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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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 [16]
MDMX and MDM2 form heterodimers through their C-terminal RING domains, and the MDM2 RING domain alone is sufficient to degrade MDMX.
“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
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 Pan and Chen, 2003
Ionizing irradiation promotes MDMX nuclear translocation and degradation by proteasomes.
“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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“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.”
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“However, MdmX has also been reported to be ubiquitinated and degraded by Mdm2 [18].”
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“It was reported that p14 stimulates Mdm2-dependent Mdmx ubiquitination and degradation by the proteasome (32).”
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Regulation of MDMX nuclear import and degradation by Chk2 and 14-3-3
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“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
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“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
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“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 · see citing works
“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 · see citing works
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 · see citing works
“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 115 · see citing works
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 115 · see citing works
“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 111 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
“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 102 · 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
“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 92 · see citing works
“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 90 · see citing works
“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 · see citing works
“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 87 · see citing works
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 · see citing works
“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 83 · 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
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 · see citing works
“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 81 · see citing works
“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 · see citing works
“, 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 · see citing works
“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 · see citing works
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 70 · see citing works
“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 · see citing works
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 · see citing works
“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 69 · see citing works
“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 69 · see citing works
“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 · 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
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 67 · see citing works
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 70 · see citing works
“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 · see citing works
“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 71 · see citing works
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 65 · see citing works
“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 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).”
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 · see citing works
“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 · see citing works
“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 · see citing works
“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 61 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 · 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
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 53 · see citing works
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 · see citing works
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 · see citing works
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 · 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;…”
Wang, H., & Yan, C. (2011) · Neoplasia · doi:10.1593/neo.11438 · Cited by 49 · see citing works
“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 48 · see citing works
“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 · see citing works
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 · see citing works
- 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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