corroborate recent findings from Pereg et al (2005) on ATM modification of this site.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
What the sources say
- Not checked yetcites Pereg et al (2005) source
boosteddirect- 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.
- Also stated in: § Discussion · plain
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
“Therefore, reduction of MDMX level sensitizes p53 to DNA damage.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Reduction of MDMX level increases p53 response to DNA damage
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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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
“This result suggested that the modification at each site was independently regulated after DNA damage.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Detection of MDMX phosphorylation by peptide-specific antibodies
hedged- 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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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
“Most of the phosphorylation sites identified on MDMX are localized near the C-terminal RING domain, consistent with the observed impact on MDM2 binding and degradation.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Studies using Chk2-null mice, Chk2-null HCT116 cells, and Chk2 siRNA resulted in different conclusions (Zhang et al, 1998;Chehab et al, 2000;Shieh et al, 2000;Ahn et al, 2003; Jallepalli et al, 2003).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
What the sources say
plain- 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.
- Based: passes — The paper gives a reason why it holds.
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
“Irradiation dosage alone is probably not the cause, since the deficiency we observed in the HCT116-Chk2À/À cells were reproducible in a range between 5 and 20 Gy (data not shown).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX by Chk2
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Therefore, ATM or ATR was important for the induction of MDMX phosphorylation after DNA damage.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > ATM is required for stimulating MDMX phosphorylation
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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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
“This work and our previous study also reveal an important function of MDM2 in regulating MDMX stability in response to mitogenic stress and DNA damage.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
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 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
“This event contributes to p53 activation after DNA damage.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
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 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
“The intricate interplay between MDM2 and MDMX and their connection to stress signaling pathways are likely to be critical for the dynamic regulation of p53.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: unclear — It is unclear whether it could be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Therefore, Chk2 contributes to p53 regulation in part through phosphorylation of MDMX.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
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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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
“It is apparent that combination of these and possibly additional changes on multiple targets in the p53 pathway lead to timely activation of p53 and G1 arrest in response to DNA damage.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
hedgeddirect- 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 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
“However, a single defect in Chk2 alone may have subtle, cell line and damage dose-dependent effects on p53 response that often elude detection.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether 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. 42
- Probably not a substantial claim. 17
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
“In vivo metabolic labeling revealed that MDMX is predominantly phosphorylated on serine, with minor modifications on threonine and no detectable modification on tyrosine.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether 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
“Western blot showed that Chk1 modified S342 and S367, but with strong preference for S342.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX by Chk2
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether 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
“Furthermore, endogenous MDMX phosphorylated on S342 or S367 were rapidly degraded after DNA damage and only accumulate after MG132 treatment.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Detection of MDMX phosphorylation by peptide-specific antibodies
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
“ATM immunoprecipitated from transfected cells phosphorylated S15 of p53 but did not show specific modification of MDMX on S342 and S367.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX by Chk2
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 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
“This treatment partially inhibited the mobility shift and degradation of MDMX after radiation (Figure 3B).”
- Also stated in: § ATM is required for stimulating MDMX phosphorylation · plain
“As expected, caffeine also blocked stabilization of p53 and induction of MDM2 and p21 (Figure 3B and data not shown).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > ATM is required for stimulating MDMX phosphorylation
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.
- Also stated in: § ATM is required for stimulating MDMX phosphorylation · plain
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, further tests of a panel of cell lines showed that MDMX downregulation also occur in p53-deficient HCT116 cells and p53-mutant DLD1 and C33A cells without induction of MDM2 (Figure 1B).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > DNA damage induces degradation of MDMX
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
“The results indicated that deletion of the MDMX C-terminal RING domain caused a complete loss of mobility shift after DNA damage, whereas deletion of the N-terminal p53-binding domain did not prevent phosphory- lation (Figure 5B).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Identification of phosphorylation sites on MDMX
hedgeddirect- 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
“Phospho-amino-acid analysis showed that MDMX was mainly phosphorylated on serine in vivo, with minor labeling of threonine and no detectable phosphorylation of tyrosine (Figure 5A).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Identification of phosphorylation sites on MDMX
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether 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
“In cotransfection experiments, MDMX ubiquitination and degradation by MDM2 can occur in both wild-type and Chk2-null HCT116 cells, suggesting that Chk2 was not absolutely necessary under these conditions.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX by Chk2
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether 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
“The results showed that agents that can induce DNA damage were all capable of inducing MDMX phosphorylation.Microtubule targeting agents taxol and nocodazole did not cause MDMX mobility shift (Figure 2B), suggesting that the effect was unique to DNA-damaging drugs.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX promotes degradation by MDM2
hedgeddirect- 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
“Chk2 modified both S342 and S367, but with strong preference for S367 (Figure 8A).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX by Chk2
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
“When the HCT116-Chk2À/À cells were compared to wildtype HCT116 after gamma irradiation (5 Gy), we reproducibly found that MDMX degradation was much less efficient (Figure 9C).MDM2 and p21 induction and p53 stabilization were also reduced compared to wild-type cells (Figure 9C).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX by Chk2
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
“However, the triple alanine compound mutant (MDMX-3A) showed significant resistance to degradation after DNA damage, and inhibited p53 activation more efficiently than wild-type MDMX (Figure 6D).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation site mutations reduce ubiquitination and degradation by MDM2
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
“Cotransfection of MDMX and Chk2 plasmid into HCT116-Chk2À/À cells restored the phosphorylation of MDMX S367 after gamma irradiation, whereas kinase-dead Chk2-A347 mutant, activated myr-Akt1 and CK1a had no effect (Figure 9A).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX by Chk2
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
“However, expression of MDM2 stimulated MDMX ubiquitination more significantly in wild-type HCT116 compared to the Chk2-null cells (Figure 9B), consistent with Chk2 being a facilitator.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX by Chk2
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
“Of the three functionally relevant phosphorylation sites identified in this study, S342 and S367 are targets of Chk2 in vitro and in vivo.”
- Also stated in: § Discussion · boosted
“We show here that Chk2 is directly involved in the phosphorylation of MDMX on S342 and S367.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
boosteddirect- 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.
- Also stated in: § Discussion · boosted
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
“Weak modification of S342 by Akt1 was detected, the significance of this reaction is not clear at present.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX by Chk2
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. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“DNA damage induced by ionizing irradiation also promotes MDMX nuclear translocation and degradation by the proteasomes (Li et al, 2002;Pan and Chen, 2003).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Introduction
What the sources say
- Not checked yetcites Li et al, 2002
- Not checked yetcites Pan and Chen, 2003 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
“Recent evidence showed that MDMX cooperates with MDM2 to promote p53 degradation (Gu et al, 2002).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Introduction
What the sources say
- Not checked yetcites Gu et al, 2002
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
“MDMX shares strong homology to MDM2 at the amino-acid sequence level and can bind to p53 and inhibit its transcriptional function.However, MDMX alone does not promote p53 ubiquitination or degradation in vivo (Stad et al, 2001).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Introduction
What the sources say
- Not checked yetcites Stad et al, 2001 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.
None of the sources cited for this claim have been checked yet.
In the paper
“Several studies showed that MDMX-null mice also die in utero in a p53-dependent fashion, which can be rescued by crossing into the p53-null background (Finch et al, 2002;Migliorini et al, 2002;Parant et al, 2002).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > 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: unclear — It is unclear whether 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
“P53 turnover is regulated by MDM2, which binds p53 and functions as an ubiquitin E3 ligase to promote p53 degradation by the proteasomes (Zhang and Xiong, 2001).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > 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.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“ATM phosphorylates p53 on serine 15, enhancing its transcriptional activity (Banin et al, 1998).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Introduction
What the sources say
- Not checked yetcites Banin et al, 1998 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.
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
“Therefore, the E3 ligase activity of MDM2 is redirected to MDMX after DNA damage and contributes to p53 activation.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > 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.
In the paper
“Stress signals such as DNA damage induce p53 accumulation by phosphorylation (Prives and Hall, 1999).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Introduction
What the sources say
- Not checked yetcites Prives and Hall, 1999 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.
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 serine 20 and inhibits MDM2 binding (Shieh et al, 1997;Banin et al, 1998;Chehab et al, 2000;Shieh et al, 2000).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > 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: 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.
In the paper
“A recent study showed that DNA damage also induces MDMX degradation in p53-deficient cells, without induction of MDM2 (Kawai et al, 2003).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Introduction
What the sources say
- Not checked yetcites Kawai et al, 2003 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
“ATM functions as the primary signal transducer of DNA double-strand breaks (Shiloh, 2003).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Introduction
What the sources say
- Not checked yetcites Shiloh, 2003 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.
In the paper
“The importance of ATM in rapid p53 activation after ionizing radiation (IR) was revealed by the delay in p53 accumulation in ATM-deficient cells (Kastan et al, 1993).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Introduction
What the sources say
- Not checked yetcites Kastan et al, 1993 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.
None of the sources cited for this claim have been checked yet.
In the paper
“Several reports showed that MDMX can be ubiquitinated and degraded by MDM2 (De Graaf et al, 2003;Kawai et al, 2003;Pan and Chen, 2003).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > 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.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“MDMX and MDM2 form heterodimers through the C-terminal RING domains and the MDM2 RING domain alone is sufficient to degrade MDMX (Sharp et al, 1999;Tanimura et al, 1999;Pan and Chen, 2003).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > 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.
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
“These results showed that phosphorylated MDMX bound to MDM2 more efficiently, which may cause its selective degradation by MDM2.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX promotes degradation by MDM2
hedgedconditional- 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
“The current results suggest that DNA damage activates ATM and subsequently Chk2.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
hedgeddirect- 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
“This suggested that a population of MDMX was phosphorylated and then rapidly degraded after ionizing irradiation.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > DNA damage induces degradation of MDMX
hedgeddirect- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“Although a role of ATM in p53 response is well established, the significance of Chk2 is still a matter of debate.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
What the sources say
boosted- 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.
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
“These results showed that Chk2 plays a role in regulating p53 response to gamma irradiation, possibly through promoting degradation of MDMX.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX by Chk2
hedgedconditional- 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
“Therefore, phosphorylation of S342, S367, and S403 may each contribute to stimulating poly-ubiquitination and degradation by MDM2, with S367 having the most dominant role.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation site mutations reduce ubiquitination and degradation by MDM2
hedgedconditional- 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
“These results suggested that degradation of MDMX after DNA damage facilitates p53 activation and cell cycle arrest.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Reduction of MDMX level increases p53 response to DNA damage
hedgeddirect- 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
“Therefore, MDMX phosphorylation occurs before p53 stabilization after ionizing irradiation, suggesting that degradation of MDMX contributes to p53 activation.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > ATM is required for stimulating MDMX phosphorylation
hedgedconditional- 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
“Multiple phosphorylation of MDMX C-terminal region may lead to conformational changes in the MDMX RING domain, increasing the affinity for MDM2 binding, and leading to ubiquitination and degradation of MDMX.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
hedgedconditional- 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: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
In the paper
“The results in Figure 9C were unexpected since a previous study using the same HCT116-Chk2À/À cell line reported that Chk2 knockout did not affect p53 response to higher doses (12 Gy) of ionizing irradiation (Jallepalli et al, 2003).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX by Chk2
What the sources say
- Not checked yetcites Jallepalli et al, 2003 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.
Probably not a substantial 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
“This is consistent with the interpretation that ATM is required for activation of Chk2, which mediates S342 and S367 phosphorylation.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX by Chk2
hedgeddirect- 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
“Therefore, phosphorylation of S367 was not necessary for MDM2 binding, but may further stimulate MDM2 binding or induce a conformational change that favor degradation by MDM2.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation site mutations reduce ubiquitination and degradation by MDM2
hedgedconditional- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“Previous studies showed that phosphorylation of S15 and S20 of p53 by ATM and Chk2 stimulate p53 transcription activation function and reduce MDM2 binding.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
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.
In the paper
“A recent study showed that DNA damage also accelerates MDM2 degradation through a mechanism that requires its own RING domain (Stommel and Wahl, 2004).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
What the sources say
- Not checked yetcites Stommel and Wahl, 2004 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.
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
“Elimination of MDMX would facilitate p53 activation by relieving p53 from MDMX binding, and reducing the E3 ligase activity of MDM2.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether 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.
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
“An identical set of 8C6 IP samples was analyzed by MDMX Western blot to confirm protein expression level.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Metabolic labeling and phospho-amino-acid analysis
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.
In the paper
“We have recently found that 14-3-3 copurifies with MDMX (Chen et al, 2005).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
What the sources say
- Not checked yetcites Chen et al, 2005 source
plaincorrelational- 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.
In the paper
“It is noteworthy that phosphorylated S367 of MDMX is a potential 14-3-3 binding site (Tzivion et al, 2001).”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
What the sources say
- Not checked yetcites Tzivion et al, 2001 source
hedgedconditional- 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
“Phosphorylation of MDM2 Y394 by c-Abl and S395 by ATM reduce its ability to promote p53 degradation.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
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
“His6-MDMX expressed in E. coli was used as a control for crossreactivity to nonphosphorylated MDMX.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > In vitro kinase reactions
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.
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
“The ubiquitin E3 ligase activity of MDM2 can be switched between targeting p53 or MDMX by stress signals, thus having both negative and positive effects on p53 function.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Discussion
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.
Caffeine's inhibition of MDMX phosphorylation and degradation after radiation is due to inhibition of ATM/ATR rather than other caffeine effects.
“MCF7 cells were treated with caffeine to inhibit ATM/ATR.”
“This treatment partially inhibited the mobility shift and degradation of MDMX after radiation (Figure 3B).”
The paper relies on this without support.
MDMX siRNA and stable knockdown specifically reduce MDMX levels without off-target effects.
“U2OS cells were transfected with MDMX siRNA for 48 h, followed by treatment with 10 Gy gamma irradiation.”
“Similar results were also observed using MCF7 cells with stable knockdown of MDMX (data not shown).”
The paper relies on this without support.
The Chk2-A347 mutant is kinase-dead and can act as a dominant-negative inhibitor of Chk2.
“kinase-dead Chk2-A347 mutant, activated myr-Akt1 and CK1a had no effect (Figure 9A).”
“In wild-type HCT116 cells, Chk2-A347 reduced S367 phosphorylation, possibly through dominant-negative effect (Figure 9A).”
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
“Additionally, phosphorylation of Mdm2 and Mdmx at serine residues close to the RING domain by ATM or ATM-dependent kinases leads to accelerated auto-degradation of both Mdm2 [54] and Mdmx [41,55–58], with consequent p53 accumulation and activation.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [55]
In the citing 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).”
From ATM activates p53 by regulating MDM2 oligomerization and E3 processivity (2009) · cites this paper as Chen et al, 2005
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 and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > In vitro kinase reactions
“The reaction products were analyzed by Western blot using PS342, PS467, and p53PS15 antibodies.”
§ ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage > Phosphorylation of MDMX by Chk2
“Western blot showed that Chk1 modified S342 and S367, but with strong preference for S342.Chk2 modified both S342 and S367, but with strong preference for S367 (Figure 8A).”
Citations
Cites
WAF1, a potential mediator of p53 tumor suppression
El-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W., & Vogelstein, B. (1993) · Cell · doi:10.1016/0092-8674(93)90500-p · Cited by 8,321
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
Bakkenist, C. J., & Kastan, M. B. (2003) · Nature · doi:10.1038/nature01368 · Cited by 3,466
Kastan, M. B., Zhan, Q., El-Deiry, W. S., Carrier, F., Jacks, T., Walsh, W. V., Plunkett, B. S., Vogelstein, B., & Fornace, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90593-2 · Cited by 3,047
ATM and related protein kinases: safeguarding genome integrity
Shiloh, Y. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1011 · Cited by 2,577
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
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
Zhang, Y., Xiong, Y., & Yarbrough, W. G. (1998) · Cell · doi:10.1016/s0092-8674(00)81401-4 · Cited by 1,626
Chk1 and Chk2 kinases in checkpoint control and cancer
Bartek, J., & Lukas, J. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00110-7 · Cited by 1,513
Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53
de Oca Luna, R. M., Wagner, D. S., & Lozano, G. (1995) · Nature · doi:10.1038/378203a0 · Cited by 1,420 · cited 2×
“ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage”
BackgroundShieh, S.-Y., Ahn, J., Tamai, K., Taya, Y., & Prives, C. (2000) · Genes & Development · doi:10.1101/gad.14.3.289 · Cited by 972
Cited by
Sorted by citations
Regulating the p53 pathway: in vitro hypotheses, in vivo veritas
Toledo, F., & Wahl, G. M. (2006) · Nature reviews. Cancer · doi:10.1038/nrc2012 · Cited by 1,286
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
The ATM–Chk2 and ATR–Chk1 Pathways in DNA Damage Signaling and Cancer
Smith, J., Tho, L. M., Xu, N., & Gillespie, D. A. (2010) · Advances in cancer research · doi:10.1016/b978-0-12-380888-2.00003-0 · Cited by 1,331
Hydrogen peroxide sensing, signaling and regulation of transcription factors
Marinho, H. S., Real, C., Cyrne, L., Soares, H., & Antunes, F. (2014) · Redox Biology · doi:10.1016/j.redox.2014.02.006 · Cited by 872
The complexity of p53 stabilization and activation
Lavin, M. F., & Gueven, N. (2006) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401925 · Cited by 701
Metadata
- Authors
- Chen, L., Gilkes, D. M., Pan, Y., Lane, W. S., & Chen, J.
- Affiliations
- Moffitt Cancer Center (US)
- Harvard University (US)
- Corresponding author
- Chen, Jiandong
- Venue
- The EMBO Journal
- Published
- 2005-09-15
- Volume
- 24
- Issue
- 19
- Pages
- 3411-3422
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1276172
- OpenAlex
- W2116326380
- Semantic Scholar
- 74f10c564d416135fbbc705c0184d57a01fc3e2a
- Cited by
- 260
- References
- 43
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 8 · 2023: 2 · 2022: 8 · 2021: 10 · 2020: 10 · 2019: 8 · 2018: 10 · 2017: 9 · 2016: 17 · 2015: 17 · 2014: 15 · 2013: 20 · 2012: 20
- FWCI
- 6.41
- 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
- American Cancer Society
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- p53 activation, MDMX, MDM2, ATM kinase, Chk2, DNA damage response, protein phosphorylation, ubiquitination, protein degradation, ionizing radiation, E3 ubiquitin ligase, tumor suppressor
- MeSH terms
- Cells, Cultured, Chromatography, High Pressure Liquid, DNA Damage, DNA-Binding Proteins, Electrophoresis, Polyacrylamide Gel, Gene Expression Regulation, Humans, Nuclear Proteins, Phosphorylation, Proto-Oncogene Proteins, Mass Spectrometry, Blotting, Western, Tumor Suppressor Protein p53, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Tumor Suppressor Proteins, RNA Interference, RNA, Small Interfering, Immunoprecipitation, Proto-Oncogene Proteins c-mdm2, Ataxia Telangiectasia Mutated Proteins, Checkpoint Kinase 2
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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