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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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MethodUSP10 Regulates p53 Localization and Stability by Deubiquitinating p53
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“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).”
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BackgroundThe ATM-mediated DNA-damage response: taking shape
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The p53 orchestra: Mdm2 and Mdmx set the tone
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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
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BackgroundStructural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX
Pazgier, M., Liu, M., Zou, G., Yuan, W., Li, C., Li, C., Li, J., Monbo, J., Zella, D., Tarasov, S. G., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900947106 · Cited by 391
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“This phosphorylation destabilizes Mdm2 by increasing its autoubiquitination and subsequent proteasomal degradation (Stommel and Wahl, 2004) (Figure 3E).”
BackgroundSmall molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells
Yang, Y., Ludwig, R. L., Jensen, J. P., Pierre, S. A., Medaglia, M. V., Davydov, I. V., Safiran, Y. J., Oberoi, P., Kenten, J. H., Phillips, A. C., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.04.029 · Cited by 327
MDM2 is a Central Node in the p53 Pathway: 12 Years and Counting
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“During stress, DNA damage induces autoubiquitination and self-degradation of MDM2 as part of the stabilization mechanism of wild-type p53 (21).”
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“In addition to mediating transfer of ubiquitin to substrate proteins, such as p53, MDM2 also ubiquitylates itself and MDMX.”
BackgroundInfluentialMonoubiquitylation promotes mitochondrial p53 translocation
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“In addition, stress induces rapid autodegradation of Mdm2 (Supplementary Figure 1E) (Ashcroft et al, 2000; Stommel and Wahl, 2004).”
BackgroundInfluentialA Stapled p53 Helix Overcomes HDMX-Mediated Suppression of p53
Bernal, F., Wade, M. R., Godes, M., Davis, T. N., Whitehead, D. G., Kung, A. L., Wahl, G. M., & Walensky, L. D. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.10.024 · Cited by 288
“This heightened turnover of HDM2 and HDMX also contributes to p53 stabilization and activation (Meulmeester et al., 2005; Pan and Chen, 2003; Stommel and Wahl, 2004).”
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ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage
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“A recent study showed that DNA damage also accelerates MDM2 degradation through a mechanism that requires its own RING domain (Stommel and Wahl, 2004).”
BackgroundCell fate decision mediated by p53 pulses
Zhang, X.-P., Liu, F., Cheng, Z., & Wang, W. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0813088106 · Cited by 253
“Thus, ATM* induces a conversion of p53 from the inactive state to the active state (p53*) (29).”
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 264
Itahana, K., Mao, H., Jin, A., Itahana, Y., Clegg, H. V., Lindström, M. S., Bhat, K. P., Godfrey, V. L., Evan, G. I., & Zhang, Y. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.09.007 · Cited by 245
“DNA Damage Induces Destabilization of Mdm2 Regardless of Mdm2 RING E3 Function Previous studies have shown that Mdm2’s half-life decreases after cells are treated with DNA-damaging agents (Stommel and Wahl, 2004).”
BackgroundCritical 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 242
“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).”
MethodPhosphorylation of p53 on Key Serines Is Dispensable for Transcriptional Activation and Apoptosis
Thompson, T., Tovar, C., Yang, H. S., Carvajal, D. M., Vu, B. T., Xu, Q., Wahl, G. M., Heimbrook, D. C., & Vassilev, L. T. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m410233200 · Cited by 232
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“MDM2 destabilization following DNA damage (Stommel and Wahl, 2004) is also the result of decreased HAUSP binding, whereas binding of p53 to HAUSP is not affected (Meulmeester et al., 2005).”
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“The intrinsic E3 ligase activity of MDM2 drives its own ubiquitination.(57) However, data from the RING mutant knock in mice do not support the”
BackgroundLiposarcoma: Molecular Genetics and Therapeutics
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“Although it is proposed that Mdm2 undergoes autoubiquitination when cells are challenged with DNA damage agents (Stommel and Wahl, 2004; Stommel and Wahl, 2005), a recent study using transgenic mice provided definitive evidence that the E3 ligase activity of Mdm2 is not required for the proper destruction of Mdm2 (Ita…”
InfluentialSelf-citationTargeting the p53–MDM2 interaction to treat cancer
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“Nutlins penetrated cell membranes and inhibited p53– MDM2 binding, leading to stabilisation of p53 and activation of p53 target genes (Stommel and Wahl, 2004; Vassilev et al, 2004).”
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“Protein lysates were prepared and analyzed on SDS-PAGE gels as described (Stommel and Wahl, 2004).”
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Intrinsic ubiquitination activity of PCAF controls the stability of the oncoprotein Hdm2
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“dtd" [ ]> The p300–CBP-associated factor (PCAF) is a histone acetyltransferase (HAT) involved in the reversible acetylation of various transcriptional regulator”
An essential function of the extreme C-terminus of MDM2 can be provided by MDMX
Uldrijan, S., Pannekoek, W., & Vousden, K. H. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601469 · Cited by 170
“…shown that the ability of MDM2 to degrade itself can be separated from the ability to degrade p53, and some forms of genotoxic damage function to stabilize p53 by promoting the auto-degradation of MDM2, and so shifting the balance between the levels of the two proteins (Stommel and Wahl, 2004).”
BackgroundTargeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry?
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Self-citationATM-Mediated Phosphorylations Inhibit Mdmx/Mdm2 Stabilization by HAUSP in Favor of p53 Activation
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“Further explanation comes from the experiments performed by Stommel and Wahl (2004), showing that phosphorylation of Mdm2 by DNA damage-induced PI3KKs, including the S395 phosphorylation, temporarily destabilizes the Mdm2 protein.56 Incubation with wortmannin, a general inhibitor of PIKK kinases,…”
Oxidative Stress and Lectin-Like Ox-LDL-Receptor LOX-1 in Atherogenesis and Tumorigenesis
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“Ang II, a critical player in atherogenesis, via its type 1 receptor (angiotensin II type 1 receptor [AT1R]) activation upregulates the expression of LOX-1 mRNA, and ox-LDL via LOX-1 upregulates the expression of AT1Rs (149, 152–154, 157–159, 250).”
ATM activates p53 by regulating MDM2 oligomerization and E3 processivity
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“DNA damage has been shown to induce rapid degradation of MDM2 partly through the ATM pathway (Stommel and Wahl, 2004).”
BackgroundHdmx modulates the outcome of p53 activation in human tumor cells
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Self-citationRegulation of p53 by the Ubiquitin-conjugating Enzymes UbcH5B/C in Vivo
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“When cells are exposed to stress, DNA damage inducible kinases are rapidly activated to phosphorylate MDM2 at an N-terminal Serine [9], leading to destabilization of this protein through MDM2-mediated autoubiquitination.”
MDMX regulation of p53 response to ribosomal stress
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“DNA damage induces phosphorylation of p53 and MDM2 on multiple residues, which weaken p53–MDM2 binding, stimulates MDM2 degradation, and suppresses MDM2 E3 ligase function (Prives and Hall, 1999; Maya et al, 2001; Goldberg et al, 2002; Stommel and Wahl, 2004).”
BackgroundRegulation of p53: a collaboration between Mdm2 and MdmX
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“com/oncotarget that DNA damage can destabilize Mdm2 by means of autoubiquitination [39,42] and Mdm2 ubiquitinates MdmX to mark it for proteasomal degradation [43,44].”
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“to depend on the activities of kinases such as ATM, ATR, or DNA-PK, which are activated upon DNA damage (Khosravi et al, 1999; Maya et al, 2001; Stommel and Wahl, 2004).”
BackgroundInfluentialNucleotide Biosynthetic Enzyme GMP Synthase Is a TRIM21-Controlled Relay of p53 Stabilization
Reddy, B. A., van der Knaap, J. A., Bot, A. G. M., Mohd-Sarip, A., Dekkers, D. H. W., Timmermans, M. A. M., Martens, J. W. M., Demmers, J., & Verrijzer, C. P. (2014) · Molecular Cell · doi:10.1016/j.molcel.2013.12.017 · Cited by 133
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“Activation of the ATM/ATR/Chk1/2 cascade leads to stabilization of p53, and subsequent upregulation of a number of antiproliferative genes, including p21 [48-53].”
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“It well known that the major role in stabilization of p53 both under normal and stressful conditions is played by Hdm2, the stability (and activity) of which is, in turn, regulated mostly by selfubiquitination followed by degradation ( 30 ).”
BackgroundMdm2 Binds to Nbs1 at Sites of DNA Damage and Regulates Double Strand Break Repair
Alt, J. R., Bouska, A., Fernandez, M. R., Cerny, R. L., Xiao, H., & Eischen, C. M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413387200 · Cited by 131
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“As an E3 ligase, Mdm2 possesses inherent self-ubiquitination activity [39–41].”
BackgroundFrom structure to dynamics: Frequency tuning in the p53–Mdm2 network
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“- DNA damage is induced by exposure to stress and has a negative influence on the level of nuclear Mdm2, by accelerating its degradation through ATMmediated phosphorylation and auto-ubiquitination (Stommel and Wahl, 2004; Stommel and Wahl, 2005).”
BackgroundMDM2 and MDMX: Alone and together in regulation of p53.
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Antiangiogenic Activity of the MDM2 Antagonist Nutlin-3
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Stress-mediated nuclear stabilization of p53 is regulated by ubiquitination and importin-α3 binding
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“The slow kinetics of nuclear export has been noted before.(41) Our conclusion is supported by the fact that most NES motifs are weak and bind to the nuclear export receptor Crm1 with relatively low affinity.”
SIRT1 Regulates Autoacetylation and Histone Acetyltransferase Activity of TIP60
Wang, J., & Chen, J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.087585 · Cited by 123
USP7 Is a Master Regulator of Genome Stability
Valles, G. J., Bezsonova, I., Woodgate, R., & Ashton, N. W. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00717 · Cited by 114
“These substrates include the tumor suppressor p53 (Hu et al., 2006; Sheng et al., 2006), the Mdm2 E3 ubiquitin ligase (Hu et al., 2006; Sheng et al., 2006; Sarkari et al., 2010), the Mdm2 homolog Mdm4 (Sarkari et al., 2010) and mini-chromosome maintenance binding-protein MCM-BP (Jagannathan et al., 2014; Figure 1 and…”
BackgroundInfluentialQuantitative analyses reveal the importance of regulated Hdmx degradation for p53 activation
Wang, Y. V., Wade, M., Wong, E., Li, Y.-C., Rodewald, L. W., & Wahl, G. M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701497104 · Cited by 116
Self-citationStabilization of p53 Is Involved in Quercetin-Induced Cell Cycle Arrest and Apoptosis in HepG2 Cells
TANIGAWA, S., FUJII, M., & HOU, D.-X. (2008) · Bioscience, Biotechnology, and Biochemistry · doi:10.1271/bbb.70680 · Cited by 135
The many substrates and functions of NEDD4-1
Huang, X., Chen, J., Cao, W., Yang, L., Chen, Q., He, J., Yi, Q., Huang, H., Zhang, E., & Cai, Z. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-2142-8 · Cited by 115
Saha, A., Murakami, M., Kumar, P., Bajaj, B. G., Sims, K., & Robertson, E. S. (2009) · Journal of Virology · doi:10.1128/jvi.02408-08 · Cited by 120
“Several pathways leading to inhibition of Mdm2 action have been identified, including the phosphorylation of Mdm2 by DNA damage-induced kinases (33, 50, 51, 70) and the interaction of Mdm2 with other cellular proteins (9, 74), including ARF, which disrupts Mdm2 regulation of p53 by blocking Mdm2 Ub ligase activity (30…”
BackgroundOscillations and bistability in the stochastic model of p53 regulation
Puszyński, K., Hat, B., & Tomasz Lipniacki, B. (2008) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2008.05.039 · Cited by 116
“As found by Stommel and Wahl (2004) the Mdm2 half-life decreased about seven-fold in the response to DNA damage and may be as low as 5 min.”
BackgroundResultInfluentialThe Fbw7 and BetaTRCP E3 ubiquitin ligases and their roles in tumorigenesis
Alan, W. L. (2012) · Frontiers in bioscience · doi:10.2741/4045 · Cited by 112
“It was previously thought that autoubiquitination was the primary means by which Mdm2 proteolysis was regulated upon DNA damage (138).”
BackgroundSTAR RNA-binding protein Quaking suppresses cancer via stabilization of specific miRNAPreprint
Chen, A.-J., Paik, J.-H., Zhang, H., Shukla, S. A., Mortensen, R., HU, J. L., Ying, H., Hu, B., Hurt, J. A., Farny, N. G., et al. (2012) · Genes & Development · doi:10.1101/gad.189001.112 · Cited by 116
Targeting intrinsically disordered proteins involved in cancer
Santofimia‐Castaño, P., Rizzuti, B., Xia, Y., Abián, O., Peng, L., Velázquez‐Campoy, A., Neira, J. L., & Iovanna, J. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03347-3 · Cited by 110
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“MDM2 levels first decreased immediately after IR, as previously reported (34), but then increased starting 2 h after IR.”
BackgroundYi, F., Saha, A., Murakami, M., Kumar, P., Knight, J. S., Cai, Q., Choudhuri, T., & Robertson, E. S. (2009) · Virology · doi:10.1016/j.virol.2009.03.027 · Cited by 117
“However, in response to cellular stresses such as DNA damage, hypoxia and oncogene activation, p53 is stabilized and activated through several mechanisms that block the Mdm2-p53 interaction (Sherr and Weber, 2000; Stommel and Wahl, 2004; Tang et al., 2006).”
BackgroundWienken, M., Dickmanns, A., Nemajerová, A., Kramer, D., Najafova, Z., Weiss, M., Karpiuk, O., Kassem, M. S., Zhang, Y., Lozano, G., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.12.008 · Cited by 116
“, 2001) and destabilized (Stommel and Wahl, 2004) in response to DNA damage, and this is essential for p53 activation in vivo (Gannon et al.”
BackgroundHigh Levels of Heat Shock Protein Hsp72 in Cancer Cells Suppress Default Senescence Pathways
Yaglom, J. A., Gabai, V. L., & Sherman, M. Y. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-3796 · Cited by 110
“In fact, it was recently reported that Hdm2 self-ubiquitination abolishes its interactions with p53 and leads to Hdm2 inactivation ( 30 ).”
BackgroundZhao, R., Yeung, S. J., Chen, J., Iwakuma, T., Su, C., Chen, B., Qu, C., Zhang, F., Chen, Y., Lin, Y., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44111 · Cited by 107
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“Mdm2 destabilization in response to DNA damage has been shown previously (Stommel and Wahl, 2004), and we observed an initial decrease in Mdm2 protein in both WT and A/A tissues.”
DNA damage strength modulates a bimodal switch of p53 dynamics for cell-fate control
Chen, X., Chen, J., Gan, S., Guan, H., Zhou, Y., Ouyang, Q., & Shi, J. (2013) · BMC Biology · doi:10.1186/1741-7007-11-73 · Cited by 109
“This suggests one possible mechanism for the observed attenuation in Mdm2 in response to high DNA damage, is that as DNA damage increases, further elevation of ATM activity triggers additional phosphorylation of Mdm2, promoting the autodegradation of Mdm2 and thus reducing its protein level.”
BackgroundInfluentialRegulation of p53 - insights into a complex process
Boehme, K. A., & Blattner, C. (2009) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409230903401507 · Cited by 107
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Jain, A. K., Allton, K. L., Duncan, A. D., & Barton, M. C. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.01705-12 · Cited by 103
“DNA damage signals stabilize and activate p53, in parallel with downregulation of negative regulators of p53, such as MDM2 (29).”
BackgroundMdmX is a substrate for the deubiquitinating enzyme USP2a
Allende-Vega, N., Sparks, A., Lane, D. P., & Saville, M. K. (2010) · Oncogene · doi:10.1038/onc.2009.330 · Cited by 100
Regulation of Mdm2 protein stability and the p53 response by NEDD4-1 E3 ligase
Xu, C., Fan, C., & Wang, X. (2014) · Oncogene · doi:10.1038/onc.2013.557 · Cited by 99
Fourier analysis and systems identification of the p53 feedback loop
Geva‐Zatorsky, N., Dekel, E., Batchelor, E., Lahav, G., & Alon, U. S. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1001107107 · Cited by 96
p53 is activated in response to disruption of the pre-mRNA splicing machinery
Allende-Vega, N., Dayal, S., Agarwala, U., Sparks, A., Bourdon, J., & Saville, M. K. (2012) · Oncogene · doi:10.1038/onc.2012.38 · Cited by 98
PPAR gamma protects cardiomyocytes against oxidative stress and apoptosis via Bcl-2 upregulation
Ren, Y., Sun, C., Sun, Y., Tan, H., Wu, Y., Cui, B., & Wu, Z. (2009) · Vascular Pharmacology · doi:10.1016/j.vph.2009.06.004 · Cited by 96
Differential Roles of ATM- and Chk2-Mediated Phosphorylations of Hdmx in Response to DNA Damage
Pereg, Y., Lam, S., Teunisse, A., Biton, S., Meulmeester, E., Mittelman, L., Buscemi, G., Okamoto, K., Taya, Y., Shiloh, Y., et al. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00562-06 · Cited by 93
“It was also suggested that such degradation occurs in the nucleus, since Hdm2 is largely nuclear and proteasome inhibition increases its nuclear abundance (56).”
BackgroundNucleolin inhibits Hdm2 by multiple pathways leading to p53 stabilization
Saxena, A. D., Rorie, C. J., Dimitrova, D. D., Daniely, Y., & Borowiec, J. A. (2006) · Oncogene · doi:10.1038/sj.onc.1209714 · Cited by 94
“Nucleolin diminishes Hdm2 protein levels As indicated above, nucleolin caused an apparent loss of Hdm2 protein, even though inhibiting Hdm2 autoubiquitination (a surprising observation because heightened auto-ubiquitination has been reported to destabilize Hdm2 (Stommel and Wahl, 2004)).”
BackgroundInfluentialZebrafish as a model system to study DNA damage and repair
Pei, D., & Strauss, P. R. (2012) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2012.10.003 · Cited by 93
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“Since p21 and MDM2 have been described as proteins with a short half-life (38, 39) and a recent study reported that reduced p21 protein expression in NSCLC cells (A-549) after RAD001 treatment was due to inhibition of global translation (12), we suppose that this could be a general mechanism facilitating the pro-apopt…”
BackgroundGankyrin: a new oncoprotein and regulator of pRb and p53
Dawson, S. P., Higashitsuji, H., Wilkinson, A. J., Fujita, J., & Mayer, R. J. (2006) · Trends in Cell Biology · doi:10.1016/j.tcb.2006.03.001 · Cited by 88
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Stommel, J. M., & Wahl, G. M. (2005) · Cell Cycle · doi:10.4161/cc.4.3.1522 · Cited by 90
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Balance of Yin and Yang: Ubiquitylation-Mediated Regulation of p53 and c-Myc
Dai, M., Jin, Y., Gallegos, J. R., & Lu, H. (2006) · Neoplasia · doi:10.1593/neo.06334 · Cited by 85
“mediates p53 degradation in both the nucleus and the cytoplasm [45–47].”
BackgroundMancini, F., Conza, G. D., Pellegrino, M., Rinaldo, C., Prodosmo, A., Giglio, S., D’Agnano, I., Florenzano, F., Felicioni, L., Buttitta, F., et al. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.154 · Cited by 82
“Destabilization of the MDM2 protein caused by increased autodegradation after DNA damage has also been described, although the type of cell response associated with it has not been established (Stommel and Wahl, 2004; Tang et al, 2006).”
BackgroundWang, Y. V., Leblanc, M., Wade, M., Jochemsen, A. G., & Wahl, G. M. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.05.008 · Cited by 79
“We previously showed that phosphorylation of Mdm2 by DNA-damageinduced kinases accelerates Mdm2 autodegradation (Stommel and Wahl, 2004).”
Self-citation
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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