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Accelerated MDM2 auto‐degradation induced by DNA‐damage kinases is required for p53 activation
Open accessAbstract
p53 activation prevents the proliferation of genetically unstable cells. Conversely, p53 antagonism by its transcriptional target, the E3 ubiquitin ligase MDM2, is critical for the viability of unstressed, cycling cells. We demonstrate that MDM2 induces the degradation of p53 in both the nucleus and the cytoplasm. As p53 and MDM2 accumulate in the nuclei of stressed cells, we investigated mechanisms enabling p53 activation despite the high MDM2 levels generated during a DNA-damage response. We show that DNA damage destabilized MDM2 by a mechanism involving damage-activated kinases and MDM2 auto-ubiquitination. p53 was stable and transcriptionally active when MDM2 was unstable, but became unstable and inactive as the damage response waned and MDM2 stabilized. Importantly, blocking MDM2 destabilization in DNA-damaged cells prevented p53 target gene activation. Our data reveal that controlled MDM2 degradation is an important new step in p53 regulation.
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“However, in addition to degrading p53, Mdm2 also undergoes auto-degradation [12,13] and targets Mdmx for degradation [14–16], which is critical for optimal p53 activation after stress.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [12]
In the citing paper
“The disruption of Mdm2 oligomers might also contribute to their destabilization following DNA damage [12].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [12]
In the citing 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).”
From ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage (2005) · cites this paper as Stommel and Wahl, 2004
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Cites
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“…Degradation Regulation of Mdm2 stability is believed to be mediated primarily through autoubiquitination (Fang et al., 2000; Honda and Yasuda, 2000; Stommel and Wahl, 2004); however, the advent of the Mdm2C462A knock-in mouse provided strong evidence suggesting that Mdm2 does not in fact…”
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“Particularly, Ser15, 20 and Thr18 are key sites for phosphorylation, which not only guide p53 for transcriptional binding on DNA target, but also disrupt the interaction of p53 with MDM2 [14,19].”
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“At the same time, protein levels of Mdm2, which is auto-degraded in an ATM-dependent manner (Stommel and Wahl, 2004), were severely decreased.”
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“Phosphorylation of p53 at particular residues inhibits Mdm2 binding ( Shieh et al, 1997 ), and auto-ubiquitylation of Mdm2 may occur after DNA damage induced by gamma radiation ( Stommel & Wahl, 2004 ).”
BackgroundChemotherapy induces NEDP1-mediated destabilization of MDM2
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“…example, in response to radiomimetic drug neocarzinostatin, MDM2 becomes phosphorylated by ATM, which abrogates MDM2 binding to the deubiquitylating enzyme HAUSP, resulting in increased ubiquitylation and degradation of MDM2 (Khosravi et al., 1999; Stommel and Wahl, 2004; Meulmeester et al., 2005).”
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Weber, H. O., Ludwig, R. L., Morrison, D. K., Kotlyarov, A., Gaestel, M., & Vousden, K. H. (2005) · Oncogene · doi:10.1038/sj.onc.1208389 · Cited by 60
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“DNA damage, particularly dsDNA breaks, also stimulate the activation of other E3 ligases that target MDM2 such as P300-CBPassociated factor (PCAF), a histone acetyltransferase and transcriptional co-activator of p53 (85, 86).”
BackgroundMaking sense of ubiquitin ligases that regulate p53
Jain, A. K., & Barton, M. C. (2010) · Cancer Biology & Therapy · doi:10.4161/cbt.10.7.13445 · Cited by 60
“33 During this process, Mdm2 may ubiquitinate itself and its partner, MdmX.24,34 Further investigations show that Mdm2-mediated regulation of p53 is more complex than initially thought, as Mdm2 also influences subcellular localization and transcriptional potential of p53 (Fig.”
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“A more common real-world stress is DNA damage, which can trigger processes that result in (a) increased auto-ubiquitination of Mdm2, (b) decreased ubiquitination of p53 by Mdm2 and (c) weaker binding of p53Mdm2 [15,29,30], corresponding in our model to increasTable 1: Model parameters”
BackgroundA synthetic–natural hybrid oscillator in human cells
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Modulation of p53 during bacterial infections
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“Meanwhile, it facilitates its own ubiquitination under certain conditions, consequently resulting in the destabilization of MDM2 itself [38].”
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“This rapidly stabilizes p53 and renders it active.(27,28) However, when comparing similar amounts of stress-stabilized p53 (Figure 1e, ‘short’ exposure), p53 from NB cells, whereas its ubiquitination does decrease somewhat, remains significantly hyperubiquitylated compared to non-NB cells.”
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MTA1 Coregulator Regulates p53 Stability and Function
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Regulation of MDM2 Stability After DNA Damage
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“For instance, the PI3K inhibitor wortmannin, which would result in the inhibition of AKT, stabilizes MDM2 and prevents DNA damage-induced MDM2 degradation (Stommel and Wahl, 2004).”
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“MDM2 also undergoes ATM dependent phosphorylation and phosphorylated MDM2 dissociates from the MDM2p53 complex leading to reduced p53 degradation and accelerated auto-degradation under stress [26,59], the efficiency of MDM2 dependent degradation of p53 is reversely correlated with activated ATM.”
BH3 activation blocks Hdmx suppression of apoptosis and cooperates with Nutlin to induce cell death
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Self-citationHispolon promotes MDM2 downregulation through chaperone-mediated autophagy
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Mechanistic Studies of MDM2-mediated Ubiquitination in p53 Regulation
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Crosstalk between p53 and nuclear factor-κB systems: pro- and anti-apoptotic functions of NF-κB
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PHD1 regulates p53‐mediated colorectal cancer chemoresistance
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“This is in line with some previous evidence showing that p53 phosphorylation is not the main determinant of p53 transcriptional activity as p53 transcription can also be triggered by mere p53 stabilization without phosphorylation (Stommel & Wahl, 2004; Kruse & Gu, 2009).”
ResultBo, M. D., Bertoni, F., Forconi, F., Zucchetto, A., Bomben, R., Marasca, R., Deaglio, S., Laurenti, L., Efremov, D. G., Gaïdano, G., et al. (2009) · Journal of Translational Medicine · doi:10.1186/1479-5876-7-76 · Cited by 45
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Senescent cells limit p53 activity via multiple mechanisms to remain viable
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Modeling the Basal Dynamics of P53 System
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“. ATM can also phosphorylate MDM2 and destabilize it”
BackgroundNuclear export regulation of COP1 by 14-3-3σ in response to DNA damage
Su, C., Zhao, R., Velázquez-Torres, G., Chen, J., Gully, C. P., Yeung, S. J., & Lee, M. (2010) · Molecular Cancer · doi:10.1186/1476-4598-9-243 · Cited by 44
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“After DNA damage ATMmediated phosphorylation of MDM2 elicits its autoubiquitylating activity, decreasing levels of ATM and MDMX, which in turn increases p53 levels.(20,21) Although MDM2 is considered the key E3 ligase for p53, continued research has revealed the involvement of a myriad of other E3 ligases in maintaini…”
BackgroundCooperative Roles of c-Abl and Cdk5 in Regulation of p53 in Response to Oxidative Stress
Lee, J., Jeong, M.-W., Kim, W., Choi, Y. H., & Kim, K. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m706201200 · Cited by 43
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“DNA damage has also shown to induce MDM2 autodegradation (78).”
BackgroundSIRT7 activates p53 by enhancing PCAF-mediated MDM2 degradation to arrest the cell cycle
Lu, Y.-F., Xu, X.-P., Lu, X.-P., Zhu, Q., Liu, G., Bao, Y.-T., Wen, H., Li, Y.-L., Gu, W., & Zhu, W.-G. (2020) · Oncogene · doi:10.1038/s41388-020-1305-5 · Cited by 40
MDM2 promotes genome instability by ubiquitinating the transcription factor HBP1
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Anatomy of Mdm2 and Mdm4 in evolution
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“In nonstressed cells, this feedback loop maintains a low level of Mdm2 and p53: the half-lives of the two proteins in unstressed cells are 20 min (Stommel and Wahl, 2004).”
The Pharmacodynamics of the p53-Mdm2 Targeting Drug Nutlin: The Role of Gene-Switching Noise
Puszyński, K., Gandolfi, A., & d’Onofrio, A. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003991 · Cited by 41
“Poly-ubiquitinated p53 (by at least four ubiquitin molecules) is then quickly degraded [52,53].”
BackgroundNovel Insights into the Molecular Mechanisms Governing Mdm2 Ubiquitination and Destruction
Inuzuka, H., Fukushima, H., Shaik, S., & Wei, W. (2010) · Oncotarget · doi:10.18632/oncotarget.202 · Cited by 39
“In agreement with previous studies, we found that Mdm2 destruction was enhanced in response to DNA damaging treatment [20, 23].”
BackgroundResultInfluentialStructural basis for DNA damage-induced phosphoregulation of MDM2 RING domain
Magnussen, H., Ahmed, S. F., Sibbet, G. J., Hristova, V. A., Nomura, K., Hock, A. K., Archibald, L. J., Jamieson, A. G., Fushman, D., Vousden, K. H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15783-y · Cited by 37
MDM2 and MDMX in Cancer and Development
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“In fact, an early step in the accumulation of p53 in response to stress, DNA damage in particular, is an associated increase in HDM2 autoubiquitination and degradation [18,19].”
BackgroundKim, Y. J., Kim, M., Park, H. K., Yu, D. B., Jung, K., Song, K., & Choi, Y. (2019) · Laboratory Investigation · doi:10.1038/s41374-019-0263-4 · Cited by 38
“MDM2 functions as a ubiquitin ligase that targets p53 through the proteasomal degradation pathway; it also participates in its own autodegradation to prohibit MDM2 activity, inhibiting p53 during periods of cellular stress [7, 8].”
BackgroundFunctions of MDMX in the Modulation of the p53‐Response
Lenos, K., & Jochemsen, A. G. (2011) · BioMed Research International · doi:10.1155/2011/876173 · Cited by 40
Genetic polymorphisms of MDM2, cumulative cigarette smoking and nonsmall cell lung cancer risk
Liu, G., Wheatley‐Price, P., Zhou, W., Park, S., Heist, R. S., Asomaning, K., Wain, J. C., Lynch, T. J., Su, L., & Christiani, D. C. (2007) · International Journal of Cancer · doi:10.1002/ijc.23178 · Cited by 38
“DNA damage-activated kinases may contribute to the destabilization of MDM2 and subsequent activation of p53.(15) Activation of p53 in response to stress (smoking) is accompanied by the stabilization of p53, which counters the ability of MDM2 to target p53 for degradation after DNA damage.”
BackgroundMouse bites dogma: how mouse models are changing our views of how P53 is regulated in vivo
Wahl, G. M. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401911 · Cited by 37
“Importantly, we also showed that proteasome inhibitors prevent P53 activation after DNA damage, even though P53 was phosphorylated in its N-terminus.135 By contrast, Nutlin addition during proteasome inhibitor treatment enabled P53 activation by reducing Mdm2 (and presumably)– MdmX interaction with P53.”
BackgroundInfluentialSelf-citationDNA damage-induced activation of ATM promotes β-TRCP-mediated Mdm2 ubiquitination and destruction
Wang, Z. P., Inuzuka, H., Zhong, J., Fukushima, H., Wan, L., Liu, P., & Wei, W. (2012) · Oncotarget · doi:10.18632/oncotarget.640 · Cited by 39
“com/oncotarget damage could possibly augment Mdm2 auto-degradation [25, 26].”
BackgroundLi, W., Peng, X., Lang, J., & Xu, C. S. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00631 · Cited by 36
The p53-Mdm2 Loop: A Critical Juncture of Stress Response
Levav-Cohen, Y., Goldberg, Z., Tan, K. H., Alsheich-Bartok, O., Zuckerman, V., Haupt, S., & Haupt, Y. (2014) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-017-9211-0_9 · Cited by 38
“Additional studies show that the complex phosphorylation of Mdm2 upon DNA damage by PI-3 kinases including ATM, ATR and DNA-PK may increase auto-ubiquitination of Mdm2 and enhance its degradation, resulting in augmented p53 abundance and transcription [100].”
BackgroundZajkowicz, A., Gdowicz‐Kłosok, A., Krześniak, M., Ścieglińska, D., & Rusin, M. (2015) · Cellular Signalling · doi:10.1016/j.cellsig.2015.05.005 · Cited by 36
Harmonic Oscillations in Homeostatic Controllers: Dynamics of the p53 Regulatory System
Jolma, I. W., Ni, X. Y., Rensing, L., & Ruoff, P. (2010) · Biophysical Journal · doi:10.1016/j.bpj.2009.11.013 · Cited by 35
“With respect to the model’s second requirement, experiments have shown that p53 becomes stabilized by a decrease in the Mdm2 stability (43) and by inhibiting Mdm2independent degradation pathways (16–21, 36, 37).”
BackgroundInfluentialFunctions of p53 in metabolism and invasion
Vousden, K. H. (2009) · Biochemical Society Transactions · doi:10.1042/bst0370511 · Cited by 36
Carr, M. I., Roderick, J. E., Gannon, H., Kelliher, M. A., & Jones, S. N. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.08.014 · Cited by 34
“Our result is in keeping with previous in vitro studies that indicate a decrease in the half-life of Mdm2 after genotoxic stress (Stommel and Wahl, 2004; Itahana et al., 2007; Inuzuka et al., 2010).”
BackgroundResultSMG7 is a critical regulator of p53 stability and function in DNA damage stress response
Luo, H., Cowen, L. E., Yu, G., Jiang, W. G., & Tang, Y. (2016) · Cell Discovery · doi:10.1038/celldisc.2015.42 · Cited by 33
Stefano, V. D., Mattiussi, M., Sacchi, A., & D’Orazi, G. (2005) · FEBS Letters · doi:10.1016/j.febslet.2005.09.008 · Cited by 34
ATM in breast and brain tumors: a comprehensive review
Mehrdad, A. E., & Mehdipour, P. (2018) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2018.0022 · Cited by 34
Chua, M. L. K., Horn, S., Somaiah, N., Davies, S., Gothard, L., A’Hern, R., Yarnold, J. R., & Rothkamm, K. (2014) · Radiation and Environmental Biophysics · doi:10.1007/s00411-014-0531-z · Cited by 33
“ATM-mediated apoptosis occurs primarily through controlling post-translational modifications of p53 and phosphorylation of Mdm2, an ubiquitin ligase which in its native unphosphorylated state, binds to p53 thereby targeting the tumour suppressor protein for degradation (Shiloh 2003; Meek 2003; Stommel and Wahl 2004).”
BackgroundTian, X., Liu, F., Zhang, X. P., Li, J., & Wang, W. (2012) · PLoS ONE · doi:10.1371/journal.pone.0038164 · Cited by 32
“Consequently, the degradation of Mdm2 is enhanced, while p53 is stabilized and activated [27].”
BackgroundMicroRNA-200 is commonly repressed in conjunctival MALT lymphoma, and targets cyclin E2
Cai, J.-P., Liu, X., Cheng, J.-W., Li, Y., Huang, X., Li, Y., Ma, X., Yu, H., Liu, H., & Wei, R.-L. (2011) · Graefe s Archive for Clinical and Experimental Ophthalmology · doi:10.1007/s00417-011-1885-4 · Cited by 33
“Whole-cell extracts for immunoblotting analysis were prepared as previously described [27].”
MethodQuantitative Assessment of the p53-Mdm2 Feedback Loop Using Protein Lysate Microarrays
Ramalingam, S., Honkanen, P., Young, L., Shimura, T., Austin, J., Steeg, P. S., & Nishizuka, S. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0342 · Cited by 33
“(6) depicting oscillations by showing the role of the DNA damage sensor, ataxia telangiectasia mutated, in both phosphorylating p53 and increasing the degradation of Mdm2 (13, 14).”
BackgroundKinetic and thermodynamic effects of phosphorylation on p53 binding to MDM2
Yadahalli, S., Neira, J. L., Johnson, C. M., Tan, Y. S., Rowling, P. J. E., Chattopadhyay, A., Verma, C. S., & Itzhaki, L. S. (2019) · Scientific Reports · doi:10.1038/s41598-018-36589-5 · Cited by 32
Jiang, H., Zou, J., Zhang, H., Fu, W., Zeng, T., Huang, H., Zhou, F., & Hou, J. (2013) · Clinical and Experimental Medicine · doi:10.1007/s10238-013-0269-y · Cited by 32
“Whole-cell extracts from the myeloma cell lines were prepared as described [18].”
MethodStochastic Modeling and Simulation of the p53-MDM2/MDMX Loop
Cai, X., & Yuan, Z.-M. (2009) · Journal of Computational Biology · doi:10.1089/cmb.2008.0231 · Cited by 32
“After DNA damage, the half-life of MDM2 reduces to about 5–10 minutes (Stommel and Wahl, 2004), possibly due to impaired deubiquitination of MDM2 by HAUSP (Li et al., 2004).”
Mathematical modelling of p53 basal dynamics and DNA damage response
Chong, K. H., Samarasinghe, S., & Kulasiri, D. (2014) · Mathematical Biosciences · doi:10.1016/j.mbs.2014.10.010 · Cited by 30
Stability of Helicobacter pylori CagA oncoprotein in human gastric epithelial cells
Ishikawa, S., Ohta, T., & Hatakeyama, M. (2009) · FEBS Letters · doi:10.1016/j.febslet.2009.06.043 · Cited by 31
“The half-reduction time of CagA was calculated according to the one-phase exponential decay formula [15].”
MethodExpression of cyclin D2, P53, Rb and ATM cell cycle genes in brain tumors
Kheirollahi, M., Mehrazin, M., Kamalian, N., & Mehdipour, P. (2010) · Medical Oncology · doi:10.1007/s12032-009-9412-8 · Cited by 31
“The evaluation of the association between ATM gene variants and breast cancer has been previously reported [25, 28–31] and a few reports on evaluation of ATM gene expression are available in breast tissues [32, 33].”
BackgroundCui, B., Johnson, S. P., Bullock, N., Ali‐Osman, F., Bigner, D. D., & Friedman, H. S. (2009) · Molecular Pharmacology · doi:10.1124/mol.108.053124 · Cited by 32
“D341 MED or Daoy cells were treated with 20 M BCNU and, 24 h after treatment, whole-cell extracts were prepared as described previously (Stommel and Wahl, 2004) and immunoprecipitations using anti-Chk1 antibody (Santa Cruz Biotechnology) were carried out as previously depicted (SchildPoulter et…”
MethodZNF668 Functions as a Tumor Suppressor by Regulating p53 Stability and Function in Breast Cancer
Hu, R., Peng, G., Dai, H., Breuer, E.-K. Y., Stemke‐Hale, K., Li, K., Gonzalez-Angulo, A. M., Mills, G. B., & Lin, S. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-0853 · Cited by 31
“modified p53 and leads to accelerated MDM2 autoubiquitination and consequently, p53 stabilization and activation (33, 39).”
Backgroundc-Abl Phosphorylation of Mdm2 Facilitates Mdm2-Mdmx Complex Formation
Waning, D. L., Lehman, J. A., Batuello, C. N., & Mayo, L. D. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.183012 · Cited by 30
Involvement of miR-605 and miR-34a in the DNA Damage Response Promotes Apoptosis Induction
Zhou, C.-H., Zhang, X., Liu, F., & Wang, W. (2014) · Biophysical Journal · doi:10.1016/j.bpj.2014.02.032 · Cited by 32
Meng, L.-H., Kohn, K. W., & Pommier, Y. G. (2007) · Oncogene · doi:10.1038/sj.onc.1210283 · Cited by 30
“Consistent with previous results, p53 is unstable in unstressed cells with a half-life of about 10min (Stommel and Wahl, 2004) (Figure 2b and c).”
BackgroundResultInfluentialJiang, L., Malik, N., Acedo, P., & Zawacka‐Pankau, J. (2019) · Cell Death Discovery · doi:10.1038/s41420-019-0157-7 · Cited by 29
Cell death induced by 7-oxysterols via lysosomal and mitochondrial pathways is p53-dependent
Li, W., Laskar, A., Sultana, N., Osman, E., Ghosh, M., Li, Q., & Yuan, X. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.09.007 · Cited by 30
“MDM2 can undergo autodegradation [26,27].”
Han, Y. S., Cao, H., Jiang, J., Xu, Y., Du, J., Wang, X., Yuan, M. Z., Wang, Z., Xu, Z. H., & Chong, K. (2008) · PLANT PHYSIOLOGY · doi:10.1104/pp.108.125294 · Cited by 28
“Each decrease of 1 unit of log2 (band intensity) is equivalent to one half-life (Stommel and Wahl, 2004).”
BackgroundHanson, R. L., Porter, J. R., & Batchelor, E. (2019) · The Journal of Cell Biology · doi:10.1083/jcb.201803063 · Cited by 27
“Previous studies identified the S395 residue of MDM2 as a key site controlling MDM2 stability, with phosphorylation of this site by the ATM serine/threonine kinase (ATM) leading to elevated levels of MDM2 degradation during the DSB response (Fig. 6 A; Maya et al., 2001; Stommel and Wahl, 2004; Batchelor et al., 2011).”
BackgroundIt Takes 15 to Tango: Making Sense of the Many Ubiquitin Ligases of p53
Love, I. M., & Grossman, S. R. (2012) · Genes & Cancer · doi:10.1177/1947601912455198 · Cited by 28
“Subsequent experiments have convincingly supported and expanded upon this hypothesis, indicating that both disruption of the MDM2/p53 complex, inactivation of intrinsic MDM2 E3 activity, and transient destabilization of MDM2 by an ATM/ATR-initiated kinase cascade are necessary for the full physiologic stabilization an…”
BackgroundDynamics of P53 in response to DNA damage: Mathematical modeling and perspective
Sun, T., & Cui, J. (2015) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2015.08.017 · Cited by 29
Metadata
- Authors
- Stommel, J. M., & Wahl, G. M.
- Affiliations
- Salk Institute for Biological Studies (US)
- Corresponding author
- Wahl, Geoffrey M
- Venue
- The EMBO Journal
- Published
- 2004-03-18
- Volume
- 23
- Issue
- 7
- Pages
- 1547-1556
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC391059
- OpenAlex
- W2091818021
- Cited by
- 386
- References
- 54
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 9 · 2023: 13 · 2022: 10 · 2021: 16 · 2020: 13 · 2019: 19 · 2018: 10 · 2017: 9 · 2016: 8 · 2015: 15 · 2014: 21 · 2013: 13 · 2012: 24
- FWCI
- 11.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- National Institutes of Health
- National Cancer Institute (CA61449, R01CA061449)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- MDM2, p53 activation, DNA damage response, E3 ubiquitin ligase, p53 stabilization, cell cycle arrest
- MeSH terms
- Animals, Cell Line, Cell Nucleus, Cytoplasm, DNA Damage, Gene Expression Regulation, Humans, Nuclear Proteins, Proto-Oncogene Proteins, Transcription, Genetic, Transcriptional Activation, Tumor Suppressor Protein p53, Phosphatidylinositol 3-Kinases, Active Transport, Cell Nucleus, Proteasome Endopeptidase Complex, Mice, Proto-Oncogene Proteins c-mdm2, Proteasome Inhibitors
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