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MDM2 Promotes Ubiquitination and Degradation of MDMX
Open accessAbstract
The p53 tumor suppressor is regulated by MDM2-mediated ubiquitination and degradation. Mitogenic signals activate p53 by induction of ARF expression, which inhibits p53 ubiquitination by MDM2. Recent studies showed that the MDM2 homolog MDMX is also an important regulator of p53. We present evidence that MDM2 promotes MDMX ubiquitination and degradation by the proteasomes. This effect is stimulated by ARF and correlates with the ability of ARF to bind MDM2. Promotion of MDM2-mediated MDMX ubiquitination requires the N-terminal domain of ARF, which normally inhibits MDM2 ubiquitination of p53. An intact RING domain of MDM2 is also required, both to interact with MDMX and to provide E3 ligase function. Increase of MDM2 and ARF levels by DNA damage, recombinant ARF adenovirus infection, or inducible MDM2 expression leads to proteasome-mediated down-regulation of MDMX levels. Therefore, MDMX and MDM2 are coordinately regulated by stress signals. The ARF tumor suppressor differentially regulates the ability of MDM2 to promote p53 and MDMX ubiquitination and activates p53 by targeting both members of the MDM2 family.
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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 [16]
In the citing paper
“MDMX and MDM2 form heterodimers through the C-terminal RING domains and the MDM2 RING domain alone is sufficient to degrade MDMX (Sharp et al, 1999;Tanimura et al, 1999;Pan and Chen, 2003).”
From ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage (2005) · cites this paper as Pan and Chen, 2003
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 Pan and Chen, 2003
In the citing paper
“DNA damage induced by ionizing irradiation also promotes MDMX nuclear translocation and degradation by the proteasomes (Li et al, 2002;Pan and Chen, 2003).”
From ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage (2005) · cites this paper as Pan and Chen, 2003
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Items 101–200 of 245
MDM2 expression is repressed by the RNA-binding protein RNPC1 via mRNA stability
Xu, E., Zhang, J., & Chen, X. (2012) · Oncogene · doi:10.1038/onc.2012.238 · Cited by 48
“We found that upon RNPC1 knockdown, the level of MDM2 protein was greatly increased, concomitantly with decreased expression of MDMX (Figure 2a, compare lane1 with 2).”
BackgroundTSA downregulates Wilms tumor gene 1 (Wt1) expression at multiple levels
Makki, M. S., Heinzel, T., & Englert, C. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn356 · Cited by 47
“In vivo ubiquitination assay was performed as described ( 31 ).”
MethodCasein Kinase 1α Regulates an MDMX Intramolecular Interaction To Stimulate p53 Binding
Wu, S., Chen, L., Becker, A., Schönbrunn, E., & Chen, J. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00851-12 · Cited by 48
“nation in a stress-dependent fashion (19, 37).”
Detection and Characterization of the In Vitro E3 Ligase Activity of the Human MID1 Protein
Han, X., Du, H., & Massiah, M. A. (2011) · Journal of Molecular Biology · doi:10.1016/j.jmb.2011.01.048 · Cited by 48
Gao, C., Xiao, G., Piersigilli, A., Gou, J., Ogunwobi, O. O., & Bargonetti, J. (2019) · Breast Cancer Research · doi:10.1186/s13058-018-1094-8 · Cited by 47
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
Zebrafish Mib and Mib2 Are Mutual E3 Ubiquitin Ligases with Common and Specific Delta Substrates
Zhang, C., Li, Q., & Jiang, Y. (2006) · Journal of Molecular Biology · doi:10.1016/j.jmb.2006.11.096 · Cited by 46
Yu, Z.-C., Huang, Y., & Shieh, S.-Y. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv1173 · Cited by 44
“In addition to p53, other substrates of MDM2, for example, APE1 (12), Mdmx (13) and histone H2B (14), have been identified.”
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].”
Backgroundp53, SKP2, and DKK3 as MYCN Target Genes and Their Potential Therapeutic Significance
Chen, L., & Tweddle, D. A. (2012) · Frontiers in Oncology · doi:10.3389/fonc.2012.00173 · Cited by 43
“Interestingly, MDM2 can promote ubiquitination and degradation of MDMX, an effect which is stimulated by p14ARF and which correlates with the ability of p14ARF to bind MDM2 (Pan and Chen, 2003; Figure 1).”
Spinnler, 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
“Several studies have demonstrated that DNA damage signalling regulates HdmX and Hdm2 protein stability.(3,4) The checkpoint kinase ATM and its downstream kinase Chk2 induce phosphorylation of Hdm2(2) and HdmX,(5) leading to their degradation.”
BackgroundSwetzig, W. M., Wang, J., & Das, G. M. (2016) · Oncotarget · doi:10.18632/oncotarget.7533 · Cited by 44
“Additional levels of regulation that are not included in the diagram include the ability of MDM4 to promote p53-mediated transcriptional upregulation of MDM2 [130], the ability of the MDM2/ MDM4 heterodimer to negatively regulate its own expression via auto-ubiquitination [10, 20, 30, 101, 146], and the ability of MDM…”
BackgroundFKBP12 enhances sensitivity to chemotherapy-induced cancer cell apoptosis by inhibiting MDM2
Liu, T., Xiong, J., Yi, S., Zhang, H., Zhou, S., Gu, L., & Zhou, M. L. (2016) · Oncogene · doi:10.1038/onc.2016.331 · Cited by 42
Ying, M., Zhang, L., Zhou, Q., Shao, X., Cao, J., Zhang, N., Li, W., Zhu, H., Yang, B., & He, Q. (2016) · Oncogene · doi:10.1038/onc.2015.503 · Cited by 41
The Role of MDM2 in Promoting Genome Stability versus Instability
Saadatzadeh, M. R., Elmi, A. N., Pandya, P. H., Bijangi‐Vishehsaraei, K., Ding, J., Stamatkin, C. W., Cohen‐Gadol, A., & Pollok, K. E. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18102216 · Cited by 44
“It is important to emphasize that the N-terminal domain of ARF can also inhibit MDM2 ubiquitination of p53 [54].”
BackgroundCompetitive ubiquitination activates the tumor suppressor p53
Li, X., Guo, M., Cai, L., Du, T., Liu, Y., Ding, H., Wang, H., Zhang, J., Chen, X., & Yan, C. (2019) · Cell Death and Differentiation · doi:10.1038/s41418-019-0463-x · Cited by 42
MDM2 promotes genome instability by ubiquitinating the transcription factor HBP1
Cao, Z., Xue, J., Cheng, Y., Wang, J., Liu, Y., Li, H., Jiang, W., Li, G., Gui, Y., & Zhang, X. (2019) · Oncogene · doi:10.1038/s41388-019-0761-2 · Cited by 38
NIRF induces G1 arrest and associates with Cdk2
Li, Y., Mori, T., Hata, H., Homma, Y., & Kochi, H. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.04.190 · 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
“In addition, when highly overexpressed, MDMX can inhibit MDM2-mediated p53 ubiquitination and degradation possibly by competing with MDM2 for binding to p53 and directly suppressing MDM2 autoubiquitination activity [23, 25, 26, 33].”
BackgroundInfluentialStructural 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
MDM4 (MDMX) Overexpression Enhances Stabilization of Stress-induced p53 and Promotes Apoptosis
Mancini, F., Gentiletti, F., D'Angelo, M., Giglio, S., Nanni, S., D’Angelo, C., Farsetti, A., Citro, G., Sacchi, A., Pontecorvi, A., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m311793200 · Cited by 38
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).”
BackgroundEGFR phosphorylates HDAC1 to regulate its expression and anti-apoptotic function
Bahl, S., Ling, H., Acharige, N. P. N., Santos‐Barriopedro, I., Pflum, M. K. H., & Seto, E. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03697-6 · Cited by 37
“Phosphotyrosine antibody cocktail (13-6620) was from Invitrogen (Thermo Fisher Scientific, Waltham, MA).”
MethodHigh Mdm4 levels suppress p53 activity and enhance its half-life in acute myeloid leukaemia
Tan, B. X., Khoo, K. H., Lim, T. M., & Lane, D. P. (2013) · Oncotarget · doi:10.18632/oncotarget.1559 · Cited by 34
“Also, unlike Mdm2, Mdm4 expression levels are not dependent on p53, though Mdm2 targets Mdm4 and itself for proteasomal degradation [7].”
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.”
BackgroundInfluence of MDM2 and MDM4 on development and survival in hereditary retinoblastoma
Reis, A. H. D. O., de Carvalho, I. N. S. R., Damasceno, P. B. D. S., Ferman, S., Lucena, E., López‐Camelo, J. S., Seuánez, H. N., & Vargas, F. R. (2011) · Pediatric Blood & Cancer · doi:10.1002/pbc.24014 · Cited by 33
“3-q15 and is involved, by regulating TP53 function in cell cycle control, apoptosis, senescence, and DNA repair [4,5].”
BackgroundAbnormal MDMX degradation in tumor cells due to ARF deficiency
Li, X., Gilkes, D., Li, B., Cheng, Q., Pernazza, D., Lawrence, H., Lawrence, N., & Chen, J. (2012) · Oncogene · doi:10.1038/onc.2011.534 · Cited by 32
“Efficient p53 activation by ARF requires both p53 stabilization (inhibition of MDM2) and elimination of MDMX. ARF stimulates MDMX ubiquitination and degradation by MDM2 Our previous study showed that ARF expression promotes MDMX ubiquitination by MDM2 (Pan and Chen 2003).”
InfluentialSelf-citationStochastic 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).”
Turning 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
Inhibition of MDM2 by a Rhein-Derived Compound AQ-101 Suppresses Cancer Development in SCID Mice
Gu, L., Zhang, H., Liu, T., Draganov, A. B., Yi, S., Wang, B., & Zhou, M. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-0566 · Cited by 29
The Development of p53-Targeted Therapies for Human Cancers
Lu, Y., Wu, M. Y., Xu, Y., & Yu, L. (2023) · Cancers · doi:10.3390/cancers15143560 · Cited by 30
Genetic changes and DNA damage responses in the prostate
af Hällström, T., & Laiho, M. (2008) · The Prostate · doi:10.1002/pros.20746 · Cited by 27
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
Calculation 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
Inhibition of MDM2 homodimerization by XIAP IRES stabilizes MDM2, influencing cancer cell survival
Liu, T., Zhang, H., Xiong, J., Yi, S., Gu, L., & Zhou, M. (2015) · Molecular Cancer · doi:10.1186/s12943-015-0334-0 · Cited by 26
“The remaining cells (90%) were used for the purification of His6-tagged MDM2, with the aid of Ni-nitrilotriacetic acid beads, as previously described [45].”
MethodStress-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
Yeh, S., Chang, C.-A., Li, C., Wang, L. H.-C., & Chen, B. (2019) · Oncotarget · doi:10.18632/oncotarget.26940 · Cited by 24
“Dysregulations of miR-30c-2 and miR-27b, epigenetic modifications of VIM, MYH9, MDM4, and ETS1 contribute to the progression from early stage to middle stage LADC MDM4, also known as MDMX, is an important player in cancer progression.”
BackgroundInfluentialProtein phosphatase 1 inhibits p53 signaling by dephosphorylating and stabilizing Mdmx
Lu, Z., Wan, G., Guo, H., Zhang, X., & Lu, X. (2012) · Cellular Signalling · doi:10.1016/j.cellsig.2012.12.014 · Cited by 25
“Previous study showed that Mdm2 is a critical E3 ubiquitin ligase that targets Mdmx for degradation in cells [42].”
BackgroundMarkey, M. P. (2010) · Frontiers in bioscience · doi:10.2741/3780 · Cited by 26
Imanishi, M., Yamamoto, Y., Wang, X., Sugaya, A., Hirose, M., Endo, S., Natori, Y., Yamato, K., & Hyodo, I. (2018) · Cancer Science · doi:10.1111/cas.13893 · Cited by 24
Datta, A., & Nicot, C. (2007) · Oncogene · doi:10.1038/sj.onc.1210718 · Cited by 23
“MDMX–MDM2 interactions lead to ubiquitination and degradation of MDMX in response to DNA damage (Pan and Chen, 2003).”
BackgroundHeminger, 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].”
The roles of mouse double minute 2 (MDM2) oncoprotein in ocular diseases: A review
Jiang, H., Luo, J., & Lei, H. (2022) · Experimental Eye Research · doi:10.1016/j.exer.2021.108910 · Cited by 23
Golestanian, S., Sharifi, A., Popowicz, G. M., Azizian, H., Foroumadi, A., Szwagierczak, A., Holak, T. A., & Amanlou, M. (2015) · Life Sciences · doi:10.1016/j.lfs.2015.12.047 · Cited by 21
MDMX acidic domain inhibits p53 DNA binding in vivo and regulates tumorigenesis
Huang, Q., Chen, L., Yang, L., Xie, X., Gan, L., Cleveland, J. L., & Chen, J. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1719090115 · Cited by 21
Slabáková, E., Kharaishvili, G., Smějová, M., Pernicová, Z., Suchánková, T., Remšík, J., Lerch, S., Straková, N., Bouchal, J., Král, M., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.5392 · Cited by 20
“The observation that the increased protein level of MDMX by CAFTD03 compared to BPH-1 is not proportional to the RNA level (Figure 1A, 1D) suggests that elevated MDMX level in CAFTD03 cells can result from a decrease in MDM2 E3 ligase activity towards MDMX [37].”
Hinokiflavone Inhibits MDM2 Activity by Targeting the MDM2-MDMX RING Domain
Ilic, V. K., Egorova, O., Tsang, E., Gatto, M., Wen, Y., Zhao, Y., & Sheng, Y. (2022) · Biomolecules · doi:10.3390/biom12050643 · Cited by 20
“Since MDM2 was reported to regulate MDMX and its own ubiquitination and degradation [37], inhibition of the MDM2-MDMX RING domain would lead to MDM2-MDMX stabilization [30].”
BackgroundMouse modelling of the MDM2/MDMX−p53 signalling axis
Tackmann, N. R., & Zhang, Y. (2017) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjx006 · Cited by 21
“For example, MDM2Y487A mice lacking MDM2 E3 ligase activity have increased protein levels of MDMX (Tollini et al., 2014), which is in line with in vitro studies suggesting that MDM2 E3 ligase activity acts to ubiquitinate MDMX (Kawai et al., 2003; Pan and Chen, 2003).”
BackgroundModification 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
Mouse models of Mdm2 and Mdm4 and their clinical implications
Xiong, S. (2013) · 癌症：英文版 · doi:10.5732/cjc.012.10286 · 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).”
BackgroundBOR-Syndrome-Associated Eya1 Mutations Lead to Enhanced Proteasomal Degradation of Eya1 Protein
Musharraf, A., Kruspe, D., Tomasch, J., Besenbeck, B., Englert, C., & Landgraf, K. (2014) · PLoS ONE · doi:10.1371/journal.pone.0087407 · Cited by 18
MacCormac, L. P., Muqit, M. M. K., Faulkes, D. J., Wood, N. W., & Latchman, D. S. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03659.x · Cited by 18
“…the antisense construct used, an under-expressing parkin cell line (82-2-4) was screened for expression of another related protein, MDM2, that has a RING domain and exhibits ubiquitin ligase activity (Pan & Chen, 2003) and no reduction of MDM2 expression upon induction with DOX was observed (Fig.”
BackgroundEl-Hamaky, A. A., El‐Hamamsy, M. H., El-Moselhy, T. F., Sharafeldin, N., & Tawfik, H. O. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117872 · Cited by 17
Tumour suppressors and cellular senescence
Chan, A. S. L., Mowla, S. N., Arora, P., & Jat, P. (2014) · IUBMB Life · doi:10.1002/iub.1335 · Cited by 20
“Even though p14 is thought to not interact directly with MDM4 (56), it potentiates the interaction between MDM2/MDM4 leading to the degradation of MDM4 and p53 activation (59).”
BackgroundMDM2 oligomers: antagonizers of the guardian of the genome
Leslie, P. L., & Zhang, Y. (2016) · Oncogene · doi:10.1038/onc.2016.88 · Cited by 18
Regulation of MDM4 (MDMX) function by p76MDM2: a new facet in the control of p53 activity
Giglio, S., Mancini, F., Pellegrino, M., Conza, G. D., Puxeddu, E., Sacchi, A., Pontecorvi, A., & Moretti, F. (2010) · Oncogene · doi:10.1038/onc.2010.324 · Cited by 17
“P76 impairs MDM4/p90/p53 association Various studies have reported the control of MDM4 protein levels by p90 upon DNA damage (Kawai et al., 2003; Pan and Chen, 2003; Chen et al., 2005; Okamoto et al., 2005; Pereg et al., 2005).”
BackgroundDownregulation of Mdm2 and Mdm4 enhances viral gene expression during adenovirus infection
Yang, H., Zheng, Z., Zhao, L., Li, Q., & Liao, D. (2012) · Cell Cycle · doi:10.4161/cc.11.3.19052 · Cited by 18
Balmer, M. T., Katz, R. D., Liao, S., Goodwine, J. S., & Gal, S. (2014) · Cancer Biology & Therapy · doi:10.4161/cbt.29112 · Cited by 16
“We hypothesize that this may be due to the decrease in the level of the Mdm2 protein which is known to induce ubiquitination and degradation of MdmX.30 Posttranslational modification (PTM) of p53 is known to affect both the level and function of this transcription factor due to interaction with its negative regulator…”
BackgroundInfluentialPan, Y., Zhao, Z., Li, J., Li, J., Luo, Y., Li, W., You, W., Zhang, Y., Li, Z., Yang, J., et al. (2022) · Cancers · doi:10.3390/cancers14194735 · Cited by 14
“Notably, it has been shown that MDM2 binds to and promotes MDMX polyubiquitylation and degradation [27,28].”
BackgroundCarotti, A., Macchiarulo, A., Giacchè, N., & Pellicciari, R. (2009) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.22464 · Cited by 13
Switching p 53 states by calcium: dynamics and interaction of stress systems
Alam, M. J., Devi, G. R., Ravins, Ishrat, R., Agarwal, S. M., & Singh, R. K. B. (2013) · Molecular BioSystems · doi:10.1039/c3mb25277a · Cited by 13
Screening E3 Substrates Using a Live Phage Display Library
Guo, Z., Wang, X., Li, H., & Gao, Y. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076622 · Cited by 13
“In addition to P53/TP53, many substrates of MDM2 have been identified individually in different laboratories; these substrates include CDKN1A [27-29], HIPK2 [30,31], RB1 [32-34], CDH1 [35], DLG4 [36], IGF1R [37], APEX1 [38], ADRBK1 [39], ARRB1 [40], ARRB2 [41], CREBBP [42], EID1 [43], IRS1 [40], JMY [44], KAT2B [45],…”
Hirose, M., Yamato, K., Endo, S., Saito, R., Ueno, T., Hirai, S., Suzuki, H., Abei, M., Natori, Y., & Hyodo, I. (2014) · Oncoscience · doi:10.18632/oncoscience.103 · Cited by 14
“MDM2 also destabilizes the structure of MDM4 via ubiquitination [18].”
BackgroundLama, R., Xu, C., Galster, S. L., Querol-García, J., Portwood, S. M., Mavis, C. K., Ruiz, F. M., Martin, D. L., Wu, J., Giorgi, M., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.933446 · Cited by 12
“The elevated MDM4 expression in MDM2knockdown cells is consistent with the report that MDM2 promotes ubiquitination and degradation of MDM4 (36).”
BackgroundThe MDMX Acidic Domain Uses Allovalency to Bind Both p53 and MDMX
Fenton, M. J., Borcherds, W. M., Chen, L., Anbanandam, A., Levy, R., Chen, J., & Daughdrill, G. W. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167844 · Cited by 12
Mdm2 and MdmX Involvement in Human Cancer
Berberich, S. J. (2014) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-017-9211-0_15 · Cited by 12
“Heterodimerization also triggers ubiquitin-mediated degradation of HdmX and MdmX [21, 46, 77].”
BackgroundBridged Analogues for p53-Dependent Cancer Therapy Obtained by S-Alkylation
Micewicz, E. D., Sharma, S. K., Waring, A. J., Luong, H. T., McBride, W. H., & Ruchala, P. P. (2015) · International Journal of Peptide Research and Therapeutics · doi:10.1007/s10989-015-9487-3 · Cited by 11
“However, MDM4, a structural homologue of MDM2, can form a MDM2/ MDMX heterodimers through their C-terminal RING finger domains, which potentiate the ubiquitination of p53, and subsequently its degradation (de Graaf et al. 2003; Linares et al. 2003; Pan and Chen 2003).”
BackgroundSun, M., Cai, J., Anderson, R. A., & Sun, Y. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.736041 · Cited by 10
“In Vivo Ubiquitination Assay—The ubiquitination of Mig6 was evaluated as described previously (63).”
MethodInactivation of the MDM2 RING domain enhances p53 transcriptional activity in mice
Tian, H., Tackmann, N. R., Jin, A., Zheng, J., & Zhang, Y. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.000122 · Cited by 9
“ligase function, which is also explained by the previous studies (31-33).”
p53 Regulation Goes Live--Mdm2 and MdmX Co-Star: Lessons Learned from Mouse Modeling
Tollini, L. A., & Zhang, Y. (2012) · Genes & Cancer · doi:10.1177/1947601912454732 · Cited by 9
Mdm2 Plays a Positive Role as an Effector of p53-Dependent Responses
Giono, L. E., & Manfredi, J. J. (2007) · Cell Cycle · doi:10.4161/cc.6.17.4647 · Cited by 9
The RING Finger Domain of MDM2 Is Essential for MDM2-mediated TGF-β Resistance
Kannemeier, C., Liao, R., & Sun, P. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-09-0844 · Cited by 8
“MDM2 also mediates the ubiquitination and degradation of MDMX (de Graaf et al., 2003; Pan and Chen, 2003).”
BackgroundGatekeepers of the Guardian: p53 Regulation by Post-Translational Modification, MDM2 and MDMX
Wahl, G. M., Stommel, J. M., Krummel, K. A., & Wade, M. R. (2005) · Springer eBooks · doi:10.1007/978-1-4020-2922-6_4 · Cited by 9
“This may be explained by the ability of ARF to bind to and inhibit the E3 ubiquitin ligase function of MDM2 (Honda and Yasuda, 1999), or by increasing the MDM2-mediated degradation of MDMX (Pan and Chen, 2003).”
BackgroundLi, L., Li, P., Ma, X., Zeng, S., Peng, Y., & Zhang, G. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115188 · Cited by 8
MDM4 as a Prognostic Factor for Patients With Gastric Cancer With Low Expression of p53
Zhang, X., Yamamoto, Y., Wang, X., Sato, M., Imanishi, M., Sugaya, A., Hirose, M., Endo, S., Moriwaki, T., Yamato, K., et al. (2021) · Anticancer Research · doi:10.21873/anticanres.14906 · Cited by 6
Epimutations and Their Effect on Chromatin Organization: Exciting Avenues for Cancer Treatment
Mohammad, A., & Jha, S. (2022) · Cancers · doi:10.3390/cancers15010215 · Cited by 6
“By interacting with the N-terminus transactivation domain (TAC) of p53, MDM2 ubiquitinates p53 and triggers degradation by the ubiquitin-proteasomes system [58].”
Hauck, P. M., Wolf, E. R., Olivos, D. J., McAtarsney, C. P., & Mayo, L. D. (2017) · Oncotarget · doi:10.18632/oncotarget.22320 · Cited by 6
“This result was expected as down-regulation of MdmX in response to overexpression of Mdm2 has been reported in the literature [24, 25].”
ResultSorting nexin 6 interacts with Cullin3 and regulates programmed death ligand 1 expression
Ghosh, C., Xing, Y., Li, S., Hoyle, R. G., Sun, M., Li, J., & Sun, Y. (2021) · FEBS Letters · doi:10.1002/1873-3468.14191 · Cited by 6
Lama, R., Galster, S. L., Xu, C., Davison, L. W., Chemler, S. R., & Wang, X. (2022) · Molecules · doi:10.3390/molecules27227665 · Cited by 6
“The elevated MDM4 expression in the MDM2-knockdown cells was consistent with the report that MDM2 promoted the ubiquitination and degradation of MDM4 [32].”
BackgroundGao, C., Xiao, G., & Bargonetti, J. (2019) · Oncotarget · doi:10.18632/oncotarget.27134 · Cited by 6
“The hetero-dimerization of MDM2 with MDMX stabilizes MDM2 and enhances its E3 ligase activity, resulting in efficient inhibition of wild-type p53 as well as proteasomal degradation of MDMX [12].”
BackgroundFunctional Interrogation of the N-Terminal Lid of MDMX in p53 Binding via Native Chemical Ligation
Chen, X., & Lu, W. (2016) · Chemical and Pharmaceutical Bulletin · doi:10.1248/cpb.c15-00975 · Cited by 5
Intra molecular interactions in the regulation of p53 pathway
Chen, J. (2016) · Translational Cancer Research · doi:10.21037/tcr.2016.09.23 · Cited by 5
“MDMX degradation is controlled by MDM2-mediated ubiquitination in a stressdependent fashion (20-22,36,66).”
BackgroundShin, U., Choi, Y., Ko, H. S., Myung, K., Lee, S., Cheon, C. K., & Lee, Y. (2023) · Human Genomics · doi:10.1186/s40246-023-00491-7 · Cited by 5
SHORT REPORT Potential for treatment of liposarcomas with the MDM2 antagonist Nutlin-3A
Paulsen, E. B., Noordhuis, P., Pédeutour, F., Sæter, G., & Myklebost, O. (2007) · Cited by 5
Liu, H., Lin, J., Li, Y., Zhou, J., Cui, X., Li, S., Yang, S., Kan, F., Du, J., Zhong, W., et al. (2025) · Advanced Science · doi:10.1002/advs.202503473 · Cited by 4
Owona, P. E., Sandrine, M. N. Y., Dongmo, Y. K. M., Goufani, R. B. A., Didier, T. F. A., Omgba, J. J. A., Bilanda, D. C., Djomeni, P. D. D., Binsaleh, A. Y., Al‐Hoshani, N., et al. (2025) · Chinese Journal of Analytical Chemistry · doi:10.1016/j.cjac.2025.100678 · Cited by 4
MDMX under stress: the MDMX-MDM2 complex as stress signals hub
de Polo, A., Vivekanandan, V., Little, J. B., & Yuan, Z.-M. (2016) · Translational Cancer Research · doi:10.21037/tcr.2016.12.18 · Cited by 4
“Whilst MDM2 undergoes self-ubiquitination and has a very short half-life in cell culture (15–30 min), MDMX halflife is much longer (3–6 hours) and its stability is controlled by MDM2-dependent ubiquitination in a stress-dependent manner (50).”
BackgroundUbiquitin Family Members in the Regulation of the Tumor Suppressor p53
Xirodimas, D. P., & Scheffner, M. (2010) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-1-4419-6676-6_10 · Cited by 5
A triple-action PROTAC for wild-type p53 cancer therapy
Bird, G. H., Adhikary, U., Schmidt, M. J., Godes, M., Tesar, B. M., Camara, C. M., Paulo, J. A., Vidlak, J. F., DeAngelo, T. M., Marquez, M., et al. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.102467 · Cited by 4
“…BET degradation is blocked by proteasome inhibition (Figure S2B), and (3) TAPTAC1 targeting appears to disrupt HDM2/HDMX complex formation (Figure S2C), which could contribute to drug-induced elevation of HDMX in SJSA-X cells (like p53, HDMX is a substrate of HDM2 E3-ligase activity 19 ).”
B-box1 Domain of MID1 Interacts with the Ube2D1 E2 Enzyme Differently Than RING E3 Ligases
Kaur, A., Gladu, E., Wright, K. M., Webb, J. A., & Massiah, M. A. (2023) · Biochemistry · doi:10.1021/acs.biochem.2c00693 · Cited by 3
Yin, Q., Hu, Y., Dong, Z., Lu, J., & Wang, H. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00913 · Cited by 3
Naumann, M. (2009) · Advances and Applications in Bioinformatics and Chemistry · doi:10.2147/aabc.s8211 · Cited by 3
Metadata
- Authors
- Pan, Y., & Chen, J.
- Affiliations
- Moffitt Cancer Center (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2003-08-01
- Volume
- 23
- Issue
- 15
- Pages
- 5113-5121
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC165735
- OpenAlex
- W2143351237
- Cited by
- 246
- References
- 33
- Citations by year
- 2025: 5 · 2024: 3 · 2023: 9 · 2022: 9 · 2021: 6 · 2020: 6 · 2019: 7 · 2018: 4 · 2017: 9 · 2016: 15 · 2015: 13 · 2014: 16 · 2013: 8 · 2012: 17
- FWCI
- 4.79
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Cancer Society
- National Institutes of Health
- 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, MDMX, p53, ARF, ubiquitination, proteasomal degradation, RING domain, E3 ubiquitin ligase, DNA damage response, tumor suppressor regulation, p53 activation
- MeSH terms
- Amino Acid Sequence, Epitopes, Cysteine Endopeptidases, DNA Damage, Humans, Models, Biological, Molecular Sequence Data, Multienzyme Complexes, Nuclear Proteins, Plasmids, Protein Binding, Proto-Oncogene Proteins, Transfection, Tumor Cells, Cultured, Blotting, Western, Signal Transduction, Down-Regulation, Tumor Suppressor Protein p53, Apoptosis, Protein Structure, Tertiary, Ubiquitin, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-mdm2
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