The DOI matches its Crossref record; 42 of the 43 references it cites were found in a registry or an index; none of the 39 sources its claims cite is checked for support yet.
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
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.
- 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
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
“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
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.
- Also stated in: § Phosphorylation site mutations reduce ubiquitination and degradation by MDM2 · 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
“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
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.
- Also stated in: § Identification of phosphorylation sites on 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
“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
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.
- Also stated in: § Phosphorylation of MDMX by Chk2 · hedged
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
“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
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.
- Also stated in: § Phosphorylation of MDMX promotes degradation by MDM2 · 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
“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
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: § Phosphorylation of MDMX by Chk2 · 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
“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
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.
- Also stated in: § Detection of MDMX phosphorylation by peptide-specific antibodies · 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
“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
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: § Phosphorylation of MDMX by Chk2 · 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
“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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Phosphorylation of MDMX promotes degradation by MDM2 · hedged
- 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.
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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.
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It may state two separate claims as one.
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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.
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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 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.
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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.
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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.
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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.
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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.
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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.
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It may state two separate claims as one.
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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.
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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.
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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.
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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.
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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.
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- 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.
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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.
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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.
- 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.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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- 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
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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
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