Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2
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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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Mdm2 undergoes auto-degradation and targets Mdmx for degradation, which is critical for optimal p53 activation after stress.
“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]
MDMX can be ubiquitinated and degraded by MDM2.
“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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“proteins were performed as described before (8).”
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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 125 · see citing works
“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 · see citing works
Chandler, D. S., Singh, R. K., Caldwell, L. C., Bitler, J. L., & Lozano, G. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-4271 · Cited by 104 · see citing works
“These forms included HDMX-A (24) and HSMX-S (25), some of which have been identified in human cancers (15).”
BackgroundDiscovery of Mdm2-MdmX E3 Ligase Inhibitors Using a Cell-Based Ubiquitination Assay
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 · see citing works
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 · see citing works
“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 · see citing works
“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 90 · see citing works
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 · see citing works
“As expected, the binding between zinc finger deletion mutant (1-300) and p53 was not stimulated by CK1 coexpression (Fig.”
BackgroundStommel, J. M., & Wahl, G. M. (2005) · Cell Cycle · doi:10.4161/cc.4.3.1522 · Cited by 87 · see citing works
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 · see citing works
Versatile functions of p53 protein in multicellular organisms
Chumakov, P. M. (2007) · Biochemistry (Moscow) · doi:10.1134/s0006297907130019 · Cited by 84 · see citing works
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 83 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
“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 70 · see citing works
“…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 72 · see citing works
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 · see citing works
“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 · see citing works
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 70 · see citing works
“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 · see citing works
“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 65 · see citing works
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 65 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
“lanes 2–3 or lanes 4–5), while MDM2 reduced MDMX protein level as reported previously [11, 12] (Fig.”
BackgroundFalcicchio, M., Ward, J. A., Macip, S., & Doveston, R. G. (2020) · Cell Death Discovery · doi:10.1038/s41420-020-00362-3 · Cited by 58 · see citing works
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 57 · see citing works
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 55 · see citing works
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 55 · see citing works
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 52 · see citing works
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 · see citing works
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 50 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
MDM4 (MDMX) and its Transcript Variants
Mancini, F., Conza, G. D., & Moretti, F. (2009) · Current Genomics · doi:10.2174/138920209787581280 · Cited by 39 · see citing works
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 · see citing works
“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 · see citing works
“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 38 · see citing works
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 38 · see citing works
“…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. M., Jochemsen, A. G., Okamoto, K., Loeffler, J., & Gaiddon, C. (2007) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402216 · Cited by 38 · see citing works
“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 · see citing works
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 · see citing works
“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].”
BackgroundInfluentialDe 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 · see citing works
“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 · see citing works
The roles of MDM2 and MDMX phosphorylation in stress signaling to p53
Chen, J. (2012) · Genes & Cancer · doi:10.1177/1947601912454733 · Cited by 33 · see citing works
“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 · see citing works
“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 · see citing works
“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 30 · see citing works
“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 · see citing works
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 · see citing works
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 26 · see citing works
“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 · see citing works
Chen, J., Zhang, D., Zhang, Y., & Li, G. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms13022176 · Cited by 26 · see citing works
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 · see citing works
Markey, M. P. (2010) · Frontiers in bioscience · doi:10.2741/3780 · Cited by 24 · see citing works
Heminger, K., Markey, M. P., Mpagi, M. D., & Berberich, S. J. (2009) · Aging · doi:10.18632/aging.100008 · Cited by 23 · see citing works
“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 22 · see citing works
“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 20 · see citing works
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 · see citing works
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 21 · see citing works
“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 · see citing works
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 · see citing works
“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
- 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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