The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Tight control of gene expression in mammalian cells by tetracycline-responsive promoters.
Gossen, M., & Bujard, H. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.12.5547 · Cited by 4,943 · cited 1×
“A U2OS stable cell line expressing tetracycline-repressible human MDM2 was created by cloning MDM2 cDNA into the pUHD15.1 vector and cotransfecting with pUHG10.3 ( 7 ).”
MethodRescue of early embryonic lethality in mdm2-deficient mice by deletion of p53
de Oca Luna, R. M., Wagner, D. S., & Lozano, G. (1995) · Nature · doi:10.1038/378203a0 · Cited by 1,420 · cited 1×
“Knock out of MDM2 in mice results in embryonic lethality due to hyperactivation of p53 (20).”
BackgroundJoazeiro, C. A. P., & Weissman, A. M. (2000) · Cell · doi:10.1016/s0092-8674(00)00077-5 · Cited by 1,249
Stott, F. J., Bates, S., James, M. C., McConnell, B. B., Starborg, M., Brookes, S., Palmero, I., Ryan, K. M., Hara, E., Vousden, K. H., et al. (1998) · The EMBO Journal · doi:10.1093/emboj/17.17.5001 · Cited by 1,178
Mdm2 Is a RING Finger-dependent Ubiquitin Protein Ligase for Itself and p53
Fang, S., Jensen, J. P., Ludwig, R. L., Vousden, K. H., & Weissman, A. M. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.12.8945 · Cited by 1,044
Regulation of Receptor Fate by Ubiquitination of Activated β 2 -Adrenergic Receptor and β-Arrestin
Shenoy, S. K., McDonald, P. H., Kohout, T. A., & Lefkowitz, R. J. (2001) · Science · doi:10.1126/science.1063866 · Cited by 824
Mapping of the p53 and mdm-2 Interaction Domains
Chen, J., Maréchal, V., & Levine, A. J. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.7.4107 · Cited by 700
MDMX: a novel p53‐binding protein with some functional properties of MDM2.
Shvarts, A., Steegenga, W. T., Riteco, N., van Laar, T., Dekker, P., Bazuine, M., van Ham, R. C., van der Houven van Oordt, W., Hateboer, G., van der Eb, A. J., et al. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00919.x · Cited by 648
Parant, J., Chavez-Reyes, A., Little, N. A., Yan, W., Reinke, V., Jochemsen, A. G., & Lozano, G. (2001) · Nature Genetics · doi:10.1038/ng714 · Cited by 517
Lin, H.-K., Wang, L., Hu, Y., Altuwaijri, S., & Chang, C. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf406 · Cited by 450
Research works printed but not linked: 5
- Finch R. A., 2002, Cancer Res., 62, 3221
- Lu W., 2002, Cancer Res., 62, 1305
- McMasters K. M., 1996, Oncogene, 13, 1731
- Ramos Y. F., 2002, Cancer Res., 61, 1839
- Zhang Y., 2001, Cell Growth Differ., 12, 175
Cited by
Sorted by citations
Awakening guardian angels: drugging the p53 pathway
Brown, C. J., Lain, S., Verma, C. S., Fersht, A. R., & Lane, D. P. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2763 · Cited by 881
“Another consequence of MDM2–MDM4 heterodimerization is that MDM4 can be ubiquitylated by MDM2and is consequently degrade”
BackgroundMoll, U. M., & Petrenko, O. (2003) · PubMed · Cited by 778
Coping with stress: multiple ways to activate p53
Horn, H. F., & Vousden, K. H. (2007) · Oncogene · doi:10.1038/sj.onc.1210263 · Cited by 522
“…(Sharp et al., 1999; Tanimura et al., 1999), which results in the stabilization of Mdm2 (Stad et al., 2001; Gu et al., 2002) or the Mdm2-mediated degradation of MdmX (de Graaf et al., 2003; Kawai et al., 2003; Pan and Chen, 2003), depending on the relative expression levels of the two proteins.”
BackgroundInfluentialThe p53 orchestra: Mdm2 and Mdmx set the tone
Wade, M., Wang, Y. V., & Wahl, G. M. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.01.009 · Cited by 450
“However, in addition to degrading p53, Mdm2 also undergoes autodegradation [12,13] and targets Mdmx for degradation [14–16], which is critical for optimal Wade et al.”
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
The Roles of MDM2 and MDMX in Cancer
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
The multiple levels of regulation by p53 ubiquitination
Lee, J. T., & Gu, W. (2010) · Cell Death & Differentiation · doi:10.1038/cdd.2009.77 · Cited by 289
A 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).”
Meulmeester, E., Maurice, M. M., Boutell, C., Teunisse, A. F. A. S., Ovaa, H., Abraham, T. E., Dirks, R. W., & Jochemsen, A. G. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.04.024 · Cited by 260
“DNA Damage-Induced Degradation of Hdmx Is Not Rescued by HAUSP Previous studies have shown that the Hdmx protein is degraded upon treatment of cells with DNA damaging agents in an Hdm2- and proteasome-dependent manner (Pan and Chen, 2003; Kawai et al., 2003a).”
BackgroundResultInfluentialMDM2 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
“tion 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, 2003a; Pan and Chen, 2003).”
BackgroundInfluentialATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage
Chen, L., Gilkes, D. M., Pan, Y., Lane, W. S., & Chen, J. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600812 · Cited by 260
“DNA damage induces degradation of MDMX Previous experiments in our laboratory revealed that MDMX is an ubiquitination substrate for MDM2 (Pan and Chen, 2003).”
BackgroundMethodInfluentialSelf-citationMechanism 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
MDMX overexpression prevents p53 activation by the MDM2 inhibitor Nutlin
Hu, B., Gilkes, D. M., Farooqi, B., Sebti, S. M., & Chen, J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.c600147200 · Cited by 236
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
Liu, 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).”
BackgroundEfficient 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
“p53 ubiquitination assay was done as previously described (14).”
MethodMdmx 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
Regulating the p53 system through ubiquitination
Yang, Y., Li, C.-C. H., & Weissman, A. M. (2004) · Oncogene · doi:10.1038/sj.onc.1207411 · Cited by 184
Phan, J., Li, Z., Kasprzak, A., Li, B., Sebti, S., Guida, W., Schönbrunn, E., & Chen, J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.073056 · Cited by 173
Self-citationChoi, M., Shi, J., Jung, S. H., Chen, X. X., & Cho, K. (2012) · Science Signaling · doi:10.1126/scisignal.2003363 · Cited by 170
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
“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
“The emerging view is that damage-induced phosphorylation of the Mdmx COOH terminus, and a p53-dependent increase in Mdm2 levels, triggers Mdmx degradation (30, 31, 47).”
BackgroundATM-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
ATM activates p53 by regulating MDM2 oligomerization and E3 processivity
Cheng, Q., Chen, L., Li, Z., Lane, W. S., & Chen, J. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.294 · Cited by 165
Self-citationQi, 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
“MDM2 can also promote the ubiquitination and proteasomal degradation of MDMX and itself (Fang et al., 2000; de Graaf et al., 2003; Pan and Chen, 2003), while MDMX can bind to and stabilize MDM2 protein (Tanimura et al., 1999).”
BackgroundRING Domain–Mediated Interaction Is a Requirement for MDM2's E3 Ligase Activity
Kawai, H., Lopez-Pajares, V., Kim, M. M., Wiederschain, D., & Yuan, Z.-M. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1313 · Cited by 160
“It has been shown that DNA damage mediates MDM2-dependent degradation of MDMX, allowing for maximal p53 activation (11, 12).”
BackgroundActivation of the tumor suppressor p53 upon impairment of ribosome biogenesis
Bursać, S., Brdovčak, M. C., Donati, G., & Volarević, S. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.08.014 · Cited by 166
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
Oliver, T. G., Meylan, E., Chang, G. P., Xue, W., Burke, J. R., Humpton, T. J., Hubbard, D., Bhutkar, A. J., & Jacks, T. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.06.012 · Cited by 163
“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
Gilkes, D. M., Chen, L., & Chen, J. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601424 · Cited by 142
“MDMX can be ubiquitinated and degraded by MDM2 (de Graaf et al, 2003; Kawai et al, 2003; Pan and Chen, 2003), this may be an important mechanism for controlling MDMX level.”
BackgroundSelf-citationRegulation of p53: a collaboration between Mdm2 and MdmX
Pei, D., Zhang, Y., & Zheng, J. (2012) · Oncotarget · doi:10.18632/oncotarget.443 · Cited by 140
“However, MdmX has also been reported to be ubiquitinated and degraded by Mdm2 [18].”
BackgroundPersistent inhibition of telomerase reprograms adult T-cell leukemia to p53-dependent senescence
Datta, A., Bellon, M., Sinha-Datta, U., Bazarbachi, A., Lepelletier, Y., Canioni, D., Waldmann, T. A., Hermine, O., & Nicot, C. (2006) · Blood · doi:10.1182/blood-2006-01-0067 · Cited by 139
Pant, V., Xiong, S., Iwakuma, T., Quintás-Cardama, A., & Lozano, G. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102241108 · Cited by 134
Okamoto, K., Kashima, K., Pereg, Y., Ishida, M., Yamazaki, S., Nota, A., Teunisse, A., Migliorini, D., Kitabayashi, I., Marine, J.-C., et al. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.21.9608-9620.2005 · Cited by 129
“It was reported that p14 stimulates Mdm2-dependent Mdmx ubiquitination and degradation by the proteasome (32).”
BackgroundMDM2 and MDMX: Alone and together in regulation of p53.
Shadfan, M., Lopez-Pajares, V., & Yuan, Z.-M. (2012) · PubMed · Cited by 125
Regulation 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
“translocation and degradation by the proteasomes (Li et al, 2002; Pan and Chen, 2003).”
BackgroundPotential for treatment of liposarcomas with the MDM2 antagonist Nutlin-3A
Müller, C. R., Paulsen, E. B., Noordhuis, P., Pedeutour, F., Sæter, G., & Myklebost, O. (2007) · International Journal of Cancer · doi:10.1002/ijc.22643 · Cited by 119
“This is most likely caused by proteasomal degradation of MDM4 mediated by the very high MDM2 levels, as previously reported.(30) Furthermore, a smaller band of 47 kDa appeared upon treatment with Nutlin in the amplified cell lines, which may be a degradation intermediate because of some inhibitory effect of Nutlin.”
BackgroundMdm2 is involved in the ubiquitination and degradation of G‐protein‐coupled receptor kinase 2
Salcedo, A., Mayor, F., & Penela, P. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601351 · Cited by 119
“Growing evidence indicates that other proteins interact with Mdm2 and can be regulated by this ligase (Lin et al, 2002; Girnita et al, 2003; Iwakuma and Lozano, 2003; Jin et al, 2003; Pan and Chen, 2003; Uchida et al, 2005).”
BackgroundUSP7 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
“Furthermore, USP7 deubiquitinates and stabilizes the Mdm2 interacting partner – and substrate (Kawai et al., 2003; Pan and Chen, 2003) – Mdm4 (also known as Mdmx) (Meulmeester et al., 2005).”
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
A Small-Molecule Inhibitor of MDMX Activates p53 and Induces Apoptosis
Wang, H., Ma, X., Ren, S., Buolamwini, J. K., & Yan, C. (2011) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-10-0581 · Cited by 117
“Moreover, although MDM2 can promote MDMX degradation (54), induction of MDM2 expression by XI-006 (Fig.”
BackgroundZhang, P., Wang, C., Gao, K., Wang, D., Mao, J., An, J., Xu, C., Wu, D., Yu, H., Liu, J. O., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.063321 · Cited by 120
The ATDC (TRIM29) Protein Binds p53 and Antagonizes p53-Mediated Functions
Yuan, Z., Villagra, A., Peng, L., Coppola, D., Glozak, M. A., Sotomayor, E. M., Chen, J., Lane, W. S., & Seto, E. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.01023-09 · Cited by 116
“expression construct (39); pC53-SN3, which expresses wild-type p53 (39); glutathione S-transferase (GST), GST-p53, and GST-p53 deletion mutant expression”
BackgroundMdm2 and MdmX partner to regulate p53
Wang, X., & Jiang, X. (2012) · FEBS Letters · doi:10.1016/j.febslet.2012.02.049 · Cited by 117
“p53/Mdm2 feedback loop through self-destruction [56,57].”
BackgroundIdentification of ribosomal protein S25 (RPS25)–MDM2–p53 regulatory feedback loop
Zhang, X., Wang, W., Wang, H., Wang, M.-H., Xu, W., & Zhang, R. (2012) · Oncogene · doi:10.1038/onc.2012.289 · Cited by 106
Yin Yang 1 Plays an Essential Role in Breast Cancer and Negatively Regulates p27
Wan, M., Huang, W., Kute, T. E., Miller, L. D., Zhang, Q., Hatcher, H., Wang, J., Stovall, D. B., Russell, G. B., Cao, P. D., et al. (2012) · American Journal Of Pathology · doi:10.1016/j.ajpath.2012.01.037 · Cited by 98
“The experiments were performed according to a previously published procedure.(46) To test the effect of YY1 increase on p27 ubiquitination, expression vectors for pSL5/p27 and pCMV/His 6-ubiquitin (0.”
MethodDiscovery 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
“Mdm2 can also directly ubiquitinate and degrade MdmX upon DNA-damage stimuli (20-22).”
Small-molecule MDM2 inhibitors in clinical trials for cancer therapy
Wang, S., & Chen, F. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114334 · Cited by 104
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
“E3 ubiquitin ligase that mediates the ubiquitination and degradation of Hdmx in response to DNA damage (21, 43), it is conceivable that an efficient degradation of Hdmx would require its recruitment to the nucleus.”
BackgroundThe Regulation of the p53-mediated Stress Response by MDM2 and MDM4Preprint
Perry, M. E. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a000968 · Cited by 100
“The MDM2 RING differs from that of MDM4 by facilitating ubiquitylation of several proteins, including MDM4 (Pan and Chen 2003).”
BackgroundMicroRNA-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
“targeting MDM4 protein for degradation during the DNA damage response [9,10].”
BackgroundRegulation 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
“Since DNA damage promotes degradation of MDMX (24, 31), it should also lead to reduced targeting of CK1 to MDM2 and thus reduce the level of MDM2 phosphorylation.”
BackgroundInfluentialSelf-citationStommel, J. M., & Wahl, G. M. (2005) · Cell Cycle · doi:10.4161/cc.4.3.1522 · Cited by 90
Discovery of Dual Inhibitors of MDM2 and XIAP for Cancer Treatment
Gu, L., Zhang, H., Liu, T., Zhou, S., Du, Y., Xiong, J., Yi, S., Qu, C.-K., Fu, H., & Zhou, M. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.08.015 · Cited by 86
“Ubiquitination Assay The ubiquitination assay was performed as described previously (Pan and Chen, 2003).”
MethodEndosomal Type Iγ PIP 5-Kinase Controls EGF Receptor Lysosomal Sorting
Sun, Y., Hedman, A. C., Tan, J. X., Schill, N. J., & Anderson, R. A. (2013) · Developmental Cell · doi:10.1016/j.devcel.2013.03.010 · Cited by 84
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
Regulation of MDMX Expression by Mitogenic Signaling
Gilkes, D. M., Pan, Y., Coppola, D., Yeatman, T., Reuther, G. W., & Chen, J. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01633-07 · Cited by 82
“Consistent with this notion, ARF overexpression stimulates MDMX ubiquitination and degradation by MDM2 (unpublished results) (32).”
BackgroundSelf-citationMancini, 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
“lated by MDM2-degradative activity (Kawai et al, 2003; Pan and Chen, 2003; Pereg et al, 2005).”
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
“, 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).”
He, Y., Yue, H., Cheng, Y., Ding, Z., Xu, Z. D., Lv, C., Wang, Z., Wang, J., Yin, C., Hao, H., et al. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-04401-4 · Cited by 73
“MDM2 is an E3 ubiquitin ligase which promotes the ubiquitination of target proteins [26].”
BackgroundStructural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity
Nomura, K., Klejnot, M., Kowalczyk, D., Hock, A. K., Sibbet, G. J., Vousden, K. H., & Huang, D. T. C. (2017) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3414 · Cited by 72
Regulation 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
“Examples for DUBs that might antagonize E4 dependent polyubiquitylation are USP47, a regulator of Base Excision Repair (BER) that controls DNA polymerase β andOTUB1, whichmediates DNA damage-dependent deubiquitylation of p53/MDM2 in the cytoplasm (Parsons et al., 2011; Sun et al., 2012).”
BackgroundMdmx promotes genomic instability independent of p53 and Mdm2
Carrillo, A. M., Bouska, A., Arrate, M. P., & Eischen, C. M. (2015) · Oncogene · doi:10.1038/onc.2014.27 · Cited by 69
FL118 Induces p53-Dependent Senescence in Colorectal Cancer Cells by Promoting Degradation of MdmX
Ling, X., Xu, C., Fan, C., Zhong, K. L., Li, F., & Wang, X. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0683 · Cited by 70
“HdmX degradation is mediated byMdm2-dependent ubiquitination after DNA damage (42, 43).”
BackgroundInhibition of p53 DNA Binding Function by the MDM2 Protein Acidic Domain
Cross, B. L., Chen, L., Cheng, Q., Li, B., Yuan, Z.-M., & Chen, J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.228981 · Cited by 72
“Our lab has shown that, following oncogenic stress, ARF binds to MDM2 selectively and blocks p53-ubiquitination, yet promotes ubiquitination of MDMX (Pan and Chen, 2003) (Figure 7).”
BackgroundThe long and the short of it: the MDM4 tail so far
Haupt, S., Mejía-Hernández, J. O., Vijayakumaran, R., Keam, S. P., & Haupt, Y. (2019) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjz007 · Cited by 70
“MDM4 levels are regulated in a stress-dependent manner by the E3 ligase activity of MDM2 (Kawai et al., 2003; Pan and Chen, 2003).”
BackgroundRegulation 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
Mdm2 promotes Cdc25C protein degradation and delays cell cycle progression through the G2/M phase
Giono, L. E., Resnick‐Silverman, L., Carvajal, L. A., Clair, S. S., & Manfredi, J. J. (2017) · Oncogene · doi:10.1038/onc.2017.254 · Cited by 68
Regulation 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).”
BackgroundTollini, L. A., Jin, A., Park, J., & Zhang, Y. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.06.006 · Cited by 66
“Mdm2 has previously been identified as the E3 ligase responsible for MdmX degradation (Kawai et al., 2003; Linke et al., 2008; Pan and Chen, 2003), and as expected, in the presence of Mdm2Y487A, stabilization of MdmX is observed (Figure 2F–”
Hároníková, L., Bonczek, O., Zatloukalová, P., Kokas, F. Z., Kucerikova, M., Coates, P. J., Fåhræus, R., & Vojtěšek, B. (2021) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-021-00293-6 · Cited by 72
Peng, L., Yuan, Z., Li, Y., Ling, H., Izumi, V., Fang, B., Fukasawa, K., Koomen, J. M., Chen, J., & Seto, E. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.612796 · Cited by 69
“Ubiquitination Assays—Ubiquitination assays were performed in vivo using either the HA-tagged (29) or the histidinetagged (27) ubiquitination method.”
BackgroundMethodInfluentialMurine 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
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).”
InfluentialEnsemble-based virtual screening reveals dual-inhibitors for the p53–MDM2/MDMX interactions
Barakat, K., Mane, J. Y., Friesen, D. E., & Tuszyński, J. A. (2009) · Journal of Molecular Graphics and Modelling · doi:10.1016/j.jmgm.2009.12.003 · Cited by 61
“In fact, the MDMX–MDM2 interaction can also lead to ubiquitination and degradation of MDMX leading to the elimination of MDMX during DNA damage response [16].”
Giono, L. E., & Manfredi, J. J. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01967-06 · Cited by 62
“In fact, whereas after DNA damage Mdm2 promotes MdmX degradation (26, 35), downregulation of Mdm2 by siRNA caused an upregulation of MdmX protein levels (data not shown).”
BackgroundInterplay 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.”
BackgroundMDM2 recruitment of lysine methyltransferases regulates p53 transcriptional output
Chen, L., Li, Z., Zwolińska, A., Smith, M. A., Cross, B. L., Koomen, J. M., Yuan, Z.-M., Jenuwein, T., Marine, J., Wright, K. L., et al. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.140 · Cited by 62
“U2OS cell line with stably transfected tet-off MDM2 were described earlier (Pan and Chen, 2003).”
MethodDeep, G., Oberlies, N. H., Kroll, D. J., & Agarwal, R. (2008) · Oncogene · doi:10.1038/onc.2008.45 · Cited by 59
“Earlier studies have shown that in response to DNA damage, Mdm2 levels are increased in cells with wildtype p53 (Pan and Chen, 2003).”
BackgroundThe USP7 protein interaction network and its roles in tumorigenesis
Al-Eidan, A., Wang, Y., Skipp, P., & Ewing, R. M. (2022) · Genes & Diseases · doi:10.1016/j.gendis.2020.10.004 · Cited by 57
“In addition, MDM2 promotes the ubiquitination of MDMX and its proteasomal degradation.(42) It has also been shown that both up or down-regulation of USP7 protein expression reduces cell proliferation in colon cancer and tumour development in vivo, as a consequence of increasing p53 levels.”
BackgroundNatural Product MDM2 Inhibitors: Anticancer Activity and Mechanisms of Action
Qin, J., Nag, S. A., Voruganti, S., Wang, W., & Zhang, R. (2012) · Current Medicinal Chemistry · doi:10.2174/092986712803988910 · Cited by 57
“Because of its sequence similarity with MDM2 and its ability to inhibit p53-induced transcription when overexpressed, MDMX has been hypothesized to act as a negative regulator of p53 through physical binding [100].”
BackgroundInfluentialp53 ubiquitination by Mdm2: A never ending tail?
Coutts, A. S., Adams, C., & Thangue, N. B. L. (2009) · DNA repair · doi:10.1016/j.dnarep.2009.01.008 · Cited by 56
MDM2 Mediates p300/CREB-binding Protein-associated Factor Ubiquitination and Degradation
Jin, Y., Zeng, S. X., Lee, H., & Lu, H. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m309916200 · Cited by 56
Phillips, A., Teunisse, A., Lam, S., Lodder, K., Darley, M., Emaduddin, M., Wolf, A., Richter, J., de Lange, J., Verlaan-de Vries, M., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.129726 · Cited by 55
Sarkari, F., La Delfa, A., Arrowsmith, C. H., Frappier, L., Sheng, Y., & Saridakis, V. (2010) · Journal of Molecular Biology · doi:10.1016/j.jmb.2010.08.017 · Cited by 54
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
Nucleolar control of p53: a cellular Achilles’ heel and a target for cancer therapy
Vlatković, N., Boyd, M. T., & Rubbi, C. P. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1361-x · Cited by 54
A novel ARF-binding protein (LZAP) alters ARF regulation of HDM2
Wang, J., He, X., Luo, Y., & Yarbrough, W. G. (2005) · Biochemical Journal · doi:10.1042/bj20050960 · Cited by 53
MDM2 Regulates Dihydrofolate Reductase Activity through Monoubiquitination
Maguire, M., Nield, P. C., Devling, T., Jenkins, R. E., Park, B. K., Polański, R., Vlatković, N., & Boyd, M. T. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5271 · Cited by 53
Secondary interaction between MDMX and p53 core domain inhibits p53 DNA binding.
Wei, X., Wu, S., Song, T., Chen, L., Gao, M., Borcherds, W., Daughdrill, G. W., & Chen, J. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1603838113 · Cited by 50
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;…”
Wang, H., & Yan, C. (2011) · Neoplasia · doi:10.1593/neo.11438 · Cited by 50
“Because MDM2 can bind MDMX and drive its ubiquitination and proteolysis [39], p53 activated by DNA damage might induce MDM2 expression leading to subsequent decrease in the MDMX expression level.”
BackgroundRegulation of MDM2 Stability After DNA Damage
Li, J., & Kurokawa, M. (2015) · Journal of Cellular Physiology · doi:10.1002/jcp.24994 · Cited by 49
“ARF also promotes MDM2-mediated degradation of MDMX (Pan and Chen, 2003).”
BackgroundLo, D., & Lu, H. (2010) · Cell Cycle · doi:10.4161/cc.9.16.12605 · Cited by 50
Autoinhibition of MDMX by intramolecular p53 mimicry
Chen, L., Borcherds, W. M., Wu, S., Becker, A., Schönbrunn, E., Daughdrill, G. W., & Chen, J. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1420833112 · Cited by 49
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
