MdmX Protects p53 from Mdm2-Mediated Degradation
Open accessAbstract
The p53 tumor suppressor protein is stabilized in response to cellular stress, resulting in activation of genes responsible for either cell cycle arrest or apoptosis. The cellular pathway for releasing normal cells from p53-dependent cell cycle arrest involves the Mdm2 protein. Recently, a p53-binding protein with homology to Mdm2 was identified and called MdmX. Like Mdm2, MdmX is able to bind p53 and inhibit p53 transactivation; however, the ability of MdmX to degrade p53 has yet to be examined. We report here that MdmX is capable of associating with p53 yet is unable to facilitate nuclear export or induce p53 degradation. In addition, expression of MdmX can reverse Mdm2-targeted degradation of p53 while maintaining suppression of p53 transactivation. Using a series of MdmX deletions, we have determined that there are two distinct domains of the MdmX protein that can stabilize p53 in the presence of Mdm2. One domain requires MdmX interaction with p53 and results in the retention of both proteins within the nucleus and repression of p53 transactivation. The second domain involves the MdmX ring finger and results in stabilization of p53 and an increase in p53 transactivation. The potential basis for stabilization and increased p53 transactivation by the MdmX ring finger domain is discussed. Based on these observations, we propose that the MdmX protein may function to maintain a nuclear pool of p53 protein in undamaged cells.
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Mdmx does not target p53 for degradation but instead stabilizes p53 and Mdm2.
“However, Mdmx does not target p53 for degradation but even prevents Mdm2-mediated degradation of p53 and also stabilizes Mdm2 (Sharp et al., 1999;Jackson and Berberich, 2000;Stad et al., 2000).”
From Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms (2001) · cites this paper as Jackson and Berberich, 2000
Mdmx is unable to shuttle from the nucleus to the cytoplasm.
“Since Mdmx is unable to shuttle from the nucleus to the cytoplasm (Jackson and Berberich, 2000)”
From Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms (2001) · cites this paper as Jackson and Berberich, 2000
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“Similar to MDM2, MDMX binds to p53 transcriptional activation domain and inhibits the transcriptional activity of p53 [35].”
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“Mdm4, on the other hand, does not appear to ubiquitinate p53 ( 17 ).”
BackgroundStad, R., Ramos, Y. F. M., Little, N., Grivell, S., Attema, J., van der Eb, A. J., & Jochemsen, A. G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003496200 · Cited by 145 · see citing works
Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2
de Graaf, P., Little, N. A., Ramos, Y. F. M., Meulmeester, E., Letteboer, S. J. F., & Jochemsen, A. G. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213034200 · Cited by 143 · see citing works
Regulation of p53: a collaboration between Mdm2 and MdmX
Pei, D., Zhang, Y., & Zheng, J. (2012) · Oncotarget · doi:10.18632/oncotarget.443 · Cited by 140 · see citing works
“Other studies have shown that MdmX is able to inhibit Mdm2-mediated p53 degradation by competing with Mdm2 for p53 binding resulting in the accumulation of p53 [20-22].”
BackgroundFang, S., Lorick, K. L., Jensen, J. P., & Weissman, A. M. (2002) · Seminars in Cancer Biology · doi:10.1016/s1044-579x(02)00095-0 · Cited by 137 · see citing works
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 · see citing works
“Mdm2-Mdm4 heterodimerization is perceived to stabilize Mdm2 by inhibiting its autoubiquitination and in turn promoting p53 ubiquitination (16, 24, 25).”
BackgroundOkamoto, 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 · see citing works
“It was reported that Mdmx inhibits transcriptional activation by p53 ( 14 , 46).”
BackgroundInfluentialMDM2 and MDMX: Alone and together in regulation of p53.
Shadfan, M., Lopez-Pajares, V., & Yuan, Z.-M. (2012) · PubMed · Cited by 125 · see citing works
Sengupta, S., & Wasylyk, B. (2001) · Genes & Development · doi:10.1101/gad.202201 · Cited by 126 · see citing works
“MdmX, a Mdm2 homolog that lacks a NES, stabilizes p53 by retention in the nucleus (Jackson and Berberich 2000; Stad et al. 2000).”
BackgroundRegulation 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 · see citing works
“conservation of the p53-binding domain, MDMX was found to bind the N-terminus of p53 and inhibit its transactivation (Jackson and Berberich 2000; Stad, Little et al. 2001).”
BackgroundInfluentialRegulation and function of the p53-related proteins: same family, different rules
Lohrum, M. A. E., & Vousden, K. H. (2000) · Trends in Cell Biology · doi:10.1016/s0962-8924(00)01736-0 · Cited by 122 · see citing works
Potential 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 · see citing works
Novel targeted therapeutics: inhibitors of MDM2, ALK and PARP
Yuan, Y., Liao, Y.-M., Hsueh, C.-T., & Mirshahidi, H. (2011) · Journal of Hematology & Oncology · doi:10.1186/1756-8722-4-16 · Cited by 118 · see citing works
“MDM4 (also known as MDMX), an MDM2 homolog, binds p53 and inhibits p53 activity without causing degradation of p53 degradation [31].”
MdmX Protein Is Essential for Mdm2 Protein-mediated p53 Polyubiquitination
Wang, X., Wang, J., & Jiang, X. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.213868 · Cited by 115 · see citing works
p53—A Natural Cancer Killer: Structural Insights and Therapeutic Concepts
Römer, L., Klein, C., Dehner, A., Kessler, H., & Büchner, J. (2006) · Angewandte Chemie International Edition · doi:10.1002/anie.200600611 · Cited by 115 · see citing works
14‐3‐3γ binds to MDMX that is phosphorylated by UV‐activated Chk1, resulting in p53 activation
Jin, Y., Dai, M., Lu, S. Z., Xu, Y., Luo, Z., Zhao, Y., & Lu, H. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601010 · Cited by 113 · see citing works
“But, unlike MDM2, MDMX tran- script is not regulated by p53 (Shvarts et al, 1996) and MDMX by itself is unable to ubiquitinate p53 (Jackson and Berberich, 2000; Stad et al, 2000).”
BackgroundCritical Role for a Central Part of Mdm2 in the Ubiquitylation of p53
Meulmeester, E., Frenk, R., Stad, R. K., de Graaf, P., Marine, J., Vousden, K. H., & Jochemsen, A. G. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.14.4929-4938.2003 · Cited by 113 · see citing works
“In spite of its inability to ubiquitylate or degrade p53 in vivo, Mdmx can inhibit transcription activation by p53 (15, 20, 30).”
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
FAM83B mediates EGFR- and RAS-driven oncogenic transformation
Cipriano, R., Graham, J., Miskimen, K. L. S., Bryson, B. L., Bruntz, R. C., Scott, S. A., Brown, H. A., Stark, G. R., & Jackson, M. W. (2012) · Journal of Clinical Investigation · doi:10.1172/jci60517 · Cited by 111 · see citing works
“ments were carried out as previously described (26), with exceptions as”
Self-citationIdentification 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
Zhu, Y. X., Tiedemann, R. E., Shi, C.-X., Yin, H., Schmidt, J. E., Bruins, L. A., Keats, J. J., Braggio, E., Sereduk, C., Mousses, S., et al. (2011) · Blood · doi:10.1182/blood-2010-08-304022 · Cited by 106 · see citing works
MdmX Is a RING Finger Ubiquitin Ligase Capable of Synergistically Enhancing Mdm2 Ubiquitination
Badciong, J. C., & Haas, A. L. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208593200 · Cited by 106 · see citing works
Regulation of p53 - insights into a complex process
Boehme, K. A., & Blattner, C. (2009) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409230903401507 · Cited by 106 · see citing works
Melatonin down‐regulates MDM 2 gene expression and enhances p53 acetylation in MCF ‐7 cells
Proietti, S., Cucina, A., Dobrowolny, G., D’Anselmi, F., Dinicola, S., Masiello, M. G., Pasqualato, A., Palombo, A., Morini, V., Reiter, R. J., et al. (2014) · Journal of Pineal Research · doi:10.1111/jpi.12150 · Cited by 96 · see citing works
“Additionally, whereas some studies reported MDMX cooperates with MDM2 in inhibiting p53 activity [34], other reports documented a MDMX-based inhibition on MDM2-based p53 degradation [35, 36].”
BackgroundMDM2 and MDMX can interact differently with ARF and members of the p53 family
Wang, X., Arooz, T., Siu, W. Y., Chiu, C. H. S., Lau, A., Yamashita, K., & Poon, R. Y. C. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)02124-x · Cited by 94 · see citing works
Bartel, F., Schulz, J., Böhnke, A., Blümke, K., Kappler, M., Bache, M., Schmidt, H., Würl, P., Taubert, H. W., & Hauptmann, S. (2005) · International Journal of Cancer · doi:10.1002/ijc.21206 · Cited by 93 · see citing works
“However, it fails to induce the nuclear export of p53 or its proteosomal degradation.(3) Although HDMX bears resemblance to MDM2, it has some distinct features.”
BackgroundMdm2 and Mdm4 Loss Regulates Distinct p53 Activities
Barboza, J., Iwakuma, T., Terzian, T., El‐Naggar, A. K., & Lozano, G. (2008) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-07-2079 · Cited by 89 · see citing works
“Although various studies have shown that MDM4 overexpression stabilizes p53 in tumor-derived cell lines (16-19, 40), we show that endogenous levels of Mdm4 are sufficient to stabilize p53A135V from Mdm2-mediated degradation because loss of Mdm4 resulted in reduced p53A135V protein half-life.”
BackgroundStommel, J. M., & Wahl, G. M. (2005) · Cell Cycle · doi:10.4161/cc.4.3.1522 · Cited by 87 · see citing works
Migliorini, D., Danovi, D., Colombo, E., Carbone, R., Pelicci, P. G., & Marine, J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m108795200 · Cited by 86 · see citing works
High levels of the p53 inhibitor MDM4 in head and neck squamous carcinomas
Valentin-Vega, Y. A., Barboza, J., Chau, G. P., El‐Naggar, A. K., & Lozano, G. (2007) · Human Pathology · doi:10.1016/j.humpath.2007.03.005 · Cited by 85 · see citing works
The RING domain of Mdm2 can inhibit cell proliferation.
Dang, J., Kuo, M.-L., Eischen, C. M., Stepanova, L., Sherr, C. J., & Roussel, M. F. (2002) · PubMed · Cited by 86 · see citing works
Versatile functions of p53 protein in multicellular organisms
Chumakov, P. M. (2007) · Biochemistry (Moscow) · doi:10.1134/s0006297907130019 · Cited by 84 · see citing works
MdmX binding to ARF affects Mdm2 protein stability and p53 transactivation
Jackson, M. W., Lindström, M. S., & Berberich, S. J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010685200 · Cited by 74 · see citing works
Self-citationDNA Damage Induces MDMX Nuclear Translocation by p53-Dependent and -Independent Mechanisms
Li, C., Chen, L., & Chen, J. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.21.7562-7571.2002 · Cited by 82 · see citing works
“MDMX has been shown to inhibit p53 transcription activity, stabilize MDM2, and inhibit p53 degradation by MDM2 (6, 15, 16).”
BackgroundPhosphorylation of MDMX Mediated by Akt Leads to Stabilization and Induces 14-3-3 Binding
Lopez-Pajares, V., Kim, M. M., & Yuan, Z.-M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m710030200 · Cited by 79 · see citing works
Mancini, 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
Jin, Y., Zeng, S. X., Sun, X., Lee, H., Blattner, C., Xiao, Z. J., & Lu, H. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01198-07 · Cited by 79 · see citing works
“It would be interesting to determine whether ubiquitylation played a role in MDMX-mediated p21 degradation, although MDMX has not yet been shown to possess an intrinsic E3 ubiquitin ligase activity ( 18 , 47).”
BackgroundMethodInfluentialMDM2 induces hyperplasia and premalignant lesions when expressed in the basal layer of the epidermis
Ganguli, G., Abecassis, J., & Wasylyk, B. (2000) · The EMBO Journal · doi:10.1093/emboj/19.19.5135 · Cited by 77 · see citing works
Regulation of p63 Function by Mdm2 and MdmX
Kadakia, M., Slader, C., & Berberich, S. J. (2001) · DNA and Cell Biology · doi:10.1089/10445490152122433 · Cited by 73 · see citing works
“Heterokaryon assays were performed as previously described (Jackson and Berberich, 2000).”
InfluentialSelf-citationGalluzzi, L., Morselli, E., Kepp, O., Vitale, I., Pinti, M., & Kroemer, G. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3504 · Cited by 74 · see citing works
“Intriguingly, although MDMX shares with MDM2 the ability to bind p53 and also proficiently represses p53 transactivation, MDMX can stimulate neither the nuclear export of p53 nor its degradation, and actually appears to protect p53 from MDM2-mediated suppression (93).”
Chávez‐Reyes, A., Parant, J. M., Amelse, L. L., Luna, R. M. D. O., Korsmeyer, S. J., & Lozano, G. (2003) · PubMed · Cited by 73 · see citing works
Structural 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
Distinct p53, p53:LANA, and LANA Complexes in Kaposi's Sarcoma-Associated Herpesvirus Lymphomas
Chen, W., Hilton, I. B., Staudt, M. R., Burd, C. E., & Dittmer, D. P. (2010) · Journal of Virology · doi:10.1128/jvi.01321-09 · Cited by 72 · see citing works
“It is thought to inhibit hdm2 function by heterodimer formation (37, 86, 91).”
Singh, R. K., Iyappan, S., & Scheffner, M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610879200 · Cited by 69 · see citing works
The 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
“Specifically, their engagement stabilizes MDM2 by inhibiting its auto-ubiquitination and in turn potentiating its E3 ligase activity toward p53 (Jackson and Berberich, 2000; Gu et al., 2002; Okamoto et al., 2009).”
BackgroundRegulation 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
“However, unlike Mdm2, MdmX does not possess the ability to directly ubiquitinate p53 (112,113).”
BackgroundThe p53 response: Emerging levels of co-factor complexity
Coutts, A. S., & La Thangue, N. B. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.03.150 · Cited by 72 · see citing works
Cell cycle regulatory E3 ubiquitin ligases as anticancer targets
Pray, T. R., Parlati, F., Huang, J., Wong, B. R., Payan, D. G., Bennett, M. K., Issakani, S. D., Molineaux, S. M., & Demo, S. D. (2002) · Drug Resistance Updates · doi:10.1016/s1368-7646(02)00121-8 · Cited by 67 · see citing works
“Another mechanism of MDM2 regulation is provided by MDMx, an MDM2 homologue that protects both p53 and MDM2 from degradation through the formation of MDMx/MDM2 oligomers (Sharp et al., 1999; Jackson and Berberich, 2000).”
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
“MdmX, anMdm2 homolog, is similarly capable of binding at its N terminus to the p53 transactivation domain to control p53 activity; however, MdmX does not harbor intrinsic E3 ubiquitin ligase activity (Jackson and Berberich, 2000; Poyurovsky et al., 2007; Shvarts et al., 1996).”
The Many Faces of MDM2 Binding Partners
Riley, M. F., & Lozano, G. (2012) · Genes & Cancer · doi:10.1177/1947601912455322 · Cited by 64 · see citing works
Hdmx and Mdm2 can repress transcription activation by p53 but not by p63
Little, N. A., & Jochemsen, A. G. (2001) · Oncogene · doi:10.1038/sj.onc.1204615 · Cited by 64 · see citing works
“…AG Jochemsen, E-mail: a.g.jochemsen@lumc.nl Received 12 March 2001; revised 24 April 2001; accepted 9 May 2001 homologue Hdmx cannot target p53 for degradation, and in fact are able to inhibit the degradation of p53 by Mdm2 (Jackson and Berberich, 2000; Sharp et al., 1999; Stad et al., 2000).”
BackgroundMDMX inhibits the p300/CBP-mediated acetylation of p53
Sabbatini, P., & McCormick, F. (2002) · DNA and Cell Biology · doi:10.1089/104454902320219077 · Cited by 62 · see citing works
“As indicated in Figure 1B, the acetylation of p53 by p300 in DKO cells was dramatically inhibited by the coexpression of MDMX. MDMX did not increase total p53 protein levels in DKO cells, as reported previously (Jackson and Berberich, 2000).”
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
“Although MDMX lacks the intrinsic E3 ligase activity of MDM2 [13], current models suggest that it functions as a major p53 transcriptional antagonist independent of MDM2 [14].”
Wang, C., Wang, J., Liu, Z., Ma, X., Wang, X., Jin, H. D., Zhang, X.-P., Fu, D., Hou, L., & Lu, Y. (2014) · Carcinogenesis · doi:10.1093/carcin/bgu015 · Cited by 62 · see citing works
“This is consistent with the observation that USP2a binding to MDM4 protects MDM4 from MDM2-initiated proteasomal degradation, thereby allowing for MDM4–p53Ser46P complex formation and the activation of p53-dependent apoptosis (8,24).”
BackgroundOsorio, E. M. V., Hoogeman, M. S., Bondar, L., Levendag, P. C., & Heijmen, B. J. M. (2009) · Medical Physics · doi:10.1118/1.3134242 · Cited by 62 · see citing works
p53 in the CNS: Perspectives on Development, Stem Cells, and Cancer
Mendrysa, S. M., Ghassemifar, S., & Malek, R. A. (2011) · Genes & Cancer · doi:10.1177/1947601911409736 · Cited by 62 · see citing works
Interplay between MDM2, MDMX, Pirh2 and COP1: the negative regulators of p53
Wang, L., He, G., Zhang, P., Wang, X., Jiang, M. H., & Yu, L. (2010) · Molecular Biology Reports · doi:10.1007/s11033-010-0099-x · Cited by 60 · see citing works
“Moreover, MDMX stabilizes MDM2 or p53 through different mechanisms [13–15].”
Falcicchio, M., Ward, J. A., Macip, S., & Doveston, R. G. (2020) · Cell Death Discovery · doi:10.1038/s41420-020-00362-3 · Cited by 58 · see citing works
- Authors
- Jackson, M. W., & Berberich, S. J.
- Affiliations
- Wright State University (US)
- ORCID
- Jackson, Mark W.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2000-02-01
- Volume
- 20
- Issue
- 3
- Pages
- 1001-1007
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC85217
- OpenAlex
- W2125124408
- Cited by
- 211
- References
- 35
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 3 · 2018: 1 · 2017: 4 · 2016: 4 · 2014: 11 · 2013: 5 · 2012: 14
- FWCI
- 7.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA-64430, R01CA064430, R29CA064430)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- MDMX, p53, MDM2, p53 degradation, p53 stabilization, p53 transactivation, RING domain, nuclear retention, tumor suppressor proteins, cell cycle arrest, apoptosis
- MeSH terms
- Amino Acid Sequence, Animals, Carcinoma, Non-Small-Cell Lung, Cell Line, Cell Nucleus, HeLa Cells, Humans, Lung Neoplasms, Molecular Sequence Data, Nuclear Proteins, Proto-Oncogene Proteins, Recombinant Proteins, Transfection, Tumor Cells, Cultured, Transcriptional Activation, Genes, p53, Tumor Suppressor Protein p53, Sequence Alignment, 3T3 Cells, Sequence Deletion, Sequence Homology, Amino Acid, Mice, Knockout, Mice, Proto-Oncogene Proteins c-mdm2
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