HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53
Open accessAbstract
The RING finger proteins HdmX and Hdm2 share significant structural and functional similarity. Hdm2 is a member of the RING finger family of ubiquitin-protein ligases E3 and targets the tumor suppressor protein p53 for degradation. Although HdmX also binds to p53, HdmX does not induce p53 degradation. Moreover, HdmX has been reported to interfere with p53 degradation in overexpression experiments. To obtain insight into the mechanism by which HdmX interferes with p53 degradation, we studied the effect of HdmX on the E3 activity of Hdm2 in vitro. Surprisingly, this revealed that HdmX stimulates Hdm2-mediated ubiquitination of p53 and that HdmX facilitates ubiquitination of Hdm2 and vice versa. In addition, down-regulation of HdmX expression within cells results in the accumulation of both p53 and Hdm2. Because HdmX alone does not have appreciable E3 activity, these data indicate that HdmX acts as a stimulator, rather than as an inhibitor, of the E3 activity of Hdm2 and that, at least under certain conditions, HdmX is actively involved in the degradation of both p53 and Hdm2.
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
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?
Mdm4 stimulates Mdm2-mediated polyubiquitination of p53.
“Mdm4 further contributes to Mdm2 stability by disrupting self-ubiquitination of the latter (Stad et al., 2001), while also stimulating Mdm2-mediated polyubiquitination of p53 (Linares et al., 2003).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Linares et al., 2003
Mdmx shows little intrinsic ubiquitin ligase activity towards p53.
“Despite conservation of the C2H2C4 RING domain, Mdmx shows little intrinsic ubiquitin ligase activity towards p53 [10].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [10]
The Mdm2-Mdmx hetero-oligomer is a more effective ligase for p53 in vitro than Mdm2 alone.
“Together with the observation that the Mdm2–Mdmx hetero-oligomer is a more effective ligase for p53 in vitro than Mdm2 alone [10], this has led to a model in which the Mdm2–Mdmx ligase complex is more efficient in targeting p53 for ubiquitylation and degradation.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [10]
MDMX does not homo-oligomerize and has no intrinsic ubiquitin ligase function, but can increase or decrease MDM2 ubiquitin ligase activity depending on MDMX abundance.
“By contrast, MDMX does not homo-oligomerize and has no intrinsic ubiquitin ligase function, although it can increase or decrease MDM2 ubiquitin ligase activity depending on MDMX abundance16.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [16]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells
Elbashir, S. M., Harborth, J., Lendeckel, W., Yalcin, A., Weber, K., & Tuschl, T. (2001) · Nature · doi:10.1038/35078107 · Cited by 9,456 · see citing works
Mdm2 promotes the rapid degradation of p53
Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997) · Nature · doi:10.1038/387296a0 · Cited by 4,506 · see citing works
The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction
Glickman, M. H., & Ciechanover, A. J. (2002) · Physiological Reviews · doi:10.1152/physrev.00027.2001 · Cited by 4,216 · see citing works
Self-citationMechanisms Underlying Ubiquitination
Pickart, C. M. (2001) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.70.1.503 · Cited by 3,731 · see citing works
Regulation of p53 stability by Mdm2
Kubbutat, M. H. G., Jones, S. N., & Vousden, K. H. (1997) · Nature · doi:10.1038/387299a0 · Cited by 3,312 · see citing works
Live or let die: the cell's response to p53
Vousden, K. H., & Lü, X. (2002) · Nature reviews. Cancer · doi:10.1038/nrc864 · Cited by 3,177 · see citing works
TAK1 is a ubiquitin-dependent kinase of MKK and IKK
Wang, C., Deng, L., Hong, M., Akkaraju, G. R., Inoue, J.-I., & Chen, Z. J. (2001) · Nature · doi:10.1038/35085597 · Cited by 2,125 · see citing works
Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53
Honda, R., Tanaka, H., & Yasuda, H. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)01480-4 · Cited by 1,951 · see citing works
Recognition of the polyubiquitin proteolytic signal
Thrower, J. S., Hoffman, L. M., Rechsteiner, M., & Pickart, C. M. (2000) · The EMBO Journal · doi:10.1093/emboj/19.1.94 · Cited by 1,718 · see citing works
Themes and variations on ubiquitylation
Weissman, A. M. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35056563 · Cited by 1,472 · see citing works
Rescue 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 · see citing works
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 · see citing works
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 · see citing works
Hashizume, R., Fukuda, M., Maeda, I., Nishikawa, H., Oyake, D., Yabuki, Y., Ogata, H., & Ohta, T. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.c000881200 · Cited by 634 · see citing works
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 · see citing works
Structure of a BRCA1-BARD1 heterodimeric RING-RING complex.
Brzović, P. S., Rajagopal, P., Hoyt, D. W., King, M., & Klevit, R. E. (2001) · Nature Structural Biology · doi:10.1038/nsb1001-833 · Cited by 494 · see citing works
Pickart, C. M. (2000) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(00)01681-9 · Cited by 454 · see citing works
Cell Cycle–Regulated Modification of the Ribosome by a Variant Multiubiquitin Chain
Spence, J. L., Gali, R. R., Dittmar, G. A. G., Sherman, F., Karin, M., & Finley, D. J. (2000) · Cell · doi:10.1016/s0092-8674(00)00011-8 · Cited by 378 · see citing works
Honda, R., & Yasuda, H. (2000) · Oncogene · doi:10.1038/sj.onc.1203464 · Cited by 376 · see citing works
MDM2 interacts with MDMX through their RING finger domains
Tanimura, S., Ohtsuka, S., Mitsui, K., Shirouzu, K., Yoshimura, A., & Ohtsubo, M. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00254-9 · Cited by 324 · see citing works
The p53 and Mdm2 families in cancer
Michael, D. (2002) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(01)00264-7 · Cited by 288 · see citing works
Stabilization of the MDM2 Oncoprotein by Interaction with the Structurally Related MDMX Protein
Sharp, D. A., Kratowicz, S. A., Sank, M. J., & George, D. L. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.53.38189 · Cited by 286 · see citing works
Mutual Dependence of MDM2 and MDMX in Their Functional Inactivation of p53
Gu, J., Kawai, H., Nie, L., Kitao, H., Wiederschain, D., Jochemsen, A. G., Parant, J. M., Lozano, G., & Yuan, Z.-M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200150200 · Cited by 265 · see citing works
The BRCA1/BARD1 heterodimer, a tumor suppressor complex with ubiquitin E3 ligase activity
Baer, R. J. (2002) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(01)00269-6 · Cited by 261 · see citing works
Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms
Stad, R., Little, N. A., Xirodimas, D. P., Frenk, R., van der Eb, A. J., Lane, D. P., Saville, M. K., & Jochemsen, A. G. (2001) · The EMBO Reports · doi:10.1093/embo-reports/kve227 · Cited by 234 · see citing works
p53-Mdm2--the affair that never ends
Alarcon-Vargas, D. (2002) · Carcinogenesis · doi:10.1093/carcin/23.4.541 · Cited by 231 · see citing works
Cell type‐specific inhibition of p53‐mediated apoptosis by mdm2.
Haupt, Y., Barak, Y., & Oren, M. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00504.x · Cited by 228 · see citing works
Autoubiquitination of the BRCA1·BARD1 RING Ubiquitin Ligase
Chen, A., Kleiman, F. E., Manley, J. L., Ouchi, T., & Pan, Z. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201252200 · Cited by 218 · see citing works
Hengstermann, A., Linares, L. K., Ciechanover, A. J., Whitaker, N. J., & Scheffner, M. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.3.1218 · Cited by 212 · see citing works
Self-citationMdmX Protects p53 from Mdm2-Mediated Degradation
Jackson, M. W., & Berberich, S. J. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.3.1001-1007.2000 · Cited by 211 · see citing works
Enhancement of BRCA1 E3 Ubiquitin Ligase Activity through Direct Interaction with the BARD1 Protein
Xia, Y., Pao, G. M., Chen, H.-W., Verma, I. M., & Hunter, T. R. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m204591200 · Cited by 195 · see citing works
Lai, Z., Ferry, K. V., Diamond, M. A., Wee, K. E., Kim, Y. B., Ma, J., Yang, T., Benfield, P. A., Copeland, R. A., & Auger, K. R. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m011517200 · Cited by 168 · see citing works
Nuber, U. A., Schwarz, S. E., Kaiser, P., Schneider, R., & Scheffner, M. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.5.2795 · Cited by 150 · see citing works
Self-citationAberrant expression of HDMX proteins in tumor cells correlates with wild-type p53.
Ramos, Y. F., Stad, R. K., Attema, J., Peltenburg, L. T. C., van der Eb, A. J., & Jochemsen, A. G. (2001) · PubMed · Cited by 149 · see citing works
Stad, 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
Activation of the Cell Death Program by Nitric Oxide Involves Inhibition of the Proteasome
Glockzin, S., von Knethen, A., Scheffner, M., & Brüne, B. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.28.19581 · Cited by 123 · see citing works
Self-citationMdmX 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
Hengstermann, A., Whitaker, N. J., Zimmer, D., Zentgraf, H., & Scheffner, M. (1998) · Oncogene · doi:10.1038/sj.onc.1202282 · Cited by 32 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Hengstermann, A., Linares, L. K., Ciechanover, A., Whitaker, N. J. & Scheffner, M. (2001) Proc. Natl. Acad. Sci. USA 98, 1218-1223.
Cited by
Sorted by citations
RING Domain E3 Ubiquitin Ligases
Deshaies, R. J., & Joazeiro, C. A. P. (2009) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.78.101807.093809 · Cited by 2,679 · see citing works
Malignant astrocytic glioma: genetics, biology, and paths to treatment
Furnari, F. B., Fenton, T., Bachoo, R. M., Mukasa, A., Stommel, J. M., Stegh, A., Hahn, W. C., Ligon, K. L., Louis, D. N., Brennan, C., et al. (2007) · Genes & Development · doi:10.1101/gad.1596707 · Cited by 2,316 · see citing works
The first 30 years of p53: growing ever more complex.
Levine, A. J., & Oren, M. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2723 · Cited by 1,967 · see citing works
Kruse, J.-P., & Gu, W. (2009) · Cell · doi:10.1016/j.cell.2009.04.050 · Cited by 1,610 · see citing works
Regulating the p53 pathway: in vitro hypotheses, in vivo veritas
Toledo, F., & Wahl, G. M. (2006) · Nature reviews. Cancer · doi:10.1038/nrc2012 · Cited by 1,286 · see citing works
MDM2, MDMX and p53 in oncogenesis and cancer therapy
Wade, M., Li, Y.-C., & Wahl, G. M. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3430 · Cited by 1,279 · see citing works
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 · see citing works
Structural insights into the catalysis and regulation of E3 ubiquitin ligases
Buetow, L., & Huang, D. T. C. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.91 · Cited by 688 · see citing works
A dynamic role of HAUSP in the p53-Mdm2 pathway
Li, M., Brooks, C. L., Kon, N., & Gu, W. (2004) · Molecular Cell · doi:10.1016/s1097-2765(04)00157-1 · Cited by 679 · see citing works
IAPs, RINGs and ubiquitylation
Vaux, D. L., & Silke, J. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1621 · Cited by 611 · see citing works
Signaling to p53: ribosomal proteins find their way
Zhang, Y., & Lu, H. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.09.024 · Cited by 591 · see citing works
Ubiquitin ligases in oncogenic transformation and cancer therapy
Senft, D., Qi, J., & Ronai, Z. A. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2017.105 · Cited by 490 · see citing works
The 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 · see citing works
Lipkowitz, S., & Weissman, A. M. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3120 · Cited by 415 · see citing works
Adhikary, S., Marinoni, F., Hock, A., Hulleman, E., Popov, N., Beier, R., Bernard, S., Quarto, M., Capra, M. C., Goettig, S., et al. (2005) · Cell · doi:10.1016/j.cell.2005.08.016 · Cited by 403 · see citing works
Self-citationThe role of mutant p53 in human cancer
Goh, A. M., Coffill, C. R., & Lane, D. P. (2010) · The Journal of Pathology · doi:10.1002/path.2784 · Cited by 398 · see citing works
Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4
Marine, J.-C., Francoz, S., Maetens, M., Wahl, G., Toledo, F., & Lozano, G. (2006) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401912 · Cited by 352 · see citing works
The predator becomes the prey: regulating the ubiquitin system by ubiquitylation and degradation
Weissman, A. M., Shabek, N., & Ciechanover, A. J. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3173 · Cited by 318 · see citing works
Self-citationAkt: A Double-Edged Sword in Cell Proliferation and Genome Stability
Xu, N., Lao, Y., Zhang, Y., & Gillespie, D. A. (2012) · Journal of Oncology · doi:10.1155/2012/951724 · Cited by 308 · see citing works
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 · see citing works
Linke, K., Mace, P. D., Smith, C. A., Vaux, D. L., Silke, J., & Day, C. L. (2008) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4402309 · Cited by 288 · see citing works
Pathological Unfoldomics of Uncontrolled Chaos: Intrinsically Disordered Proteins and Human Diseases
Uversky, V. N., Davé, V., Iakoucheva, L. M., Malaney, P., Metallo, S. J., Pathak, R. R., & Joerger, A. C. (2014) · Chemical Reviews · doi:10.1021/cr400713r · Cited by 288 · see citing works
The Chaperone-associated Ubiquitin Ligase CHIP Is Able to Target p53 for Proteasomal Degradation
Esser, C., Scheffner, M., & Höhfeld, J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501574200 · Cited by 261 · see citing works
Self-citationMdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells <i>in vivo</i>
Francoz, S., Froment, P., Bogaerts, S., De Clercq, S., Maetens, M., Doumont, G., Bellefroid, E., & Marine, J.-C. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508476103 · Cited by 260 · see citing works
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 · see citing works
Tisato, V., Voltan, R., Gonelli, A., Secchiero, P., & Zauli, G. (2017) · Journal of Hematology & Oncology · doi:10.1186/s13045-017-0500-5 · Cited by 255 · see citing works
Faesen, A. C., Dirac, A. M. G., Shanmugham, A., Ovaa, H., Anastassis Perrakis, A., & Sixma, T. K. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.06.034 · Cited by 251 · see citing works
Mechanism of p53 stabilization by ATM after DNA damage
Cheng, Q., & Chen, J. (2010) · Cell Cycle · doi:10.4161/cc.9.3.10556 · Cited by 248 · see citing works
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 · see citing works
p53 as a target for the treatment of cancer
Duffy, M. J., Synnott, N. C., McGowan, P. M., Crown, J. P., O’Connor, D. P., & Gallagher, W. M. (2014) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2014.10.004 · Cited by 230 · see citing works
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 229 · see citing works
Marine, J.-C. W., Dyer, M. A., & Jochemsen, A. G. (2007) · Journal of Cell Science · doi:10.1242/jcs.03362 · Cited by 228 · see citing works
Molecular and Genomic Alterations in Glioblastoma Multiforme
Crespo, I., Vital, A. L., Gonzalez-Tablas, M., Patino, M. D. C., Otero, A., Lopes, M. C., de Oliveira, C., Domingues, P., Orfao, A., & Tabernero, M. D. (2015) · The American Journal of Pathology · doi:10.1016/j.ajpath.2015.02.023 · Cited by 225 · see citing works
p53-family proteins and their regulators: hubs and spokes in tumor suppression
Collavin, L., Lunardi, A., & Sal, G. D. (2010) · Cell Death and Differentiation · doi:10.1038/cdd.2010.35 · Cited by 219 · see citing works
Efficient 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 214 · see citing works
Dayal, S., Sparks, A., Jacob, J., Allende-Vega, N., Lane, D. P., & Saville, M. K. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m805871200 · Cited by 200 · see citing works
Toledo, F., Krummel, K. A., Lee, C. J., Liu, C.-W., Rodewald, L.-W., Tang, M., & Wahl, G. M. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.03.014 · Cited by 199 · see citing works
The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo
Huang, L., Yan, Z., Liao, X., Li, Y., Yang, J., Wang, Z.-G., Zuo, Y., Kawai, H., Shadfan, M., Ganapathy, S., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102309108 · Cited by 193 · see citing works
Mdmx 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 186 · see citing works
Protein partners of deubiquitinating enzymes
Ventii, K., & Wilkinson, K. D. (2008) · Biochemical Journal · doi:10.1042/bj20080798 · Cited by 185 · see citing works
Intrinsic ubiquitination activity of PCAF controls the stability of the oncoprotein Hdm2
Linares, L. K., Kiernan, R. E., Triboulet, R., Chable-Bessia, C., Latreille, D., Cuvier, O., Lacroix, M., Cam, L. L., Coux, O., & Benkirane, M. (2007) · Nature Cell Biology · doi:10.1038/ncb1545 · Cited by 180 · see citing works
Self-citationRegulation of androgen receptor and histone deacetylase 1 by Mdm2-mediated ubiquitylation
Gaughan, L. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki141 · Cited by 174 · see citing works
The regulation of MDM2 oncogene and its impact on human cancers
Zhao, Y., Yu, H., & Hu, W. (2014) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmt147 · Cited by 173 · see citing works
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 · see citing works
Targeting 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 · see citing works
ATM-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 166 · see citing works
Limiting the power of p53 through the ubiquitin proteasome pathwayPreprint
Pant, V., & Lozano, G. (2014) · Genes & Development · doi:10.1101/gad.247452.114 · Cited by 165 · see citing works
Saleh, M. N., Patel, M. R., Bauer, T. M., Goel, S., Falchook, G. S., Shapiro, G. I., Chung, K. Y., Infante, J. R., Conry, R. M., Rabinowits, G., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-0715 · Cited by 159 · see citing works
RING 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 156 · see citing works
Current strategies to target p53 in cancer
Chen, F., Wang, W., & El‐Deiry, W. S. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.04.031 · Cited by 158 · see citing works
The Rsp5 ubiquitin ligase is coupled to and antagonized by the Ubp2 deubiquitinating enzyme
Kee, Y., Lyon, N., & Huibregtse, J. M. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600710 · Cited by 158 · see citing works
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 · see citing works
Systematic 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 146 · see citing works
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 · 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
Song, M. S., Song, S. J., Kim, S. Y., Oh, H. J., & Lim, D. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.115 · Cited by 134 · see citing works
Glycogen synthase kinase 3-dependent phosphorylation of Mdm2 regulates p53 abundance
Kulikov, R., Boehme, K. A., & Blattner, C. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.16.7170-7180.2005 · Cited by 132 · see citing works
The roles and regulation of MDM2 and MDMX: it is not just about p53Preprint
Klein, A. M., de Queiroz, R. M., Venkatesh, D., & Prives, C. L. (2021) · Genes & Development · doi:10.1101/gad.347872.120 · Cited by 132 · see citing works
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 · see citing works
MDM2 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
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 · 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
Quantitative 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
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
USP7 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
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
Mdm2 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
Novel Dyskerin-Mediated Mechanism of p53 Inactivation through Defective mRNA Translation
Montanaro, L., Calienni, M., Bertoni, S., Rocchi, L., Sansone, P., Storci, G., Santini, D., Ceccarelli, C., Taffurelli, M., Carnicelli, D., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-4024 · Cited by 110 · see citing works
Structure of the Fanconi anaemia monoubiquitin ligase complex
Shakeel, S., Rajendra, E., Alcón, P., O’Reilly, F. J., Chorev, D. S., Maslen, S., Degliesposti, G., Russo, C. J., He, S., Hill, C. H., et al. (2019) · Nature · doi:10.1038/s41586-019-1703-4 · Cited by 107 · see citing works
Identification 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
Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives
Fang, Y., Liao, G., & Yu, B. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.01.003 · Cited by 106 · see citing works
Targeting prostate cancer based on signal transduction and cell cycle pathways
Lee, J. T., Lehmann, B. D., Terrian, D. M., Chappell, W. H., Stivala, F., Libra, M., Martelli, A. M., Steelman, L. S., & McCubrey, J. A. (2008) · Cell Cycle · doi:10.4161/cc.7.12.6166 · Cited by 104 · see citing works
Lim, S. D., Yim, W. C., Moon, J.-C., Kim, D. S., Lee, B., & Jang, C. S. (2009) · Plant Molecular Biology · doi:10.1007/s11103-009-9576-9 · Cited by 104 · see citing works
Madden, M. M., Muppidi, A., Li, Z., Li, X., Chen, J., & Lin, Q. (2011) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2011.01.004 · Cited by 104 · see citing works
The ubiquitin codes in cellular stress responses
Sheng, X., Xia, Z., Yang, H., & Hu, R. (2023) · Protein & Cell · doi:10.1093/procel/pwad045 · Cited by 113 · see citing works
Discovery 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
Ribosomal proteins as unrevealed caretakers for cellular stress and genomic instability
Kim, T. H., Leslie, P. L., & Zhang, Y. (2014) · Oncotarget · doi:10.18632/oncotarget.1784 · Cited by 100 · see citing works
Estrada‐Ortiz, N., Neochoritis, C. G., & Dömling, A. S. S. (2015) · ChemMedChem · doi:10.1002/cmdc.201500487 · Cited by 100 · see citing works
Fåhræus, R., & Olivares‐Illana, V. (2013) · Oncogene · doi:10.1038/onc.2013.410 · Cited by 97 · 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
Phosphatases in the cellular response to DNA damage
Freeman, A. K., & Monteiro, Á. N. A. (2010) · Cell Communication and Signaling · doi:10.1186/1478-811x-8-27 · Cited by 93 · see citing works
Aggregation and Prion-Like Properties of Misfolded Tumor Suppressors: Is Cancer a Prion Disease?Preprint
da Costa, D. C. F., de Oliveira, G. A. P., Cino, E. A., Soares, I. N., Rangel, L. P., & Silva, J. L. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a023614 · Cited by 89 · see citing works
Mdm2 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
Stommel, J. M., & Wahl, G. M. (2005) · Cell Cycle · doi:10.4161/cc.4.3.1522 · Cited by 87 · see citing works
Small-molecule inhibitors of MDM2 as new anticancer therapeutics
Dickens, M. P., Fitzgerald, R. P., & Fischer, P. M. (2009) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2009.10.003 · Cited by 86 · see citing works
miR-661 downregulates both Mdm2 and Mdm4 to activate p53
Hoffman, Y., Bublik, D. R., Pilpel, Y., & Oren, M. (2013) · Cell Death and Differentiation · doi:10.1038/cdd.2013.146 · Cited by 86 · see citing works
Glioma oncoprotein Bcl2L12 inhibits the p53 tumor suppressorPreprint
Stegh, A. H., Brennan, C., Mahoney, J. E., Forloney, K. L., Jenq, H. T., Luciano, J. P., Protopopov, A. I., Chin, L., & DePinho, R. A. (2010) · Genes & Development · doi:10.1101/gad.1924710 · Cited by 87 · see citing works
The Fundamental Role of the p53 Pathway in Tumor Metabolism and Its Implication in Tumor Therapy
Shen, L., Sun, X. Y., Fu, Z., Yang, G., Li, J., & Yao, L. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-3040 · 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
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
The role of MDM2 and MDM4 in breast cancer development and prevention
Haupt, S., Vijayakumaran, R., Miranda, P. J., Burgess, A., Lim, E., & Haupt, Y. (2017) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjx007 · Cited by 80 · see citing works
Phosphorylation of MDMX Mediated by Akt Leads to Stabilization and Induces 14-3-3 Binding
Lopez-Pajares, V., Kim, M. M., & Yuan, Z.-M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m710030200 · Cited by 79 · see citing works
Nie, J., Xie, P., Liu, L., Xing, G., Chang, Z., Yin, Y., Tian, C., He, F., & Zhang, L. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.126920 · Cited by 79 · see citing works
Translational approaches targeting the p53 pathway for anti‐cancer therapy
Essmann, F., & Schulze‐Osthoff, K. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01570.x · Cited by 77 · see citing works
Mdmx enhances p53 ubiquitination by altering the substrate preference of the Mdm2 ubiquitin ligase
Okamoto, K., Taya, Y., & Nakagama, H. (2009) · FEBS Letters · doi:10.1016/j.febslet.2009.07.021 · Cited by 76 · see citing works
Iron-Dependent Regulation of MDM2 Influences p53 Activity and Hepatic Carcinogenesis
Dongiovanni, P., Fracanzani, A. L., Cairo, G., Megazzini, C., Gatti, S., Rametta, R., Fargion, S. R., & Valenti, L. V. C. (2009) · American Journal Of Pathology · doi:10.2353/ajpath.2010.090249 · Cited by 75 · 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
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
Singh, R. K., Iyappan, S., & Scheffner, M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610879200 · Cited by 69 · see citing works
Self-citationDysregulation of ubiquitin ligases in cancer
Qi, J., & Ronai, Z. A. (2015) · Drug Resistance Updates · doi:10.1016/j.drup.2015.09.001 · Cited by 69 · see citing works
- Authors
- Linares, L. K., Hengstermann, A., Ciechanover, A., Müller, S., & Scheffner, M.
- Affiliations
- Center for Biochemistry, Medical Faculty, and Center for Molecular Medicine, University of Cologne, Joseph-Stelzmann-Strasse 52, 50931 Cologne, Germany; and Department of Biochemistry and The Rappaport Family Institute for Research in the Medical Sciences, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel
- Technion – Israel Institute of Technology (IL)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-09-24
- Volume
- 100
- Issue
- 21
- Pages
- 12009-12014
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC218704
- OpenAlex
- W2046135777
- Cited by
- 361
- References
- 38
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 5 · 2023: 11 · 2022: 15 · 2021: 17 · 2020: 17 · 2019: 14 · 2018: 10 · 2017: 16 · 2016: 16 · 2015: 12 · 2014: 30 · 2013: 19 · 2012: 30
- FWCI
- 4.81
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- KOPS (University of Konstanz) (submittedVersion)
- Funders
- German-Israeli Foundation for Scientific Research and Development
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- HDMX, MDM2, p53 degradation, ubiquitination, E3 ubiquitin ligase, RING finger protein, protein degradation, tumor suppressor, protein-protein interaction, p53 accumulation
- MeSH terms
- Amino Acid Sequence, Base Sequence, Cell Line, Humans, Molecular Sequence Data, Nuclear Proteins, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Transfection, Tumor Suppressor Protein p53, Ubiquitin, RNA, Small Interfering, Ubiquitin-Protein Ligases, Proto-Oncogene Proteins c-mdm2, In Vitro Techniques
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
