ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage
Open accessAbstract
The p53 tumor suppressor protein, a key regulator of cellular responses to genotoxic stress, is stabilized and activated after DNA damage. The rapid activation of p53 by ionizing radiation and radiomimetic agents is largely dependent on the ATM kinase. p53 is phosphorylated by ATM shortly after DNA damage, resulting in enhanced stability and activity of p53. The Mdm2 oncoprotein is a pivotal negative regulator of p53. In response to ionizing radiation and radiomimetic drugs, Mdm2 undergoes rapid ATM-dependent phosphorylation prior to p53 accumulation. This results in a decrease in its reactivity with the 2A10 monoclonal antibody. Phage display analysis identified a consensus 2A10 recognition sequence, possessing the core motif DYS. Unexpectedly, this motif appears twice within the human Mdm2 molecule, at positions corresponding to residues 258-260 and 393-395. Both putative 2A10 epitopes are highly conserved and encompass potential phosphorylation sites. Serine 395, residing within the carboxy-terminal 2A10 epitope, is the major target on Mdm2 for phosphorylation by ATM in vitro. Mutational analysis supports the conclusion that Mdm2 undergoes ATM-dependent phosphorylation on serine 395 in vivo in response to DNA damage. The data further suggests that phosphorylated Mdm2 may be less capable of promoting the nucleo-cytoplasmic shuttling of p53 and its subsequent degradation, thereby enabling p53 accumulation. Our findings imply that activation of p53 by DNA damage is achieved, in part, through attenuation of the p53-inhibitory potential of Mdm2.
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Claims the paper makes
- Findingown data
Mdm2 undergoes ATM-dependent phosphorylation on serine 395 in vivo in response to DNA damage.
“Mutational analysis supports the conclusion that Mdm2 undergoes ATM-dependent phosphorylation on serine 395 in vivo in response to DNA damage.”
Quote in the paperSubstantial claim - Findingown data
Phage display analysis identified a consensus 2A10 recognition sequence possessing the core motif DYS.
“Phage display analysis identified a consensus 2A10 recognition sequence, possessing the core motif DYS.”
Quote in the paperSubstantial claim - Findingown data
Serine 395 of human Mdm2 is the major target for phosphorylation by ATM in vitro.
“Serine 395, residing within the carboxy-terminal 2A10 epitope, is the major target on Mdm2 for phosphorylation by ATM in vitro.”
Quote in the paperSubstantial claim - Findingown data
Microinjection of the 2A10 antibody increases substantially the steady state levels of endogenous wild-type p53.
“We now report that microinjection of the 2A10 antibody increases substantially the steady state levels of endogenous wild-type p53.”
Quote in the paperSubstantial claim - Findingown data
Substitution of S395 to aspartic acid (S395D) diminishes the capacity of Mdm2 to drive p53 degradation.
“Substitution of S395 to aspartic acid (S395D), presumably mimicking phosphorylation, diminishes the capacity of Mdm2 to drive p53 degradation.”
Quote in the paperSubstantial claim- The authors state this as an assumption: The S395D substitution mimics phosphorylation of S395.
- Findingown data
Microinjection of the anti-Mdm2 monoclonal antibody 2A10 into primary MEFs induces p53 accumulation.
“Microinjection of 2A10 induces p53 accumulation.”
Quote in the paperNot a substantial claim - Findingown data
S395D is inefficient in promoting the cytoplasmic export of p53, which is crucial for effective p53 degradation.
“Furthermore, S395D is inefficient in promoting the cytoplasmic export of p53, crucial for effective p53 degradation.”
Quote in the paperSubstantial claim- The authors state this as an assumption: The S395D substitution mimics phosphorylation of S395.
- Findingown data
Mdm2 S395D is impaired in promoting p53 degradation.
“Mdm2 S395D is impaired in promoting p53 degradation.”
Quote in the paperSubstantial claim - Findingown data
Serine 395 is the major site on Mdm2 for phosphorylation by ATM in vitro.
“Serine 395 is the major site on Mdm2 for phosphorylation by ATM in vitro.”
Quote in the paperSubstantial claim - Findingown data
Ser395 is required for ATM-dependent phosphorylation of Mdm2 in vivo.
“Ser395 is required for ATM-dependent phosphorylation in vivo.”
Quote in the paperSubstantial claim - Findingown data
Mutation of serine 395 decreases 2A10 immunoreactivity.
“Mutation of serine 395 decreases 2A10 immunoreactivity.”
Quote in the paperSubstantial claim - Interpretationown data
Phosphorylation of Mdm2 on S395 reduces its ability to down-regulate p53.
“The data in Figure 6 suggests strongly that phosphorylation of Mdm2 on S395 reduces its ability to down-regulate p53.”
Quote in the paperSubstantial claim- The authors state this as an assumption: The S395D substitution mimics phosphorylation of S395.
- Interpretationreasoning
Activation of p53 by DNA damage is achieved, in part, through attenuation of the p53-inhibitory potential of Mdm2.
“Our findings imply that activation of p53 by DNA damage is achieved, in part, through attenuation of the p53-inhibitory potential of Mdm2.”
Quote in the paperSubstantial claim - Interpretationown data
ATM-dependent phosphorylation of Mdm2 on S395 plays a significant role in enabling the rapid stabilization and activation of p53 in response to particular types of DNA damage.
“This lends strong support to the notion that ATM-dependent phosphorylation of Mdm2 on S395 plays a significant role in enabling the rapid stabilization and activation of p53 in response to particular types of DNA damage.”
Quote in the paperSubstantial claim - Interpretationreasoning
The simultaneous ATM-dependent phosphorylation of both p53 and Mdm2 ensures a well-coordinated p53 response.
“Overall, our findings imply that the simultaneous ATM-dependent phosphorylation of both p53 and Mdm2 ensures a well-coordinated p53 response.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 6
- May combine two claims. 2
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataMdm2 contains two putative 2A10 epitopes.
“Mdm2 encompasses two putative 2A10 epitopes.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataAll positive phage clones selected by 2A10 fell into only two sequence classes.
“All clones were found to fall into only two sequence classes.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataThe consensus 2A10 epitope is 1-DYS-5, with position 1 preferentially D and position 5 preferentially L.
“the consensus 2A10 epitope was deduced as 1-DYS-5, where 1 is preferentially D and 5 is preferentially L”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataPhosphorylated Mdm2 is less capable of promoting the nucleo-cytoplasmic shuttling of p53 and its subsequent degradation, thereby enabling p53 accumulation.
“The data further suggests that phosphorylated Mdm2 may be less capable of promoting the nucleo-cytoplasmic shuttling of p53 and its subsequent degradation, thereby enabling p53 accumulation.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenCells were scored independently, in a double-blind fashion, by three individuals.
“Cells were scored independently, in a double-blind fashion, by three individuals.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataImmunoprecipitated FLAG-ATM was confirmed by Western blotting with α-FLAG M2 monoclonal antibody.
“Immunoprecipitated FLAG-ATM was confirmed by Western blotting with ␣-FLAG M2 monoclonal antibody.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe constructs were confirmed by DNA sequencing.
“The constructs were confirmed by DNA sequencing.”
Quote in the paperNot a substantial claim
The authors state this as an assumption.
The S395D substitution mimics phosphorylation of S395.
“Substitution of S395 to aspartic acid (S395D), presumably mimicking phosphorylation, diminishes the capacity of Mdm2 to drive p53 degradation.”
The authors state this as an assumption.
Retroviral expression of human Mdm2 at low levels does not perturb the biology of recipient MEFs.
“Retroviral delivery was chosen because it yielded very low levels of human Mdm2, expected not to perturb the biology of the recipient MEFs.”
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?
After DNA damage, MDM2 is phosphorylated at serine 395 by ATM, serine 407 by ATR, and tyrosine 394 by c-Abl, which together with other modifications neutralizes MDM2/MDMX inhibition of p53 and sustains p53 signaling.
“Following DNA damage, MDM2 is phosphorylated on serine 395 by ATM,24 on serine 407 by ATR,36 and on tyrosine 394 by c-abl,37,47 which along with other posttranslational modifications of MDMX and p53 neutralizes the inhibitory effect of MDM2/MDMX on p53 and results in sustained p53-mediated signaling.10”
From Combination therapy in a xenograft model of glioblastoma: Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist (2017) · cites this paper as [24]
Mdm2 S395D mutant is impaired in p53 degradation and strongly inhibited in stimulating p53 nuclear export, with preliminary data suggesting ubiquitin ligase activity not decreased.
“This effect was explained by the observation that the Mdm2 S395D mutant was strongly inhibited in its ability to stimulate nuclear export of p53, while preliminary data suggested that the ubiquitin ligase activity was not decreased.”
From Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms (2001) · cites this paper as Maya et al., 2001
Phosphorylation of Mdm2 and Mdmx at serine residues close to the RING domain by ATM or ATM-dependent kinases leads to accelerated auto-degradation of both Mdm2 and Mdmx, with consequent p53 accumulation and activation.
“Additionally, phosphorylation of Mdm2 and Mdmx at serine residues close to the RING domain by ATM or ATM-dependent kinases leads to accelerated auto-degradation of both Mdm2 [54] and Mdmx [41,55–58], with consequent p53 accumulation and activation.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [54]
MDM2 is phosphorylated by ATM, ATR, and C-Abl on sites near its C terminus.
“MDM2 is phosphorylated by ATM, ATR, and C-Abl on sites near the C terminus (Maya et al, 2001;Sionov et al, 2001;Shinozaki et al, 2003).”
From ATM activates p53 by regulating MDM2 oligomerization and E3 processivity (2009) · cites this paper as Maya et al, 2001
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Cited works that were retracted
Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.
Cites a retracted work: 10.1016/s0092-8674(00)80887-9
InfoThe cited work was retracted on 2002-08-23 (notice 10.1016/s0092-8674(02)00902-9), not before this paper was published (2001-05-01).
Cited work 10.1016/s0092-8674(00)80887-9 · retracted 2002-08-23 · notice 10.1016/s0092-8674(02)00902-9 · this paper published 2001-05-01
“10.1016/S0092-8674(00)80887-9”
Cites
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Self-citationRetractedMdm2 promotes the rapid degradation of p53
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“cells was done as described previously (Haupt et al. 1997).”
BackgroundResultInfluentialSelf-citationRegulation of p53 stability by Mdm2
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BackgroundSelf-citationDNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2
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BackgroundSearching for Peptide Ligands with an Epitope Library
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“The hexapeptide epitope library was kindly provided by George P. Smith (University of Missouri, Columbia, MO) and was constructed by using the phage fd-derived vector fUSE5 as described (Scott and Smith 1990).”
MethodInfluentialActivation of the ATM Kinase by Ionizing Radiation and Phosphorylation of p53
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Self-citationOncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53
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“Transcription of the mdm2 gene is strongly activated by p53 (Barak et al. 1993; Wu et al. 1993).”
BackgroundEnhanced Phosphorylation of p53 by ATM in Response to DNA Damage
Banin, S., Moyal, L., Shieh, S.-Y., Taya, Y., Anderson, C. W., Chessa, L., Smorodinsky, N. I., Prives, C., Reiss, Y., Shiloh, Y., et al. (1998) · Science · doi:10.1126/science.281.5383.1674 · Cited by 1,797 · see citing works
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“The ability of Mdm2 to ubiquinate p53 is negatively regulated by ARF (Pomerantz et al. 1998; Honda and Yasuda 1999; Zhang and Xiong 1999; Fang et al. 2000), suggesting that modifications affecting ARF binding might also modulate Mdm2 function.”
BackgroundInfluentialOncoprotein MDM2 conceals the activation domain of tumour suppressor p53
Oliner, J. D., Pietenpol, J. A., Thiagalingam, S., Gyuris, J., Kinzler, K. W., & Vogelstein, B. (1993) · Nature · doi:10.1038/362857a0 · Cited by 1,447 · cited 2× · see citing works
“The Mdm2 protein, in turn, binds p53 and conceals its transactivation domain (Momand et al. 1992; Oliner et al. 1993).”
BackgroundThe complexity of p53 modulation: emerging patterns from divergent signalsPreprint
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“Mdm2 is also an in vitro target of CKII (Gotz et al. 1999), but the relevance remains unknown.”
BackgroundSelf-citationmdm2 expression is induced by wild type p53 activity.
Barak, Y., Juven, T., Haffner, R., & Oren, M. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb05678.x · Cited by 1,290 · cited 1× · see citing works
“Transcription of the mdm2 gene is strongly activated by p53 (Barak et al. 1993; Wu et al. 1993).”
BackgroundSelf-citationMdm2 Is a RING Finger-dependent Ubiquitin Protein Ligase for Itself and p53
Fang, S., Jensen, J. P., Ludwig, R. L., Vousden, K. H., & Weissman, A. M. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.12.8945 · Cited by 1,044 · cited 3× · see citing works
“Within Mdm2, the RING finger domain is of particular importance for this E3 activity, in vitro as well as in vivo (Kubbutat et al. 1997; Honda and Yasuda 1999; Fang et al. 2000).”
BackgroundNucleolar Arf sequesters Mdm2 and activates p53
Weber, J. D., Taylor, L. J., Roussel, M. F., Sherr, C. J., & Bar-Sagi, D. (1999) · Nature Cell Biology · doi:10.1038/8991 · Cited by 940 · cited 1× · see citing works
“Transcription of the mdm2 gene is strongly activated by p53 (Barak et al. 1993; Wu et al. 1993).”
BackgroundDNA damage induces phosphorylation of the amino terminus of p53
Siliciano, J. D., Canman, C. E., Taya, Y., Sakaguchi, K., Appella, E., & Kastan, M. B. (1997) · Genes & Development · doi:10.1101/gad.11.24.3471 · Cited by 818 · see citing works
Self-citationSubstrate Specificities and Identification of Putative Substrates of ATM Kinase Family Members
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“The cellular levels of the p53 protein significantly increase in response to stress such as DNA damage, activation of oncogenes, and hypoxia (for review, see Giaccia and Kastan 1998; Oren 1999; Prives and Hall 1999; Vousden 2000).”
BackgroundThe many substrates and functions of ATM.
Kastan, M. B., & Lim, D.-S. (2000) · Nature Reviews Molecular Cell Biology · doi:10.1038/35043058 · Cited by 779 · see citing works
Self-citationStommel, J. M., Marchenko, N. D., Jimenez, G. S., Moll, U. M., Hope, T. J., & Wahl, G. M. (1999) · The EMBO Journal · doi:10.1093/emboj/18.6.1660 · Cited by 738 · cited 5× · see citing works
“However, other domains, including the nuclear localization and nuclear export signals, also participate in the in vivo regulation of Mdm2 function (Roth et al. 1998; Lain et al. 1999; Tao and Levine 1999a,b).”
BackgroundInfluentialAssociation of p19ARF with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53
Honda, R., & Yasuda, H. (1999) · The EMBO Journal · doi:10.1093/emboj/18.1.22 · Cited by 724 · cited 5× · see citing works
“The ability of Mdm2 to ubiquinate p53 is negatively regulated by ARF (Pomerantz et al. 1998; Honda and Yasuda 1999; Zhang and Xiong 1999; Fang et al. 2000), suggesting that modifications affecting ARF binding might also modulate Mdm2 function.”
BackgroundInfluentialMapping of the p53 and mdm-2 Interaction Domains
Chen, J., Maréchal, V., & Levine, A. J. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.7.4107 · Cited by 689 · cited 4× · see citing works
“The Mdm2-specific monoclonal antibodies 2A10, 2A9, and 4B2 ( Chen et al. 1993 ) were a generous gift of Dr. Arnold Levine.”
BackgroundInfluentialSherr, C. J., & Weber, J. D. (2000) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(99)00038-6 · Cited by 654 · cited 1× · see citing works
“Several cellular proteins, including E2F1, Ras, Myc, -catenin, pRb, and c-Abl, can stabilize p53; in many cases, stabilization is achieved through induction of ARF (for review, see Sharpless and DePinho 1999; Sherr and Weber 2000).”
BackgroundIn vivo ubiquitination and proteasome-mediated degradation of p53(1).
Maki, C. G., Huibregtse, J. M., & Howley, P. M. (1996) · PubMed · Cited by 645 · see citing works
MDM2 — master regulator of the p53 tumor suppressor protein
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“The positions of the main identified structural domains of the protein ( Momand et al. 2000 ) are also indicated.”
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ATM and ATR: networking cellular responses to DNA damage
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Self-citationRegulation of the p53 Tumor Suppressor Protein
Oren, M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.51.36031 · Cited by 561 · cited 4× · see citing works
“This negative auto-regulatory feedback loop enables the tight regulation of p53 activity and stability (Freedman and Levine 1999; Juven-Gershon and Oren 1999; Momand et al. 2000).”
BackgroundInfluentialSelf-citationP19 ARF stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2
Tao, W., & Levine, A. J. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.12.6937 · Cited by 539 · see citing works
The INK4A/ARF locus and its two gene products.
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Genetic Control of Programmed Cell Death in the Nematode Caenorhabditis Elegans
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ATM associates with and phosphorylates p53: mapping the region of interaction
Khanna, K. K., Keating, K. E., Kozlov, S., Scott, S. P., Gatei, M. H., Hobson, K., Taya, Y., Gabrielli, B. G., Chan, D. W., Lees‐Miller, S. P., et al. (1998) · Nature Genetics · doi:10.1038/3882 · Cited by 481 · cited 8× · see citing works
“ATM-dependent Mdm2 phosphorylation can be monitored with 2A10 (Khosravi et al 1999).”
BackgroundInfluentialRapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage
Khosravi, R., Maya, R., Gottlieb, T., Oren, M., Shiloh, Y., & Shkedy, D. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.26.14973 · Cited by 461 · see citing works
Self-citationDumaz, N., & Meek, D. W. (1999) · The EMBO Journal · doi:10.1093/emboj/18.24.7002 · Cited by 455 · cited 3× · see citing works
“Within Mdm2, the RING finger domain is of particular importance for this E3 activity, in vitro as well as in vivo (Kubbutat et al. 1997; Honda and Yasuda 1999; Fang et al. 2000).”
BackgroundRegulation of p53 function and stability by phosphorylation.
Ashcroft, M., Kubbutat, M. H. G., & Vousden, K. H. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.3.1751 · Cited by 452 · see citing works
Phosphorylation of p53 Serine 15 Increases Interaction with CBP
Lambert, P. F., Kashanchi, F., Radonovich, M. F., Shiekhattar, R., & Brady, J. N. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.49.33048 · Cited by 423 · see citing works
Design of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo
Böttger, A., Böttger, V., Sparks, A., Liu, W.-L., Howard, S. F., & Lane, D. P. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00374-5 · Cited by 363 · cited 1× · see citing works
“Moreover, Mdm2 promotes the rapid degradation of p53 (Bottger et al. 1997; Haupt et al. 1997; Kubbutat et al. 1997).”
BackgroundThe MDM2 RING-finger domain is required to promote p53 nuclear export
Geyer, R. K., Yu, Z. K., & Maki, C. G. (2000) · Nature Cell Biology · doi:10.1038/35023507 · Cited by 361 · cited 6× · see citing works
“Cytoplasmic export of p53 requires its prior ubiquitination by Mdm2 (Boyd et al. 2000; Geyer et al. 2000).”
BackgroundMethodInfluentialStress Signals Utilize Multiple Pathways To Stabilize p53
Ashcroft, M. A., Taya, Y., & Vousden, K. H. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.9.3224-3233.2000 · Cited by 356 · cited 1× · see citing works
“After the second and third rounds of biopanning, individual amplified phage clones were tested by ELISA (Balass et al. 1993) for specific binding to mAb 2A10.”
MethodNucleocytoplasmic shuttling of oncoprotein Hdm2 is required for Hdm2-mediated degradation of p53
Tao, W., & Levine, A. J. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.6.3077 · Cited by 355 · cited 8× · see citing works
“export of p53 into the cytoplasm is essential for its effective Mdm2-mediated degradation (Roth et al. 1998; Lain et al. 1999; Tao and Levine 1999a, b).”
BackgroundInfluentialZhang, Y., & Xiong, Y. (1999) · Molecular Cell · doi:10.1016/s1097-2765(00)80351-2 · Cited by 347 · cited 3× · see citing works
“…activity of Mdm2, and in addition sequesters Mdm2 in the nucleolus, away from p53 (Honda and Yasuda 1999; Tao and Levine 1999a,b; Weber et al. 1999; Zhang and Xiong 1999); a nucleolar localization signal within the RING domain of Mdm2 is also required for its nucleolar sequestration by ARF (Lohrum…”
BackgroundAn intact HDM2 RING-finger domain is required for nuclear exclusion of p53
Boyd, S. D., Tsai, K. Y., & Jacks, T. (2000) · Nature Cell Biology · doi:10.1038/35023500 · Cited by 334 · see citing works
Cooperative Signals Governing ARF-Mdm2 Interaction and Nucleolar Localization of the Complex
Weber, J. D., Kuo, M.-L., Bothner, B. B., DiGiammarino, E. L., Kriwacki, R. W., Roussel, M. F., & Sherr, C. J. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.7.2517-2528.2000 · Cited by 273 · cited 2× · see citing works
“In addition, the degradation and stability of p53 are strongly dependent on the subcellular localization of both p53 and Mdm2. p53 can shuttle between the nucleus and the cytoplasm (Middeler et al. 1997; Weber et al. 1999).”
BackgroundMidgley, C., Desterro, J. M. P., Saville, M. K., Howard, S. F., Sparks, A., Hay, R. T., & Lane, D. P. (2000) · Oncogene · doi:10.1038/sj.onc.1203593 · Cited by 250 · cited 1× · see citing works
“Similar observations were reported recently by Lane and coworkers (Midgley et al. 2000).”
ResultMapping of the p53 and mdm-2 Interaction Domains
Chen, J., Maréchal, V., & Levine, A. J. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.7.4107-4114.1993 · Cited by 247 · see citing works
(1997) · PubMed · Cited by 243 · see citing works
Mechanisms of switching on p53: a role for covalent modification?
Meek, D. W. (1999) · Oncogene · doi:10.1038/sj.onc.1202951 · Cited by 235 · see citing works
Juven‐Gershon, T., & Oren, M. (1999) · Molecular Medicine · doi:10.1007/bf03402141 · Cited by 193 · cited 1× · see citing works
“This negative auto-regulatory feedback loop enables the tight regulation of p53 activity and stability (Freedman and Levine 1999; Juven-Gershon and Oren 1999; Momand et al. 2000).”
BackgroundSelf-citationUtilization of Oriented Peptide Libraries to Identify Substrate Motifs Selected by ATM
O'Neill, T., Dwyer, A. J., Ziv, Y., Chan, D. W., Lees-Miller, S. P., Abraham, R. H., Lai, J. H., Hill, D., Shiloh, Y., Cantley, L. C., et al. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001002200 · Cited by 189 · see citing works
Self-citationIdentification of a cryptic nucleolar-localization signal in MDM2
Lohrum, M. A. E., Ashcroft, M. A., Kubbutat, M. H. G., & Vousden, K. H. (2000) · Nature Cell Biology · doi:10.1038/35004057 · Cited by 186 · see citing works
Jimenez, G. S., Khan, S. H., Stommel, J. M., & Wahl, G. M. (1999) · Oncogene · doi:10.1038/sj.onc.1203013 · Cited by 176 · see citing works
Stress-activated kinases regulate protein stability
Fuchs, S. Y., Fried, V. A., & Ronai, Z. A. (1998) · Oncogene · doi:10.1038/sj.onc.1202184 · Cited by 156 · see citing works
Self-citationDNA damage induced p53 stabilization: no indication for an involvement of p53 phosphorylation
Blattner, C., Tobiasch, E., Litfen, M., Rahmsdorf, H. J., & Herrlich, P. (1999) · Oncogene · doi:10.1038/sj.onc.1202480 · Cited by 151 · cited 1× · see citing works
“In fact, in some situations p53 phosphorylation does not appear to contribute at all to its stabilization (Ashcroft et al. 1999; Blattner et al. 1999; Dumaz and Meek 1999).”
BackgroundLaín, S., Midgley, C., Sparks, A., Lane, E., & Lane, D. P. (1999) · Experimental Cell Research · doi:10.1006/excr.1999.4433 · Cited by 144 · see citing works
Covalent and noncovalent modifiers of the p53 protein
Jayaraman, L., & Prives, C. L. (1999) · Cellular and Molecular Life Sciences · doi:10.1007/s000180050271 · Cited by 131 · see citing works
Freedman, D. A., & Levine, A. J. (1999) · PubMed · Cited by 114 · see citing works
Balass, M., Heldman, Y., Cabilly, S., et al. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.22.10638 · Cited by 96 · cited 2× · see citing works
“After the second and third rounds of biopanning, individual amplified phage clones were tested by ELISA (Balass et al. 1993) for specific binding to mAb 2A10.”
MethodSelf-citationMiddeler, G., Zerf, K., Jenovai, S., et al. (1997) · Oncogene · doi:10.1038/sj.onc.1200949 · Cited by 89 · see citing works
Kapoor, M., Hamm, R. L., Yan, W., Taya, Y., & Lozano, G. (2000) · Oncogene · doi:10.1038/sj.onc.1203300 · Cited by 86 · cited 1× · see citing works
“…to a family of protein kinases that possess a phosphoinositide 3-kinase-related domain at their carboxyl termini; these enzymes are involved in controlling genome stability, cell cycle progression, and responses to DNA damage in various organisms (for review, see Kastan and Lim 2000; Shiloh 2001).”
BackgroundMaya, R., & Oren, M. (2000) · Oncogene · doi:10.1038/sj.onc.1203658 · Cited by 41 · cited 4× · see citing works
“To better evaluate the relationship between Mdm2 phosphorylation and p53 accumulation, we took advantage of the fact that the ATM-dependent phosphorylation of Mdm2 decreases its reactivity with the monoclonal antibody (MoAb) 2A10 (Khosravi et al. 1999; Maya and Oren 2000 ).”
BackgroundMethodInfluentialSelf-citationIdentification of a CK2 phosphorylation site in mdm2.
Götz, C., Kartarius, S., Scholtes, P., Nastainczyk, W., & Montenarh, M. (1999) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.1999.00882.x · Cited by 39 · cited 5× · see citing works
“In fact, Mdm2 can be phosphorylated on multiple sites (Henning et al. 1997; Mayo et al. 1997; Gotz et al. 1999), as well as be modified by covalent attachment of Sumo (Buschmann et al. 2000).”
BackgroundInfluentialRoth, J., Dobbelstein, M., Freedman, D., Shenk, T. E., & Levine, A. J. (1998) · Gastroenterology · doi:10.1016/s0016-5085(98)82742-x · Cited by 31 · see citing works
MDM2 is a target of simian virus 40 in cellular transformation and during lytic infection
Henning, W., Rohaly, G., Kolzau, T., Knippschild, U., Maacke, H., & Deppert, W. (1997) · Journal of Virology · doi:10.1128/jvi.71.10.7609-7618.1997 · Cited by 29 · cited 4× · see citing works
“Within Mdm2, the RING finger domain is of particular importance for this E3 activity, in vitro as well as in vivo (Kubbutat et al. 1997; Honda and Yasuda 1999; Fang et al. 2000).”
BackgroundInfluentialBalass, M., Heldman, Y., Cabilly, S., et al. (1993) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1002/jmr.300080127 · Cited by 26
Self-citationCellular senescence and cancer
(1999) · doi:10.1002/(sici)1096-9896(199901)187:1 · cited 3×
“In the case of DNA damage, this is achieved partly through posttranslational modification of p53, most notably phosphorylation (for review, see Fuchs et al. 1998; Giaccia and Kastan 1998; Jayaraman and Prives 1999; Meek 1999; Oren 1999; Prives and Hall 1999; Kapoor et al. 2000).”
Background
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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 · see citing works
“These include p53, Mdm2 and Chk2 in the G1 checkpoin”
BackgroundSelf-citationCell-cycle checkpoints and cancer
Kastan, M. B., & Bartek, J. (2004) · Nature · doi:10.1038/nature03097 · Cited by 2,836 · see citing works
Self-citationATM and related protein kinases: safeguarding genome integrity
Shiloh, Y. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1011 · Cited by 2,577 · see citing works
Self-citationNegative Control of p53 by Sir2α Promotes Cell Survival under Stress
Luo, J., Nikolaev, A. Y., Imai, S.-I., Chen, D., Su, F., Shiloh, A., Guarente, L., & Gu, W. (2001) · Cell · doi:10.1016/s0092-8674(01)00524-4 · Cited by 2,081 · see citing works
Cell cycle checkpoint signaling through the ATM and ATR kinases
Abraham, R. T. (2001) · Genes & Development · doi:10.1101/gad.914401 · Cited by 1,966 · see citing works
MDM2, MDMX and p53 in oncogenesis and cancer therapy
Wade, M., Li, Y.-C., & Wahl, G. M. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3430 · Cited by 1,279 · see citing works
Hickson, I., Zhao, Y., Richardson, C. J., Green, S. J., Martin, N. M. B., Orr, A. I., Reaper, P. M., Jackson, S. P., Curtin, N. J., & Smith, G. C. M. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-2727 · Cited by 1,220 · see citing works
“The role of the ATM protein in the stabilization of p53 in response to DNA double-strand break-inducing agents is very well established (4, 10, 11, 13, 44).”
BackgroundRequirement of the MRN complex for ATM activation by DNA damage
Uziel, T., Lerenthal, Y., Moyal, L., Andegeko, Y., Mittelman, L., & Shiloh, Y. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg541 · Cited by 1,075 · see citing works
Self-citationThe INK4a/ARF network in tumour suppression
Sherr, C. J. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35096061 · Cited by 984 · see citing works
p53 ubiquitination: Mdm2 and beyond
Brooks, C. L., & Gu, W. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.020 · Cited by 924 · see citing works
“In addition, modifications occurring on Mdm2 can also disrupt their direct interaction during specific DNA damage events, such as ionizing radiation, when Mdm2 is phosphorylated at serine 395 (Maya et al., 2001).”
BackgroundHydrogen 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 851 · see citing works
“The H2O2activated kinases Ataxia telangiectasia mutated (ATM) [196] and c-ABL [197] phosphorylate MDM2 leading to the fast activation of TP53 [198][199].”
BackgroundMoll, U. M., & Petrenko, O. (2003) · PubMed · Cited by 778 · see citing works
The many substrates and functions of ATM.
Kastan, M. B., & Lim, D.-S. (2000) · Nature Reviews Molecular Cell Biology · doi:10.1038/35043058 · Cited by 779 · see citing works
Self-citationThe p53–Mdm2 module and the ubiquitin system
Michael, D., & Oren, M. (2002) · Seminars in Cancer Biology · doi:10.1016/s1044-579x(02)00099-8 · Cited by 759 · see citing works
Self-citationThe complexity of p53 stabilization and activation
Lavin, M. F., & Gueven, N. (2006) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401925 · Cited by 701 · see citing works
“The phosphorylated form of MDM2 appears to be less capable of nucleo-cytoplasmic shuttling of p53, suggesting that the MDM2 phosphorylation destabilizes the interaction with p53.(57) ATM also plays a key role in phosphorylating p53 on Ser 15 and other sites in response to DNA double-strand”
BackgroundRegulation of p53 Translation and Induction after DNA Damage by Ribosomal Protein L26 and Nucleolin
Takagi, M., Absalon, M. J., McLure, K. G., & Kastan, M. B. (2005) · Cell · doi:10.1016/j.cell.2005.07.034 · Cited by 656 · see citing works
Self-citationUSP10 Regulates p53 Localization and Stability by Deubiquitinating p53
Yuan, J., Luo, K., Zhang, L., Cheville, J. C., & Lou, Z. (2010) · Cell · doi:10.1016/j.cell.2009.12.032 · Cited by 637 · see citing works
“Furthermore, ATM-dependent phosphorylation of Mdm2 and Mdmx could destabilize these proteins and compromise their activity (Khosravi et al., 1999; Maya et al., 2001; Meulmeester et al., 2005; Pereg et al., 2005; Stommel and Wahl, 2004).”
Regulation of HDM2 activity by the ribosomal protein L11
Lohrum, M. A. E., Ludwig, R. L., Kubbutat, M. H. G., Hanlon, M., & Vousden, K. H. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00134-x · Cited by 626 · see citing works
“CANCER CELL : JUNE 2003 · VOL. 3 · COPYRIGHT 2003 CELL PRESS 577 al., 2001; Chehab et al., 2000; Goldberg et al., 2002; Hirao et al., 2000; Maya et al., 2001; Shieh et al., 2000).”
Akt Enhances Mdm2-mediated Ubiquitination and Degradation of p53
Ogawara, Y., Kishishita, S., Obata, T., Isazawa, Y., Suzuki, T., Tanaka, K., Masuyama, N., & Gotoh, Y. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m109745200 · Cited by 617 · see citing works
Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damagePreprint
Kim, S., Xu, B., & Kastan, M. B. (2002) · Genes & Development · doi:10.1101/gad.970602 · Cited by 581 · see citing works
“Perhaps the situation is analogous to the Atm-dependent G1 checkpoint in which Atm apparently simultaneously phosphorylates multiple proteins (p53, Chk2, and Mdm2) to cause the arrest (Kastan and Lim 2000).”
BackgroundInfluentialSelf-citationMammalian G1- and S-phase checkpoints in response to DNA damage
Bártek, J., & Lukas, J. (2001) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00280-5 · Cited by 573 · see citing works
Regulation and mechanisms of mammalian double-strand break repair
Valerie, K. C., & Povirk, L. F. (2003) · Oncogene · doi:10.1038/sj.onc.1206679 · Cited by 572 · see citing works
Ferroptosis, radiotherapy, and combination therapeutic strategies
Lei, G., Mao, C., Yan, Y., Zhuang, L., & Gan, B. (2021) · Protein & Cell · doi:10.1007/s13238-021-00841-y · Cited by 518 · see citing works
Recent advances in apoptosis, mitochondria and drug resistance in cancer cells
Indran, I. R., Tufo, G., Pervaiz, S., & Brenner, C. (2011) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2011.03.010 · Cited by 524 · see citing works
“Phosphorylation of p53 disrupts p53's interaction with Mdm2 and ushers its activation [32,33].”
BackgroundCoping with stress: multiple ways to activate p53
Horn, H. F., & Vousden, K. H. (2007) · Oncogene · doi:10.1038/sj.onc.1210263 · Cited by 522 · see citing works
“…of p53 (Shieh et al., 1997; Siliciano et al., 1997; Banin et al., 1998; Khosravi et al., 1999; de Toledo et al., 2000; Sakaguchi et al., 2000; Maya et al., 2001), phosphorylation of Mdm2 and MdmX also enhances the degradation of these proteins by reducing their association with HAUSP –…”
BackgroundAcetylation of p53 inhibits its ubiquitination by Mdm2
Li, M., Luo, J., Brooks, C. L., & Gu, W. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200578200 · Cited by 503 · see citing works
Fei, P., & El‐Deiry, W. S. (2003) · Oncogene · doi:10.1038/sj.onc.1206677 · Cited by 497 · see citing works
Dai, M., Zeng, S. X., Jin, Y., Sun, X., David, L. L., & Lu, H. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.17.7654-7668.2004 · Cited by 495 · see citing works
“For instance, DNA damage-induced phosphorylation of p53 or MDM2 suppresses p53-MDM2 binding, thus inhibiting MDM2-mediated p53 suppression (3, 8, 28, 39, 56).”
BackgroundTwo Molecularly Distinct G2/M Checkpoints Are Induced by Ionizing Irradiation
Xu, B., Kim, S., Lim, D., & Kastan, M. B. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.4.1049-1059.2002 · Cited by 470 · see citing works
“Substrates and target sites of the ATM kinase have been implicated in control of the G1 (p53, Chk2, and Mdm2) (1, 2, 7, 16, 17, 18, 19, 25), S-phase (Nbs1 and Chk2) (9, 15, 33), and G2 (Brca1 and hRad17) (3, 30) checkpoint pathways.”
BackgroundSelf-citationS-phase–specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51
Taniguchi, T., García-Higuera, I., Andreassen, P. R., Gregory, R. C., Grompe, M., & D’Andrea, A. D. (2002) · Blood · doi:10.1182/blood-2002-01-0278 · Cited by 458 · see citing works
“Consistent with this model, recent studies have shown that ATM-dependent phosphorylation of another ubiquitin ligase, MDM2, may regulate its ability to ubiquitinate p53 [41].”
ResultMyc pathways provoking cell suicide and cancer
Nilsson, J. A., & Cleveland, J. L. (2003) · Oncogene · doi:10.1038/sj.onc.1207261 · Cited by 462 · see citing works
Regulating tumor suppressor genes: post-translational modifications
Chen, L., Liu, S., & Tao, Y. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0196-9 · Cited by 449 · see citing works
“interaction between p53 and MDM2 is broken, such as during a DNA damage event in which MDM2 is phosphorylated at serine 395.(268) Notably, low level of MDM2 activity induces p53 monoubiquitination and nuclear output, while high level of MDM2 activity promotes p53 polyubiquitination and nuclear degradation.”
BackgroundThe p53 orchestra: Mdm2 and Mdmx set the tone
Wade, M., Wang, Y. V., & Wahl, G. M. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.01.009 · Cited by 450 · see citing works
“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 Wade et al.”
BackgroundChk2‐deficient mice exhibit radioresistance and defective p53‐mediated transcription
Takai, H., Naka, K., Okada, Y., Watanabe, M., Harada, N., Saito, S., Anderson, C. W., Appella, E., Nakanishi, M., Suzuki, H., et al. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf506 · Cited by 435 · see citing works
Recurrent Initiation: A Mechanism for Triggering p53 Pulses in Response to DNA Damage
Batchelor, E., Mock, C. S., Bhan, I., Loewer, A., & Lahav, G. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.03.016 · Cited by 422 · see citing works
“ATM also phosphorylates the checkpoint kinase Chk2 (Ahn et al., 2000; Matsuoka et al., 2000 ), which directly phosphorylates p53, further contributing to p53 stabilization (Chehab et al., 1999).”
BackgroundDNA damage checkpoints in mammals
Niida, H., & Nakanishi, M. (2005) · Mutagenesis · doi:10.1093/mutage/gei063 · Cited by 431 · see citing works
“Mdm2 phosphorylation by ATM reduces its capability to promote nucleo–cytoplasmic shuttling and the subsequent degradation of p53 (85).”
BackgroundThe MDM2-p53 pathway revisited
Nag, S. A., Jiangjiang, Q., Kalkunte, S. S., Ming-hai, W., & Zhang, R. (2013) · Journal of Biomedical Research · doi:10.7555/jbr.27.20130030 · Cited by 414 · see citing works
“Another facet of MDM2 regulation involves posttranslational modifications([43]) including phosphorylation of the MDM2 protein by upstream molecules such as ATM (decreases MDM2 stability)([43-45]) and Akt (increases MDM2 translocation from the cytoplasm into the nucleus, allowing p53 degradation)([46-49]).”
BackgroundThe PTEN, Mdm2, p53 tumor suppressor–oncoprotein network
Mayo, L. D., & Donner, D. B. (2002) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(02)02166-7 · Cited by 408 · see citing works
Recombinational DNA repair and human disease
Thompson, L. H., & Schild, D. (2002) · Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis · doi:10.1016/s0027-5107(02)00224-5 · Cited by 417 · see citing works
Moody, C. A., & Laimins, L. A. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000605 · Cited by 382 · see citing works
“ATM directly activates p53 by phosphorylation at serine 15, as well as by phosphorylating Mdm2, the ubiquitin ligase that regulates p53 stability [18,19,20].”
BackgroundChk2 kinase — a busy messenger
Bártek, J., Falck, J., & Lukas, J. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35103059 · Cited by 400 · see citing works
PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints
Lu, X., Nannenga, B., & Donehower, L. A. (2005) · Genes & Development · doi:10.1101/gad.1291305 · Cited by 389 · see citing works
“ATM/ATR-induced phosphorylation at this site may inhibit MDM2–p53 interactions, thus inhibiting MDM2-mediated proteolytic degradation of p53 (Shieh et al. 1997; Maya et al. 2001).”
BackgroundIwakuma, T., & Lozano, G. (2003) · PubMed · Cited by 390 · see citing works
Palii, S. S., Emburgh, B. O. V., Sankpal, U. T., Brown, K. D., & Robertson, K. D. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01799-07 · Cited by 382 · see citing works
“ATM directly phosphorylates p53 at serine 15, contributing to its stabilization and increased activity as a transcription factor (12), which in turn leads to activation of a key transcriptional target of p53, the cyclindependent kinase (CDK) inhibitor p21, causing G1 arrest (58, 59).”
BackgroundMammalian cell cycle checkpoints: signalling pathways and their organization in space and time
Lukas, J., Lukas, C., & Bartek, J. (2004) · DNA Repair · doi:10.1016/j.dnarep.2004.03.006 · Cited by 381 · see citing works
The evolution of diverse biological responses to DNA damage: insights from yeast and p53
Wahl, G. M., & Carr, A. M. (2001) · Nature Cell Biology · doi:10.1038/ncb1201-e277 · Cited by 376 · see citing works
Mdm2-mediated ubiquitylation: p53 and beyond
Marine, J.-C., & Lozano, G. (2010) · Cell Death & Differentiation · doi:10.1038/cdd.2009.68 · Cited by 354 · see citing works
Stimulus‐dependent dynamics of p53 in single cells
Batchelor, E., Loewer, A., Mock, C. S., & Lahav, G. (2011) · Molecular Systems Biology · doi:10.1038/msb.2011.20 · Cited by 322 · see citing works
“Error bars represent s.e.m. & 2011 EMBO and Macmillan Publishers Limited Molecular Systems Biology 2011 5 Mdm2 is phosphorylated by ATM on Ser-395 (Khosravi et al, 1999; Maya et al, 2001; Michael and Oren, 2003).”
BackgroundThe role of p53 in chemosensitivity and radiosensitivity
El‐Deiry, W. S. (2003) · Oncogene · doi:10.1038/sj.onc.1206949 · Cited by 337 · see citing works
Activation of the p53 tumor suppressor protein
Vousden, K. H. (2002) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/s0304-419x(02)00035-5 · Cited by 337 · see citing works
Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway
Deisenroth, C., & Zhang, Y. (2010) · Oncogene · doi:10.1038/onc.2010.189 · Cited by 303 · see citing works
Yin, Y., Stephen, C. W., Luciani, M. G., & Fåhræus, R. (2002) · Nature Cell Biology · doi:10.1038/ncb801 · Cited by 305 · see citing works
DNA damage kinase signaling: checkpoint and repair at 30 years
Lanz, M. C., Dibitetto, D., & Smolka, M. B. (2019) · The EMBO Journal · doi:10.15252/embj.2019101801 · Cited by 259 · see citing works
“…2 phosphorylation. ª 2019 The Authors The EMBO Journal 38 : e 101801 | 2019 p53 nuclear export and its subsequent degradation (Mayo et al , 1997; Maya et al , 2001; Shinozaki et al , 2003). lethality of rad53 cells can be rescued by deletion of SML1 , an inhibitor of the ribonucleotide…”
ATM: Genome stability, neuronal development, and cancer cross paths
(2001) · Advances in Cancer Research · doi:10.1016/s0065-230x(01)83007-4 · Cited by 299 · see citing works
Self-citationFeng, J., Tamaskovic, R., Yang, Z., Brazil, D. P., Merlo, A., Hess, D., & Hemmings, B. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m404936200 · Cited by 294 · see citing works
The Wip1 Phosphatase Acts as a Gatekeeper in the p53-Mdm2 Autoregulatory Loop
Lu, X., Ma, O., Nguyen, T., Jones, S. N., Oren, M., & Donehower, L. A. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.08.033 · Cited by 282 · see citing works
Self-citationDisrupting Circadian Homeostasis of Sympathetic Signaling Promotes Tumor Development in Mice
Lee, S., Donehower, L. A., Herron, A. J., Moore, D. D., & Fu, L. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010995 · Cited by 286 · see citing works
“The phosphorylation at these two sites blocks MDM2-p53 interaction, leading to MDM2 autoubiquitination and p53 induction [58].”
BackgroundMethodRegulation of the p53 response and its relationship to cancer
Meek, D. W. (2015) · Biochemical Journal · doi:10.1042/bj20150517 · Cited by 291 · see citing works
The p53 and Mdm2 families in cancer
Michael, D. (2002) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(01)00264-7 · Cited by 288 · see citing works
Posttranslational modification of MDM2.
Meek, D. W., & Knippschild, U. (2003) · PubMed · Cited by 280 · see citing works
Abuetabh, Y., Wu, H. H., Chai, C., Yousef, H. A., Persad, S., Sergi, C. M., & Leng, R. P. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00863-4 · Cited by 275 · see citing works
Rainey, M. D., Charlton, M. E., Stanton, R. V., & Kastan, M. B. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-0763 · Cited by 267 · see citing works
“These compounds were screened using an in vitro ELISA assay, with potential inhibitors being identified by a decreased ability of purified ATM kinase to phosphorylate GST-p53(1-101) substrate (data not shown).”
InfluentialSelf-citationATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage
Chen, L., Gilkes, D. M., Pan, Y., Lane, W. S., & Chen, J. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600812 · Cited by 260 · see citing works
“MDM2 phosphorylation on serine 395 by ATM and tyrosine 394 by c-Abl has also been shown to affect MDM2’s ability to regulate p53 (Maya et al, 2001; Goldberg et al, 2003).”
BackgroundMechanism of p53 stabilization by ATM after DNA damage
Cheng, Q., & Chen, J. (2010) · Cell Cycle · doi:10.4161/cc.9.3.10556 · Cited by 248 · see citing works
p53 and ribosome biogenesis stress: The essentials
Golomb, L., Volarević, S., & Oren, M. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.04.014 · Cited by 242 · see citing works
“One way for this to happen is through post-translational modifications (PTMs) such as phosphorylation [51,52] and acetylation [53,54] of p53 as well as Mdm2 [55,56].”
BackgroundSelf-citationLu, X., Nguyen, T., Moon, S.-H., Darlington, Y. F., Sommer, M., & Donehower, L. A. (2008) · Cancer and Metastasis Reviews · doi:10.1007/s10555-008-9127-x · Cited by 244 · see citing works
“Importantly, DNA damage results in ATM phosphorylation of Mdm2 at Ser395 and this phosphorylation is associated with Mdm2 destabilization [31].”
BackgroundThe ATM Kinase Induces MicroRNA Biogenesis in the DNA Damage Response
Zhang, X., Wan, G., Berger, F. G., He, X., & Lu, X. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.01.020 · Cited by 239 · see citing works
“KSRP immunoprecipitates were run in SDS-PAGE and then dried for X-ray film exposure (Maya et al., 2001).”
Mdm2 Regulates p53 mRNA Translation through Inhibitory Interactions with Ribosomal Protein L26
Ofir-Rosenfeld, Y., Boggs, K., Michael, D., Kastan, M. B., & Oren, M. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.08.031 · Cited by 240 · see citing works
“It is conceivable that IR-induced modifications of Mdm2 (Blattner et al., 2002; Maya et al., 2001) may not only alter the impact of Mdm2 on p53 but also reduce the ability of Mdm2 to interfere with the binding of L26 to p53 mRNA.”
BackgroundSelf-citationCritical role for Daxx in regulating Mdm2
Tang, J., Qu, L., Zhang, J., Wang, W., Michaelson, J. S., Degenhardt, Y., El‐Deiry, W. S., & Yang, X. (2006) · Nature Cell Biology · doi:10.1038/ncb1442 · Cited by 239 · see citing works
“U2OS cells were transfected with Flag-tagged full length Daxx, Daxx(347-740) (defective in Mdm2 binding), or Daxx(1-260) (defective in Hausp binding).”
MethodWang, W., Nag, S. A., Zhang, X., Wang, M., Wang, H., Zhou, J., & Zhang, R. (2014) · Medicinal Research Reviews · doi:10.1002/med.21327 · Cited by 224 · see citing works
Surf the Post-translational Modification Network of p53 Regulation
Gu, B., & Zhu, W. (2012) · International Journal of Biological Sciences · doi:10.7150/ijbs.4283 · Cited by 234 · see citing works
p73 induction after DNA damage is regulated by checkpoint kinases Chk1 and Chk2Preprint
Urist, M. J., Tanaka, T., Poyurovsky, M. V., & Prives, C. L. (2004) · Genes & Development · doi:10.1101/gad.1221004 · Cited by 234 · see citing works
“In particular, the ATM kinase has been shown to phosphorylate both p53 and Mdm2 (Banin et al. 1998; Canman et al. 1998; Khosravi et al. 1999; de Toledo et al. 2000; Maya et al. 2001).”
Backgroundp53-Mdm2--the affair that never ends
Alarcon-Vargas, D. (2002) · Carcinogenesis · doi:10.1093/carcin/23.4.541 · Cited by 231 · see citing works
The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53
Higashitsuji, H., Higashitsuji, H., Itoh, K., Sakurai, T., Nagao, T., Sumitomo, H., Masuda, T., Dawson, S. P., Shimada, Y., Mayer, R. J., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.06.006 · Cited by 228 · see citing works
Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms
Stad, R., Little, N. A., Xirodimas, D. P., Frenk, R., van der Eb, A. J., Lane, D. P., Saville, M. K., & Jochemsen, A. G. (2001) · The EMBO Reports · doi:10.1093/embo-reports/kve227 · Cited by 234 · see citing works
Cellular Responses to DNA Damage: One Signal, Multiple Choices
Su, T. T. (2006) · Annual Review of Genetics · doi:10.1146/annurev.genet.40.110405.090428 · Cited by 227 · see citing works
Brumbaugh, K. M., Otterness, D. M., Geisen, C., Oliveira, V. A., Brognard, J., Li, X., Lejeune, F., Tibbetts, R. S., Maquat, L. E., & Abraham, R. T. (2004) · Molecular Cell · doi:10.1016/j.molcel.2004.05.005 · Cited by 222 · see citing works
Ma‐Lauer, Y., Carbajo-Lozoya, J., Hein, M. Y., Müller, M. A., Deng, W., Lei, J., Meyer, B., Kusov, Y., von Brunn, B., Bairad, D. R., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1603435113 · Cited by 214 · see citing works
“CDK9 phosphorylates RCHY1 at Ser211/ Thr217 and MDM2 at Ser395, causing degradation of RCHY1 and attenuated activity of MDM2 toward p53, respectively (24, 25).”
BackgroundTraven, A., & Heierhorst, J. (2005) · BioEssays · doi:10.1002/bies.20204 · Cited by 207 · see citing works
“Phosphorylation of p53 and MDM2 stabilizes p53 by reducing its degradation((79)) and activates its transcriptional activity by increased binding to other transcription factors.”
BackgroundInfluentialShi, D., & Gu, W. J. (2012) · Genes & Cancer · doi:10.1177/1947601912455199 · Cited by 214 · see citing works
“Cytoplasm is the major compartment of p53 degradation; therefore, p53 degradation is slowed down and p53 protein accumulates.(47) The reverse reaction of phosphorylation on MDM2 Ser395 is catalyzed by the Wip1 phosphatases, also known as PPM1D.”
BackgroundCyclin G Recruits PP2A to Dephosphorylate Mdm2
Okamoto, K., Li, H., Jensen, M. R., Zhang, T., Taya, Y., Thorgeirsson, S. S., & Prives, C. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00504-x · Cited by 215 · see citing works
Tyrosine phosphorylation of Mdm2 by c‐Abl: implications for p53 regulation
Goldberg, Z., Sionov, R. V., Berger, M., Zwang, Y., Perets, R., Etten, R. A. V., Oren, M., Taya, Y., & Haupt, Y. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf384 · Cited by 200 · see citing works
Self-citationPhosphorylation of HDM2 by Akt
Ashcroft, M., Ludwig, R. L., Woods, D. B., Copeland, T. D., Weber, H. O., MacRae, E. J., & Vousden, K. H. (2002) · Oncogene · doi:10.1038/sj.onc.1205276 · Cited by 197 · see citing works
“Phosphorylation by DNA-dependent protein kinase (DNA±PK) (Mayo et al., 1997) casein kinase 2 (CK2) (Gotz et al., 1999; Guerra et al., 1997), ATM kinase (Khosravi et al., 1999; Maya et al., 2001) and cyclin A-CDK complexes (Zhang and Prives, 2001) has been shown to modulate HDM2 function.”
BackgroundInhibition of MDM2 by hsp90 Contributes to Mutant p53 Stabilization
Peng, Y., Chen, L., Li, C., Lu, W., & Chen, J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102817200 · Cited by 180 · see citing works
Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage
Pereg, Y., Shkedy, D., de Graaf, P., Meulmeester, E., Edelson-Averbukh, M., Salek, M., Biton, S., Teunisse, A. F. A. S., Lehmann, W. D., Jochemsen, A. G., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408595102 · Cited by 181 · see citing works
Self-citationp53 and NF‐κB: different strategies for responding to stress lead to a functional antagonism
Ak, P., & Levine, A. J. (2010) · The FASEB Journal · doi:10.1096/fj.10-160549 · Cited by 178 · see citing works
“MDM-2/ MDM-4 complexes and p53/MDM-2 complexes are regulated by phosphoylation with protein kinases (ATM and CHK1/2) that are activated by DNA damage (6).”
BackgroundRegulating the p53 system through ubiquitination
Yang, Y., Li, C.-C. H., & Weissman, A. M. (2004) · Oncogene · doi:10.1038/sj.onc.1207411 · Cited by 179 · see citing works
The Regulation of Multiple p53 Stress Responses is Mediated through MDM2
Hu, W., Feng, Z., & Levine, A. J. (2012) · Genes & Cancer · doi:10.1177/1947601912454734 · Cited by 176 · see citing works
The enigmatic effects of caffeine in cell cycle and cancer
Bode, A. M., & Dong, Z. (2006) · Cancer Letters · doi:10.1016/j.canlet.2006.03.032 · Cited by 177 · see citing works
“ATM and ATR also prevent p53 degradation through their phosphorylation of mouse double minute 2 (MDM2) [23], which disrupts MDM2's association with p53 thereby preventing p53 ubiquitination and degradation.”
BackgroundImmunoglobulin Class Switch Recombination Is Impaired in Atm-deficient Mice
Lumsden, J. M., McCarty, T. C., Petiniot, L. K., Shen, R., Barlow, C., Wynn, T. A., Morse, H. C., Gearhart, P. J., Wynshaw-Boris, A. J., Max, E. E., et al. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20041074 · Cited by 172 · see citing works
“In the presence of DNA damage, ATM phosphorylates a variety of protein targets, including p53 (7–9), CHK2 (10, 11), MDM2 (12, 13), BRCA1 (14, 15), and NBS1 (16–18), and activates multiple signal transduction pathways (19, 20).”
BackgroundATM-Dependent Phosphorylation of ATF2 Is Required for the DNA Damage Response
Bhoumik, A., Takahashi, S., Breitweiser, W., Shiloh, Y., Jones, N., & Ronai, Z. A. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.04.015 · Cited by 169 · see citing works
“ATM/ATR substrates include the transcription factor p53 (Banin et al., 1998), p53’s E3 ubiquitin ligase Mdm2 (Maya et al., 2001), the BRCA1 protein (Cortez et al., 1999), the checkpoint protein Chk2 (Matsuoka et al., 1998), the cohesin subunit Smc1 (Kim et al., 2002), and the damage response proteins H2AX, Mdc1/NFBD1,…”
BackgroundSelf-citationThe regulation of MDM2 oncogene and its impact on human cancers
Zhao, Y., Yu, H., & Hu, W. (2014) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmt147 · Cited by 173 · see citing works
“The phosphorylation of MDM2 at these two positions blocks the ability of MDM2 to export p53 to cytoplasm [70].”
BackgroundDai, M., Sun, X., & Lu, H. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01662-07 · Cited by 174 · see citing works
“DNA damage induces phosphorylation of both p53 and MDM2, unties the p53-MDM2 feedback loop, and consequently activates p53 (2, 5, 25, 39, 41).”
BackgroundSenescence Regulation by the p53 Protein Family
Qian, Y., & Chen, X. (2012) · Methods in molecular biology · doi:10.1007/978-1-62703-239-1_3 · Cited by 170 · see citing works
“Likewise, phosphorylation of MDM2 at Ser-395 by ATM attenuates the capability of MDM2 in exporting nuclear p53 to cytoplasm for subsequent p53 degradation, thereby enabling p53 accumulation (38, 39).”
BackgroundGenotoxic and non-genotoxic pathways of p53 induction
Pluquet, O., & Hainaut, P. L. (2001) · Cancer Letters · doi:10.1016/s0304-3835(01)00698-x · Cited by 170 · see citing works
ATM-Mediated Phosphorylations Inhibit Mdmx/Mdm2 Stabilization by HAUSP in Favor of p53 Activation
Meulmeester, E., Pereg, Y., Shiloh, Y., & Jochemsen, A. G. (2005) · Cell Cycle · doi:10.4161/cc.4.9.1981 · Cited by 166 · see citing works
Self-citationGajjar, M. K., Candeias, M. M., Malbert-Colas, L., Mazars, A., Fujita, J., Olivares‐Illana, V., & Fåhræus, R. (2012) · Cancer Cell · doi:10.1016/j.ccr.2011.11.016 · Cited by 168 · see citing works
“Importantly, when we instead used the 2A10 mAb, which does not recognize the phosphorylated Ser 395 epitope (Maya et al., 2001), we detected little p53 mRNA in the qRNA-coIP even in the presence of ATM, indicating that nonphosphorylated Mdm2 has weak affinity to the p53 mRNA (Figure 3B; Figure S3B).”
BackgroundMethodATM activates p53 by regulating MDM2 oligomerization and E3 processivity
Cheng, Q., Chen, L., Li, Z., Lane, W. S., & Chen, J. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.294 · Cited by 165 · see citing works
“MDM2 is phosphorylated by ATM, ATR, and C-Abl on sites near the C terminus (Maya et al, 2001; Sionov et al, 2001; Shinozaki et al, 2003).”
BackgroundThe role of DNA damage responses in p53 biology
Speidel, D. (2015) · Archives of Toxicology · doi:10.1007/s00204-015-1459-z · Cited by 165 · see citing works
“Posttranslational modifications of both p53 and Mdm2, including phosphorylation of p53 at serine 20 and phosphorylation of Mdm2 at serine 395, are rapidly triggered upon DNA damage, disrupt the p53-Mdm2 complex and inhibit Mdm2 by other means (Chehab et al. 1999; Cheng et al. 2009; Hu et al. 2012; Maya et al. 2001; Mo…”
BackgroundRegulation of NF‐κB and p53 through activation of ATR and Chk1 by the ARF tumour suppressor
Rocha, S., Garrett, M. D., Campbell, K. J., Schumm, K., & Perkins, N. D. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600608 · Cited by 161 · see citing works
“These could include Hdm2, a known ATR/ATM substrate (Khosravi et al, 1999; de Toledo et al, 2000; Maya et al, 2001; Shinozaki et al, 2003), and other transcription factors or proteins with proliferative or antiapoptotic functions.”
Background
- Authors
- Maya, R., Balass, M., Kim, S.-T., Shkedy, D., Leal, J.-F. M., Shifman, O., Moas, M., Buschmann, T., Ronai, Z., Shiloh, Y., Kastan, M. B., Katzir, E., & Oren, M.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2001-05-01
- Volume
- 15
- Issue
- 9
- Pages
- 1067-1077
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC312683
- OpenAlex
- W2158005145
- Cited by
- 716
- References
- 71
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 9 · 2023: 12 · 2022: 15 · 2021: 18 · 2020: 25 · 2019: 25 · 2018: 13 · 2017: 18 · 2016: 24 · 2015: 21 · 2014: 33 · 2013: 28 · 2012: 53
- Type
- posted content
- Language
- en
- Open access
- diamond
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- MDM2, ATM kinase, p53 activation, DNA damage response, ionizing radiation, p53 stabilization, nucleocytoplasmic shuttling, p53 degradation
- MeSH terms
- Animals, Antibodies, Monoclonal, Aspartic Acid, Cell Nucleus, Cells, Cultured, DNA Damage, DNA-Binding Proteins, Fibroblasts
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