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Hdmx Protein Stability Is Regulated by the Ubiquitin Ligase Activity of Mdm2
Open accessAbstract
The stability of the p53 tumor suppressor protein is critically regulated by the Hdm2 and Hdmx proteins. Hdm2 protein levels are auto-regulated by the self-ubiquitination activity of Hdm2 and on the transcriptional level by p53-activated transcription of the hdm2 gene. Little is known about the regulation of Hdmx expression levels, apart from the observation that the Mdmx protein can be cleaved by caspase-3 in a p53-inducible manner. In the functional analysis of two mutant Hdmx proteins, products of two alternatively spliced mRNAs, it was found that Hdmx proteins are targets for ubiquitination by Mdm2. The stability of the Hdmx protein is partly dependent on the presence of its internal acidic domain. Mdm2 appears only to require an intact RING domain to be able to ubiquitinate Hdmx and target it for proteasomal degradation. These findings highlight the intricate functional relationships between p53, Mdm2, and Hdmx.
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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 [14]
In the citing paper
“Several reports showed that MDMX can be ubiquitinated and degraded by MDM2 (De Graaf et al, 2003;Kawai et al, 2003;Pan and Chen, 2003).”
From ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage (2005) · cites this paper as De Graaf et al, 2003
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Karni-Schmidt, O., Lokshin, M., & Prives, C. L. (2016) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012414-040349 · Cited by 302
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“In addition to mediating transfer of ubiquitin to substrate proteins, such as p53, MDM2 also ubiquitylates itself and MDMX.”
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Self-citationMDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation
Wang, C., Ivanov, A. V., Chen, L., Fredericks, W. J., Seto, E., Rauscher, F. J., & Chen, J. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600791 · Cited by 263
ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage
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Mechanism of p53 stabilization by ATM after DNA damage
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MDMX overexpression prevents p53 activation by the MDM2 inhibitor Nutlin
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In Vivo Activation of the p53 Tumor Suppressor Pathway by an Engineered Cyclotide
Ji, Y., Majumder, S., Millard, M., Borra, R., Bi, T., Elnagar, A. Y., Neamati, N., Shekhtman, A. G., & Camarero, J. A. (2013) · Journal of the American Chemical Society · doi:10.1021/ja405108p · Cited by 237
Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization
Graves, B., Thompson, T., Xia, M., Janson, C., Lukacs, C., Deo, D., Di Lello, P., Fry, D., Garvie, C., Huang, K.-S., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1203789109 · Cited by 230
“However, MDMX can enhance ligase activity of MDM2 toward p53 by forming MDM2/MDMX heterodimers (7, 8).”
BackgroundLiu, M., Li, C., Pazgier, M., Li, C., Mao, Y., Lv, Y., Gu, B., Wei, G., Yuan, W., Zhan, C., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1008930107 · Cited by 236
Marine, J.-C. W., Dyer, M. A., & Jochemsen, A. G. (2007) · Journal of Cell Science · doi:10.1242/jcs.03362 · Cited by 228
“Several groups have shown that Mdm2 can bind to and ubiquitylate Mdmx to stimulate its proteasome-dependent degradation (Pan and Chen, 2003; de Graaf et al., 2003; Kawai et al., 2003).”
BackgroundSelf-citationEfficient p53 Activation and Apoptosis by Simultaneous Disruption of Binding to MDM2 and MDMX
Hu, B., Gilkes, D. M., & Chen, J. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1140 · Cited by 215
Mdmx as an essential regulator of p53 activity
Marine, J., & Jochemsen, A. G. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.03.151 · Cited by 189
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
Self-citationAn 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
“In addition to p53, several other proteins are targeted for degradation by MDM2, including MDM2 itself and the MDM2-related protein MDMX (Mdm4 in mice) (de Graaf et al, 2003; Kawai et al, 2003a; Pan and Chen, 2003).”
BackgroundTargeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry?
Wade, M., & Wahl, G. M. (2009) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-08-0423 · Cited by 170
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 173
Qi, S., Cheng, G., Cheng, X., Xu, Z., Xu, B., Zhang, W., & Qin, J. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00233 · Cited by 167
Synergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development
Xiong, S., Van Pelt, C. S., Elizondo-Fraire, A. C., Liu, G., & Lozano, G. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508500103 · Cited by 155
Caspase-2-Mediated Cleavage of Mdm2 Creates a p53-Induced Positive Feedback Loop
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“Mdm2 has been shown to degrade MdmX upon DNA damage (de Graaf et al., 2003; Pan and Chen, 2003), suggesting that cleaved Mdm2 p60 could enhance MdmX levels and counter p53 activity.”
BackgroundSystematic Mutational Analysis of Peptide Inhibition of the p53–MDM2/MDMX Interactions
Li, C. V., Pazgier, M., Li, C., Yuan, W., Liu, M., Wei, G., Lu, W., & Lu, W. (2010) · Journal of Molecular Biology · doi:10.1016/j.jmb.2010.03.005 · Cited by 149
MDMX regulation of p53 response to ribosomal stress
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Regulation of p53: a collaboration between Mdm2 and MdmX
Pei, D., Zhang, Y., & Zheng, J. (2012) · Oncotarget · doi:10.18632/oncotarget.443 · Cited by 140
“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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“proteins were performed as described before (8).”
BackgroundMethodResultInfluentialRegulation of MDMX nuclear import and degradation by Chk2 and 14-3-3
LeBron, C., Chen, L., Gilkes, D. M., & Chen, J. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601032 · Cited by 122
“Several reports showed that MDMX can be ubiquitinated and degraded by MDM2 (de Graaf et al, 2003; Kawai et al, 2003; Pan and Chen, 2003).”
BackgroundMdm2 Induces Mono-Ubiquitination of FOXO4
Brenkman, A. B., de Keizer, P. L. J., van den Broek, N. J. F., Jochemsen, A. G., & Burgering, B. M. T. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002819 · Cited by 132
“pMT2-HA-FOXO4 and pMT2-Flag-FOXO4, His-Ubiquitin, Flag-Mdm2, the inactive Mdm2 RING-finger mutant C464A, MycMdm2-delta-RING domain, MycMDM2-delta-p53 mutants and Myc-Mdm2 have been described previously [8,27].”
BackgroundQuantitative 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
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“These forms included HDMX-A (24) and HSMX-S (25), some of which have been identified in human cancers (15).”
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Herman, A. G., Hayano, M., Poyurovsky, M. V., Shimada, K., Skouta, R., Prives, C., & Stockwell, B. R. (2011) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0104 · Cited by 100
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
“Cell lysis, Western blotting analysis, and immunoprecipitations were carried out by standard methods as described previously ( 14 ).”
MethodBartel, F., Schulz, J., Böhnke, A., Blümke, K., Kappler, M., Bache, M., Schmidt, H., Würl, P., Taubert, H. W., & Hauptmann, S. (2005) · International Journal of Cancer · doi:10.1002/ijc.21206 · Cited by 93
“and de Graaf et al.(13) revealed that the truncated proteins encoded by both MDMX-S and HDMX-S are more efficient at suppressing p53-mediated transactivation and induction of apoptosis than FL-MDMX or FL-HDMX, respectively.”
BackgroundInfluentialMicroRNA-34a Modulates MDM4 Expression via a Target Site in the Open Reading Frame
Mandke, P., Wyatt, N., Fraser, J., Bates, B., Berberich, S. J., & Markey, M. P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042034 · Cited by 92
Regulation of p53-MDMX interaction by casein kinase 1 alpha
Chen, L., Li, C., Pan, Y., & Chen, J. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.15.6509-6520.2005 · Cited by 88
“As expected, the binding between zinc finger deletion mutant (1-300) and p53 was not stimulated by CK1 coexpression (Fig.”
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Cul7/p185/p193 Binding to Simian Virus 40 Large T Antigen Has a Role in Cellular Transformation
Ali, S. H., Kasper, J. S., Arai, T., & DeCaprio, J. A. (2004) · Journal of Virology · doi:10.1128/jvi.78.6.2749-2757.2004 · Cited by 84
Versatile functions of p53 protein in multicellular organisms
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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
“This speculation is seemingly contradicted by the fact that MDMX is imported to and degraded in the nucleus by MDM2 in response to ionizing irradiation [55,56].”
BackgroundSpontaneous Tumorigenesis in Mice Overexpressing the p53-Negative Regulator Mdm4
Xiong, S., Pant, V., Suh, Y.-A., Van Pelt, C. S., Wang, Y., Valentin-Vega, Y. A., Post, S. M., & Lozano, G. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1457 · Cited by 82
Phosphorylation of MDMX Mediated by Akt Leads to Stabilization and Induces 14-3-3 Binding
Lopez-Pajares, V., Kim, M. M., & Yuan, Z.-M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m710030200 · Cited by 79
McEvoy, J., Ulyanov, A., Brennan, R., Wu, G., Pounds, S., Zhang, J., & Dyer, M. A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042739 · Cited by 80
Wang, 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
“These phosphorylations reduce binding of HAUSP, a ubiquitinspecific protease (Meulmeester et al., 2005), which appears to render Mdmx vulnerable to Mdm2-mediated ubiquitylation and proteasomal degradation (Kawai et al., 2003; de Graaf et al., 2003; Pan and Chen, 2003).”
Self-citationMdmx enhances p53 ubiquitination by altering the substrate preference of the Mdm2 ubiquitin ligase
Okamoto, K., Taya, Y., & Nakagama, H. (2009) · FEBS Letters · doi:10.1016/j.febslet.2009.07.021 · Cited by 76
“Proteins conjugated with His-tagged ubiquitin were purified as described before [28], and analyzed by Western blot analysis.”
MethodRegulation of the DNA damage response by ubiquitin conjugation
Brinkmann, K., Schell, M. J., Hoppe, T., & Kashkar, H. (2015) · Frontiers in Genetics · doi:10.3389/fgene.2015.00098 · Cited by 75
“…stabilization and activation (Cheng and Chen, 2010); however, MDM2 additionally promotes ubiquitylation and degradation of MDMX in response to DNA damage, again acting in a negative feedback loop (de Graaf et al., 2003; Kawai et al., 2003; Pan and Chen, 2003; Pereg et al., 2005; Xia et al., 2008).”
BackgroundRegulation of the Mdm2–p53 pathway by the ubiquitin E3 ligase MARCH7
Zhao, K., Yang, Y., Zhang, G., Wang, C., Wang, D., Wu, M., & Mei, Y. (2018) · EMBO Reports · doi:10.15252/embr.201744465 · Cited by 70
Regulation of p53 and MDM2 Activity by MTBP
Brady, M., Vlatković, N., & Boyd, M. T. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.2.545-553.2005 · Cited by 69
“In addition to regulating p53 levels by targeting p53 for proteasomal degradation (18, 25), MDM2 also transfers ubiquitin to itself (11), MDMX (8, 40), the 2 adrenergic receptor (43), glucocorticoid receptor (24), TIP60 (28), and PCAF (21).”
Backgroundc-Abl Phosphorylates Hdmx and Regulates Its Interaction with p53
Zuckerman, V., Lenos, K., Popowicz, G. M., Silberman, I., Grossman, T., Marine, J.-C., Holak, T. A., Jochemsen, A. G., & Haupt, Y. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m809211200 · Cited by 68
Self-citationRegulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis
Carr, M. I., & Jones, S. N. (2016) · Translational Cancer Research · doi:10.21037/tcr.2016.11.75 · Cited by 71
“Notably, the turnover of MdmX is mediated by Mdm2 (126-128).”
BackgroundFurgason, J. M., Koncar, R. F., Michelhaugh, S. K., Sarkar, F. H., Mittal, S., Sloan, A. E., Barnholtz‐Sloan, J. S., & Bahassi, E. M. (2015) · Oncoscience · doi:10.18632/oncoscience.178 · Cited by 65
“MDM4 appears to be post-transcriptionally regulated in response to DNA damage through both destabilization of mRNA and post-translational modification [8,9].”
BackgroundMurine double minute 2: p53-independent roads lead to genome instability or death
Bouska, A. C., & Eischen, C. M. (2009) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2009.02.006 · Cited by 68
Small molecule compounds targeting the p53 pathway: are we finally making progress?
Yu, X., Narayanan, S., Vázquez, A., & Carpizo, D. R. (2014) · APOPTOSIS · doi:10.1007/s10495-014-0990-3 · Cited by 68
Xiong, X., Zhao, Y., Tang, F., Wei, D., Thomas, D. G., Wang, X., Liu, Y., Zheng, P., & Sun, Y. (2014) · eLife · doi:10.7554/elife.02236 · Cited by 66
“Furthermore, Mdm4 is a direct substrate of Mdm2 for targeted ubiquitylation and degradation (de Graaf et al., 2003; Kawai et al., 2003; Pan and Chen, 2003).”
The road to the vertebral formula
Mallo, M., Vinagre, T., & Carapuo, M. (2009) · The International Journal of Developmental Biology · doi:10.1387/ijdb.072276mm · Cited by 63
Interplay between MDM2, MDMX, Pirh2 and COP1: the negative regulators of p53
Wang, L., He, G., Zhang, P., Wang, X., Jiang, M. H., & Yu, L. (2010) · Molecular Biology Reports · doi:10.1007/s11033-010-0099-x · Cited by 60
“lanes 2–3 or lanes 4–5), while MDM2 reduced MDMX protein level as reported previously [11, 12] (Fig.”
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Prodosmo, A., Giglio, S., Moretti, S., Mancini, F., Barbi, F., Avenia, N., Conza, G. D., Schünemann, H. J., Pistola, L., Ludovini, V., et al. (2008) · Journal of Molecular Medicine · doi:10.1007/s00109-008-0322-6 · Cited by 56
Levav-Cohen, Y., Goldberg, Z., Zuckerman, V., Grossman, T., Haupt, S., & Haupt, Y. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.03.152 · Cited by 57
Deubiquitinating enzyme regulation of the p53 pathway: A lesson from Otub1
Sun, X. (2014) · World Journal of Biological Chemistry · doi:10.4331/wjbc.v5.i2.75 · Cited by 56
Dynamic regulation of PCNA ubiquitylation/deubiquitylation
Fox, J. T., Lee, K., & Myung, K. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.05.053 · Cited by 50
Role of Mdm4 in drug sensitivity of breast cancer cells
Lam, S., Lodder, K., Teunisse, A. F. A. S., Rabelink, M. J. W. E., Schutte, M., & Jochemsen, A. G. (2010) · Oncogene · doi:10.1038/onc.2009.522 · Cited by 52
A Critical Role for Noncoding 5S rRNA in Regulating Mdmx Stability
Li, M., & Gu, W. J. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.08.020 · Cited by 54
“Notably, like p53, Mdmx is ubiquitinated and degraded by Mdm2 (de Graaf et al., 2003; Kawai et al., 2003; Pan and Chen, 2003); several studies indicate that degradation of Mdmx is crucial for optimal activation of p53 function (Jin et al., 2006; LeBron et al., 2006; Lopez-Pajares et al., 2008;…”
MDM2 interacts with and downregulates a sarcomeric protein, TCAP
Tian, L.-F., Li, H., Jin, B.-F., Pan, X., Man, J.-H., Zhang, P., Li, W., Liang, B., Liu, H., Zhao, J., et al. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.04.108 · Cited by 45
Han, X., Garcia‐Manero, G., McDonnell, T. J., Lozano, G., Medeiros, L. J., Xiao, L., Rosner, G. L., Nguyen, M. H., Fernandez, M., Valentin-Vega, Y. A., et al. (2006) · Modern Pathology · doi:10.1038/modpathol.3800727 · Cited by 45
“Several splicing variants of HDM4, including HDM4-A, HDM4-G, HDM4-S (or HDM4-E), a human homolog of MDMX-S in the mouse, have been described”
BackgroundMarcar, L., Ihrig, B., Hourihan, J. M., Bray, S. E., Quinlan, P., Jordan, L. B., Thompson, A. M., Hupp, T. R., & Meek, D. W. (2015) · PLoS ONE · doi:10.1371/journal.pone.0127713 · Cited by 42
“Firstly, it is a stimulatory partner of MDM2 [26] that is itself regulated by MDM2-mediated ubiquitylation [27,28,29].”
BackgroundSpinnler, C., Hedström, E., Li, H., de Lange, J., Nikulenkov, F., Teunisse, A. F. A. S., Vries, M. V., Grinkevich, V. V., Jochemsen, A. G., & Selivanova, G. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.45 · Cited by 42
“It is an E3 ligase that, upon certain signals, forms a heterodimer with HdmX, leading to its ubiquitination and subsequent degradation by the proteasome.(4,5,32) To address whether Hdm2 is involved in HdmX downregulation after RITA treatment, we depleted Hdm2 by means of siRNA.”
BackgroundZhang, J., Yu, G., Yang, Y., Wang, Y., Guo, M., Yin, Q., Yan, C., Tian, J., Fu, F., & Wang, H. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106128 · Cited by 43
MDM4 (MDMX) and its Transcript Variants
Mancini, F., Conza, G. D., & Moretti, F. (2009) · Current Genomics · doi:10.2174/138920209787581280 · Cited by 40
Otub1 stabilizes MDMX and promotes its proapoptotic function at the mitochondria
Chen, Y., Wang, Y.-G., Li, Y., Sun, X., & Dai, M. (2016) · Oncotarget · doi:10.18632/oncotarget.14278 · Cited by 38
“As shown in Figure 2A and expected [32, 33], the ubiquitinated species of MDMX were drastically increased by the overexpression of MDM2 (compare lane 3 to lane 2, top panel).”
BackgroundFull-length hdmX transcripts decrease following genotoxic stress
Markey, M., & Berberich, S. J. (2008) · Oncogene · doi:10.1038/onc.2008.266 · Cited by 38
“Several years later, the MdmX protein was shown to be downregulated following DNA damage through Mdm2mediated proteasome degradation (Gu et al., 2002; Li et al., 2002; Migliorini et al., 2002; de Graaf et al., 2003).”
MDM2 and MDMX in Cancer and Development
Marine, J. (2011) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/b978-0-12-380916-2.00003-6 · Cited by 39
Functions 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
“…obtained by glycolysis rather than via oxidative phosphorylation [4]. p53 is activated by a plethora of stimuli, including DNA damage, hypoxia, and oncogene activation, the final outcome of the activation being very dependent on the strength and type of the stimulus and the type of targeted cell.”
BackgroundMultiple neurotoxic stresses converge on MDMX proteolysis to cause neuronal apoptosis
Benosman, S., Groß, I., Clarke, N., Jochemsen, A. G., Okamoto, K., Loeffler, J., & Gaiddon, C. (2007) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402216 · Cited by 38
“Several studies reported that MDMX can be ubiquitinated by MDM2 and subsequently degraded through the proteasome after a toxic treatment in various cell lines.(35,36) Interestingly, Gentiletti et al.”
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
The ATM regulated DNA damage response pathway as a chemo- and radiosensitisation target
Alao, J. P. (2009) · Expert Opinion on Drug Discovery · doi:10.1517/17460440902835475 · Cited by 36
“It has been proposed that ATM destabilises both Mdm2 and Mdmx by preventing their interaction with the HAUSP (herpes virus-associated ubiquitin-specific protease) deubiquitylating enzyme [70].”
BackgroundInfluentialWidespread Overexpression of Epitope-Tagged Mdm4 Does Not Accelerate Tumor Formation In Vivo
De Clercq, S., Gembarska, A., Denecker, G., Maetens, M., Naessens, M., Haigh, K., Haigh, J. J., & Marine, J.-C. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00330-10 · Cited by 35
“Mdm4 levels rapidly decline in an Mdm2dependent manner following DNA damage (6, 23, 38).”
BackgroundAdenoviral E1A Targets Mdm4 to Stabilize Tumor Suppressor p53
Li, Z., Day, C., Yang, J.-Y., Tsai, W.-B., Lozano, G., Shih, H.-M., & Hung, M. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-2419 · Cited by 33
The roles of MDM2 and MDMX phosphorylation in stress signaling to p53
Chen, J. (2012) · Genes & Cancer · doi:10.1177/1947601912454733 · Cited by 33
“The MDMX level is controlled by MDM2-mediated ubiquitination in a stress-dependent fashion.(42,100,101) A fraction of MDMX from cells with DNA damage has delayed migration consistent with phosphorylation in an ATM-dependent fashion.”
BackgroundStochastic 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
“Reaction 26 specifies the ubiquitination of MDMX catalyzed by MDM2 (de Graaf et al., 2003; Pan and Chen, 2003; Ma et al., 2006).”
Stochastic and Deterministic Models of Cellular p53 Regulation
Leenders, G. B., & Tuszyński, J. A. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00064 · Cited by 28
“Chk2 along with Chk1 also phosphorylate p53 (Shieh et al., 2000).”
BackgroundMDM2 and MDM4 splicing: an integral part of the cancer spliceome
Jeyaraj, S. C. (2009) · Frontiers in bioscience · doi:10.2741/3402 · Cited by 31
“MDM4-Alt1 retains only the p53-binding domain similar to MDM4-S, which has been shown to bind p53 more strongly, and therefore maintains a p53 suppressive activity (Figure 5) (25, 50).”
BackgroundTurning the RING Domain Protein MdmX into an Active Ubiquitin-Protein Ligase*
Iyappan, S., Wollscheid, H.-P., Rojas‐Fernández, A., Marquardt, A., Tang, H., Singh, R. K., & Scheffner, M. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.115113 · Cited by 29
Macchiarulo, A., Giacchè, N., Carotti, A., Baroni, M., Cruciani, G., & Pellicciari, R. (2008) · Journal of Chemical Information and Modeling · doi:10.1021/ci800146m · Cited by 29
Biderman, L., Poyurovsky, M. V., Assia, Y., Manley, J. L., & Prives, C. L. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.06150-11 · Cited by 27
“In the nucleus, it interacts with the RING domain of Mdm2 (63), undergoes ubiquitination by Mdm2, and degradation by the 26S proteasome (13).”
BackgroundCalculation of hot spots for protein–protein interaction in p53/PMI‐MDM2/MDMX complexes
Huang, D., Qi, Y., Song, J., & Zhang, J. Z. H. (2018) · Journal of Computational Chemistry · doi:10.1002/jcc.25592 · Cited by 26
Chen, J., Zhang, D., Zhang, Y., & Li, G. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms13022176 · Cited by 27
Stress-Induced Alternative Splice Forms of MDM2 and MDMX Modulate the p53-Pathway in Distinct Ways
Jacob, A. G., Singh, R. K., Comiskey, D. F., Rouhier, M. F., Mohammad, F., Bebee, T. W., & Chandler, D. S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0104444 · Cited by 24
Markey, M. P. (2010) · Frontiers in bioscience · doi:10.2741/3780 · Cited by 26
Heminger, K., Markey, M. P., Mpagi, M. D., & Berberich, S. J. (2009) · Aging · doi:10.18632/aging.100008 · Cited by 22
“The heterodimerization of Hdm2 and HdmX also plays a critical role in the response to DNA damage enabling Hdm2 to promote the ubiquitination and rapid proteasomal degradation of HdmX, thereby facilitating the tumor suppressor activity of p53 [13-15].”
Liang, M., Han, X., Vadhan‐Raj, S., Nguyen, M. H., Zhang, Y. H., Fernandez, M., Drakos, E., Konoplev, S. N., Yin, C. C., Miranda, R. N., et al. (2010) · Modern Pathology · doi:10.1038/modpathol.2009.170 · Cited by 24
“12 and HDM2 predominantly affects the stability of p53 by degradation through its E3 ubiquitin ligase activity”
BackgroundHan, X., Medeiros, L. J., Zhang, Y. H., You, M. J., Andreeff, M., Konopleva, M. Y., & Bueso-Ramos, C. (2016) · Clinical Lymphoma Myeloma & Leukemia · doi:10.1016/j.clml.2016.03.012 · Cited by 19
Modification of MDMX by sumoylation
Pan, Y., & Chen, J. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.05.012 · Cited by 20
Structure and function of MDM2 and MDM4 in health and disease
Zhu, I. Y., Lloyd, A., Critchley, W. R., Saikia, Q., Jade, D., Divan, A., Zeqiraj, E., Harrison, M. A., Brown, C. J., & Ponnambalam, S. (2025) · Biochemical Journal · doi:10.1042/bcj20240757 · Cited by 22
“Functional studies in cancer cell lines indicate that MDM4-A retains the ability to bind and inhibit p53-mediated transcriptional activation, potentially accounting for its correlation with reduced survival in melanoma patients [35].”
MDM4 alternative splicing and implication in MDM4 targeted cancer therapies.
Wu, J., Lu, G., & Wang, X. (2021) · PubMed Central · Cited by 19
PIG3 Regulates p53 Stability by Suppressing Its MDM2-Mediated Ubiquitination
Jin, M., Park, S., Kim, S. W., Kim, H., Hyun, J. W., & Lee, J.-H. (2017) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2017.086 · Cited by 17
“MDM2 is an ubiquitination E3 ligase that promotes ubiquitination of itself, p53, and several other cellular proteins, including androgen receptor, Tip60, glucocorticoid receptor, and the MDM2 homolog MDMX (de Graaf et al., 2003; Kawai et al., 2003; Pan and Chen, 2003).”
Background
Metadata
- Authors
- de Graaf, P., Little, N. A., Ramos, Y. F. M., Meulmeester, E., Letteboer, S. J. F., & Jochemsen, A. G.
- Affiliations
- Leiden University Medical Center (NL)
- Corresponding author
- Jochemsen, Aart G.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-10
- Volume
- 278
- Issue
- 40
- Pages
- 38315-38324
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2163552821
- Cited by
- 143
- References
- 52
- Citations by year
- 2025: 1 · 2024: 5 · 2023: 1 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 1 · 2018: 3 · 2017: 2 · 2016: 8 · 2015: 6 · 2014: 7 · 2013: 3 · 2012: 8
- FWCI
- 4.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- 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
- HDMX, MDM2, p53, protein stability, ubiquitination, ubiquitin ligase activity, RING domain, proteasomal degradation, alternative splicing, caspase-3 cleavage, acidic domain, tumor suppressor regulation
- MeSH terms
- Cycloheximide, Exons, Genetic Vectors, Humans, Lac Operon, Ligases, Luciferases, Microscopy, Fluorescence, Models, Genetic, Nuclear Proteins, Plasmids, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, Protein Synthesis Inhibitors, Proto-Oncogene Proteins, RNA, RNA, Messenger, Time Factors, Transcription, Genetic, Transfection, Tumor Cells, Cultured, Blotting, Western, Tumor Suppressor Protein p53, Alternative Splicing, Protein Structure, Tertiary, Reverse Transcriptase Polymerase Chain Reaction, Caspases, Ubiquitin, Proto-Oncogene Proteins c-mdm2, Caspase 3
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