Accelerated MDM2 auto‐degradation induced by DNA‐damage kinases is required for p53 activation
Open accessAbstract
p53 activation prevents the proliferation of genetically unstable cells. Conversely, p53 antagonism by its transcriptional target, the E3 ubiquitin ligase MDM2, is critical for the viability of unstressed, cycling cells. We demonstrate that MDM2 induces the degradation of p53 in both the nucleus and the cytoplasm. As p53 and MDM2 accumulate in the nuclei of stressed cells, we investigated mechanisms enabling p53 activation despite the high MDM2 levels generated during a DNA-damage response. We show that DNA damage destabilized MDM2 by a mechanism involving damage-activated kinases and MDM2 auto-ubiquitination. p53 was stable and transcriptionally active when MDM2 was unstable, but became unstable and inactive as the damage response waned and MDM2 stabilized. Importantly, blocking MDM2 destabilization in DNA-damaged cells prevented p53 target gene activation. Our data reveal that controlled MDM2 degradation is an important new step in p53 regulation.
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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 [12]
Disruption of Mdm2 oligomers might also contribute to their destabilization following DNA damage.
“The disruption of Mdm2 oligomers might also contribute to their destabilization following DNA damage [12].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [12]
DNA damage also accelerates MDM2 degradation through a mechanism requiring its own RING domain.
“A recent study showed that DNA damage also accelerates MDM2 degradation through a mechanism that requires its own RING domain (Stommel and Wahl, 2004).”
From ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage (2005) · cites this paper as Stommel and Wahl, 2004
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Cites
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661 · see citing works
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
Bakkenist, C. J., & Kastan, M. B. (2003) · Nature · doi:10.1038/nature01368 · Cited by 3,466 · see citing works
Momand, J., Zambetti, G. P., Olson, D. C., George, D., & Levine, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90644-r · Cited by 3,113 · see citing works
Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53
Oliner, J. D., Pietenpol, J. A., Thiagalingam, S., Gyuris, J., Kinzler, K. W., & Vogelstein, B. (1993) · Nature · doi:10.1038/362857a0 · Cited by 1,447 · 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 · cited 2× · see citing works
“The importance of MDM2 in p53 regulation is evidenced by the embryonic lethality of MDM2 knockout mice, presumably due to unrestrained p53 activity (Jones et al, 1995; Montes de Oca Luna et al, 1995).”
BackgroundRescue of embryonic lethality in Mdm2-deficient mice by absence of p53
Jones, S. N., Roe, A. E., Donehower, L. A., & Bradley, A. (1995) · Nature · doi:10.1038/378206a0 · Cited by 1,280 · cited 4× · see citing works
“The importance of MDM2 in p53 regulation is evidenced by the embryonic lethality of MDM2 knockout mice, presumably due to unrestrained p53 activity (Jones et al, 1995; Montes de Oca Luna et al, 1995).”
BackgroundInfluentialPost‐translational modifications and activation of p53 by genotoxic stresses
Appella, E., & Anderson, C. W. (2001) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2001.02225.x · Cited by 1,071 · 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
The INK4a/ARF network in tumour suppression
Sherr, C. J. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35096061 · Cited by 984 · see citing works
The MDM2 gene amplification database
Momand, J. (1998) · Nucleic Acids Research · doi:10.1093/nar/26.15.3453 · Cited by 982 · see citing works
c-Myc Can Induce DNA Damage, Increase Reactive Oxygen Species, and Mitigate p53 Function
Vafa, O., Wade, M., Kern, S., Beeche, M., Pandita, T. K., Hampton, G. M., & Wahl, G. M. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00520-8 · Cited by 876 · see citing works
Self-citationLeptomycin B Inhibition of Signal-Mediated Nuclear Export by Direct Binding to CRM1
Kudo, N. R., Wolff, B., Sekimoto, T., Schreiner, E. P., Yoneda, Y., Yanagida, M., Horinouchi, S., & Yoshida, M. (1998) · Experimental Cell Research · doi:10.1006/excr.1998.4136 · Cited by 812 · see citing works
The p53–Mdm2 module and the ubiquitin system
Michael, D., & Oren, M. (2002) · Seminars in Cancer Biology · doi:10.1016/s1044-579x(02)00099-8 · Cited by 759 · see citing works
Stommel, J. M., Marchenko, N. D., Jimenez, G. S., Moll, U. M., Hope, T. J., & Wahl, G. M. (1999) · The EMBO Journal · doi:10.1093/emboj/18.6.1660 · Cited by 738 · see citing works
Self-citationLin, J., Chen, J., Elenbaas, B., & Levine, A. J. (1994) · Genes & Development · doi:10.1101/gad.8.10.1235 · Cited by 652 · see citing works
Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage.
Chehab, N. H., Malikzay, A., Stavridi, E. S., & Halazonetis, T. D. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.24.13777 · Cited by 583 · see citing works
(1998) · PubMed · Cited by 525 · see citing works
Nuclear Export Is Required for Degradation of Endogenous p53 by MDM2 and Human Papillomavirus E6
Freedman, D. A., & Levine, A. J. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.12.7288 · Cited by 513 · see citing works
Regulation of p53 function and stability by phosphorylation.
Ashcroft, M., Kubbutat, M. H. G., & Vousden, K. H. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.3.1751 · Cited by 452 · see citing works
Povirk, L. F. (1996) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/0027-5107(96)00023-1 · Cited by 432 · see citing works
Henderson, B. R., & Eleftheriou, A. (2000) · Experimental Cell Research · doi:10.1006/excr.2000.4825 · Cited by 394 · see citing works
Honda, R., & Yasuda, H. (2000) · Oncogene · doi:10.1038/sj.onc.1203464 · Cited by 376 · see citing works
The evolution of diverse biological responses to DNA damage: insights from yeast and p53
Wahl, G. M., & Carr, A. M. (2001) · Nature Cell Biology · doi:10.1038/ncb1201-e277 · Cited by 376 · see citing works
Self-citationDesign of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo
Böttger, A., Böttger, V., Sparks, A., Liu, W.-L., Howard, S. F., & Lane, D. P. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00374-5 · Cited by 363 · see citing works
The MDM2 RING-finger domain is required to promote p53 nuclear export
Geyer, R. K., Yu, Z. K., & Maki, C. G. (2000) · Nature Cell Biology · doi:10.1038/35023507 · Cited by 361 · see citing works
Stress Signals Utilize Multiple Pathways To Stabilize p53
Ashcroft, M. A., Taya, Y., & Vousden, K. H. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.9.3224-3233.2000 · Cited by 356 · see citing works
Koumenis, C., Alarcon, R. M., Hammond, E. M., Sutphin, P. D., Hoffman, W., Murphy, M. E., Derr, J. L., Taya, Y., Lowe, S. W., Kastan, M. B., et al. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.4.1297-1310.2001 · Cited by 343 · see citing works
An intact HDM2 RING-finger domain is required for nuclear exclusion of p53
Boyd, S. D., Tsai, K. Y., & Jacks, T. (2000) · Nature Cell Biology · doi:10.1038/35023500 · Cited by 334 · see citing works
Sakaguchi, K., Saito, S., Higashimoto, Y., Roy, S., Anderson, C. W., & Appella, E. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.13.9278 · Cited by 293 · 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
C-Terminal Ubiquitination of p53 Contributes to Nuclear Export
Lohrum, M. A. E., Woods, D. B., Ludwig, R. L., Bálint, É., & Vousden, K. H. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.24.8521-8532.2001 · Cited by 237 · see citing works
Mendrysa, S. M., McElwee, M. K., Michalowski, J., O'Leary, K. A., Young, K. M., & Perry, M. E. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.2.462-473.2003 · Cited by 234 · see citing works
Phosphorylation of HDM2 by Akt
Ashcroft, M., Ludwig, R. L., Woods, D. B., Copeland, T. D., Weber, H. O., MacRae, E. J., & Vousden, K. H. (2002) · Oncogene · doi:10.1038/sj.onc.1205276 · Cited by 197 · see citing works
Kobet, E., Zeng, X., Zhu, Y., Keller, D., & Lu, H. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.23.12547 · Cited by 193 · see citing works
DNA damage induced p53 stabilization: no indication for an involvement of p53 phosphorylation
Blattner, C., Tobiasch, E., Litfen, M., Rahmsdorf, H. J., & Herrlich, P. (1999) · Oncogene · doi:10.1038/sj.onc.1202480 · Cited by 151 · see citing works
Craig, A. L., Burch, L. R., VOJTESEK, B., MIKUTOWSKA, J., Thompson, A. M., & Hupp, T. R. (1999) · Biochemical Journal · doi:10.1042/bj3420133 · Cited by 146 · see citing works
Mateu, M. G., & Fersht, A. R. (1998) · The EMBO Journal · doi:10.1093/emboj/17.10.2748 · Cited by 146 · see citing works
Alarcon, R. M., Koumenis, C., Geyer, R. K., Maki, C. G., & Giaccia, A. J. (1999) · PubMed · Cited by 143 · see citing works
Laı́n, S., Midgley, C., Sparks, A., Lane, E. B., & Lane, D. P. (1999) · Experimental Cell Research · doi:10.1006/excr.1999.4433 · Cited by 135 · see citing works
O’Keefe, K. J., Li, H., & Zhang, Y. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.18.6396-6405.2003 · Cited by 133 · see citing works
Mdm2 haplo‐insufficiency profoundly inhibits Myc‐induced lymphomagenesis
Alt, J. R., Greiner, T. C., Cleveland, J. L., & Eischen, C. M. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg133 · Cited by 129 · see citing works
Cocompartmentalization of p53 and Mdm2 Is a Major Determinant for Mdm2-Mediated Degradation of p53
Xirodimas, D. P., Stephen, C. W., & Lane, D. P. (2001) · Experimental Cell Research · doi:10.1006/excr.2001.5314 · Cited by 127 · see citing works
Oligomerization Is Required for p53 to be Efficiently Ubiquitinated by MDM2
Maki, C. G. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.23.16531 · Cited by 125 · see citing works
Mutation of Mouse p53 Ser23 and the Response to DNA Damage
Wu, Z., Earle, J., Saito, S., Anderson, C. W., Appella, E., & Xu, Y. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.8.2441-2449.2002 · Cited by 103 · see citing works
Nuclear degradation of p53 occurs during down‐regulation of the p53 response after DNA damage
Shirangi, T. R., Zaika, A., & Moll, U. M. (2002) · The FASEB Journal · doi:10.1096/fj.01-0617fje · Cited by 96 · see citing works
Zimmermann, J., Erdmann, D., Lalande, I., Grossenbacher, R., Noorani, M., & Fürst, P. (2000) · Oncogene · doi:10.1038/sj.onc.1203606 · Cited by 91 · see citing works
MDM2 Inhibits PCAF (p300/CREB-binding Protein-associated Factor)-mediated p53 Acetylation
Jin, Y., Zeng, S. X., Dai, M., Yang, X., & Lu, H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204078200 · Cited by 86 · see citing works
Tolbert, D., Lu, X., Yin, C., Tantama, M., & Dyke, T. V. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.1.370-377.2002 · Cited by 85 · see citing works
p53 Activation by Nitric Oxide Involves Down-regulation of Mdm2
Wang, X., Michael, D., de MURCIA, G., & Oren, M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m112068200 · Cited by 84 · see citing works
Blaydes, J. P., & Wynford‐Thomas, D. (1998) · Oncogene · doi:10.1038/sj.onc.1201880 · Cited by 63 · see citing works
Inoue, T. M., Geyer, R. K., Yu, Z. K., & Maki, C. G. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)02123-8 · Cited by 43 · see citing works
Nuclear export inhibitor leptomycin B induces the appearance of novel forms of human Mdm2 protein
Ménendez, S., Higgins, M., Berkson, R., Edling, C. E., Lane, D. P., & Laı́n, S. (2003) · British Journal of Cancer · doi:10.1038/sj.bjc.6600752 · Cited by 12 · see citing works
Tantama, M., Dyke, T. V., Tolbert, D., Lu, X., & Yin, C. (2020) · doi:10.17615/3ex8-8w58 · Cited by 4 · see citing works
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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
Self-citationp53 ubiquitination: Mdm2 and beyond
Brooks, C. L., & Gu, W. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.020 · Cited by 924 · see citing works
USP10 Regulates p53 Localization and Stability by Deubiquitinating p53
Yuan, J., Luo, K., Zhang, L., Cheville, J. C., & Lou, Z. (2010) · Cell · doi:10.1016/j.cell.2009.12.032 · Cited by 637 · see citing works
“Furthermore, ATM-dependent phosphorylation of Mdm2 and Mdmx could destabilize these proteins and compromise their activity (Khosravi et al., 1999; Maya et al., 2001; Meulmeester et al., 2005; Pereg et al., 2005; Stommel and Wahl, 2004).”
The P53 pathway: what questions remain to be explored?
Levine, A. J., Hu, W., & Feng, Z. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401910 · Cited by 654 · see citing works
Oscillations and variability in the p53 system
Geva‐Zatorsky, N., Rosenfeld, N., Itzkovitz, S., Milo, R., Sigal, A., Dekel, E., Yarnitzky, T., Liron, Y., Polak, P. P., Lahav, G., et al. (2006) · Molecular Systems Biology · doi:10.1038/msb4100068 · Cited by 640 · see citing works
Tumour suppression by p53: a role for the DNA damage response?
Meek, D. W. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2716 · Cited by 604 · see citing works
Chauhan, D., Tian, Z., Nicholson, B., Kumar, K. G. S., Zhou, B., Carrasco, R., McDermott, J. L., Leach, C. A., Fulcinniti, M., Kodrasov, M. P., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.08.007 · Cited by 589 · see citing works
The ATM-mediated DNA-damage response: taking shape
Shiloh, Y. (2006) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2006.05.004 · Cited by 539 · 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
Self-citationRecurrent Initiation: A Mechanism for Triggering p53 Pulses in Response to DNA Damage
Batchelor, E., Mock, C. S., Bhan, I., Loewer, A., & Lahav, G. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.03.016 · Cited by 422 · see citing works
Structural 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 · see citing works
Mdm2-mediated ubiquitylation: p53 and beyond
Marine, J.-C., & Lozano, G. (2010) · Cell Death & Differentiation · doi:10.1038/cdd.2009.68 · Cited by 354 · see citing works
A plausible model for the digital response of p53 to DNA damage
Ma, L., Wagner, J., Rice, J. J., Hu, W., Levine, A. J., & Stolovitzky, G. A. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501352102 · Cited by 351 · see citing works
Two-phase dynamics of p53 in the DNA damage response
Zhang, X.-P., Liu, F., & Wang, W. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1100600108 · Cited by 333 · see citing works
Stimulus‐dependent dynamics of p53 in single cells
Batchelor, E., Loewer, A., Mock, C. S., & Lahav, G. (2011) · Molecular Systems Biology · doi:10.1038/msb.2011.20 · Cited by 322 · see citing works
Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells
Yang, Y., Ludwig, R. L., Jensen, J. P., Pierre, S. A., Medaglia, M. V., Davydov, I. V., Safiran, Y. J., Oberoi, P., Kenten, J. H., Phillips, A. C., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.04.029 · Cited by 321 · see citing works
MDM2 is a Central Node in the p53 Pathway: 12 Years and Counting
Bond, G. L., Hu, W., & Levine, A. J. (2005) · Current Cancer Drug Targets · doi:10.2174/1568009053332627 · Cited by 310 · see citing works
Li, D., Marchenko, N. D., Schulz‐Heddergott, R., Fischer, V., Velasco-Hernández, T., Talos, F., & Moll, U. M. (2011) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-10-0534 · Cited by 298 · see citing works
Feng, J., Tamaskovic, R., Yang, Z., Brazil, D. P., Merlo, A., Hess, D., & Hemmings, B. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m404936200 · Cited by 294 · see citing works
Monoubiquitylation promotes mitochondrial p53 translocation
Marchenko, N. D., Wolff, S., Erster, S., Becker, K., & Moll, U. M. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601560 · Cited by 286 · 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
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 284 · see citing works
Self-citationLi, M., Zhang, Z., Hill, D. L., Wang, H., & Zhang, R. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-3066 · Cited by 273 · 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
ATM 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 · see citing works
Cell fate decision mediated by p53 pulses
Zhang, X.-P., Liu, F., Cheng, Z., & Wang, W. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0813088106 · Cited by 253 · 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
Itahana, K., Mao, H., Jin, A., Itahana, Y., Clegg, H. V., Lindström, M. S., Bhat, K. P., Godfrey, V. L., Evan, G. I., & Zhang, Y. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.09.007 · Cited by 245 · see citing works
Critical role for Daxx in regulating Mdm2
Tang, J., Qu, L., Zhang, J., Wang, W., Michaelson, J. S., Degenhardt, Y., El‐Deiry, W. S., & Yang, X. (2006) · Nature Cell Biology · doi:10.1038/ncb1442 · Cited by 239 · see citing works
Phosphorylation of p53 on Key Serines Is Dispensable for Transcriptional Activation and Apoptosis
Thompson, T., Tovar, C., Yang, H. S., Carvajal, D. M., Vu, B. T., Xu, Q., Wahl, G. M., Heimbrook, D. C., & Vassilev, L. T. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m410233200 · Cited by 232 · see citing works
Self-citationMarine, 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
Zhang, J., Sun, Q., Zhang, Z., Ge, S., Han, Z.-G., & Chen, W.-T. (2012) · Oncogene · doi:10.1038/onc.2012.28 · Cited by 224 · see citing works
Shi, D., & Gu, W. J. (2012) · Genes & Cancer · doi:10.1177/1947601912455199 · Cited by 214 · see citing works
Liposarcoma: Molecular Genetics and Therapeutics
Conyers, R. K., Young, S., & Thomas, D. M. (2010) · Sarcoma · doi:10.1155/2011/483154 · Cited by 213 · see citing works
Inuzuka, H., Tseng, A., Gao, D., Zhai, B., Zhang, Q. H., Shaik, S., Wan, L., Cambronne, X. A., Mock, C. S., Yin, H., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.06.015 · Cited by 205 · see citing works
Self-citationTargeting the p53–MDM2 interaction to treat cancer
Klein, C., & Vassilev, L. T. (2004) · British Journal of Cancer · doi:10.1038/sj.bjc.6602164 · Cited by 204 · 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
Self-citationDayal, 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
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
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
Self-citationATM-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
Oxidative Stress and Lectin-Like Ox-LDL-Receptor LOX-1 in Atherogenesis and Tumorigenesis
Lü, J., Mitra, S., Wang, X., Khaidakov, M., & Mehta, J. L. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3792 · Cited by 167 · see citing works
Hdmx modulates the outcome of p53 activation in human tumor cells
Wade, M., Wong, E. T., Tang, M., Stommel, J. M., & Wahl, G. M. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605405200 · Cited by 163 · see citing works
Self-citationATM 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 · see citing works
Regulation of p53 by the Ubiquitin-conjugating Enzymes UbcH5B/C in Vivo
Saville, M. K., Sparks, A., Xirodimas, D. P., Wardrop, J., Stevenson, L. F., Bourdon, J.-C., Woods, Y. L., & Lane, D. P. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403362200 · Cited by 158 · see citing works
Gao, M., & Karin, M. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.08.017 · Cited by 159 · see citing works
Signalling and survival pathways in multiple myeloma
Bommert, K., Bargou, R. C., & Stühmer, T. (2006) · European Journal of Cancer · doi:10.1016/j.ejca.2005.12.026 · Cited by 158 · see citing works
Secchiero, P., Barbarotto, E., Tiribelli, M., Zerbinati, C., di Iasio, M. G., Gonelli, A., Cavazzini, F., Campioni, D., Fanin, R., Cuneo, A., et al. (2006) · Blood · doi:10.1182/blood-2005-11-4465 · Cited by 157 · see citing works
Yadavilli, S., Mayo, L. D., Higgins, M., Laı́n, S., Hegde, V. K., & Deutsch, W. A. (2009) · DNA repair · doi:10.1016/j.dnarep.2009.07.003 · Cited by 155 · 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
Nucleotide Biosynthetic Enzyme GMP Synthase Is a TRIM21-Controlled Relay of p53 Stabilization
Reddy, B. A., van der Knaap, J. A., Bot, A. G. M., Mohd-Sarip, A., Dekkers, D. H. W., Timmermans, M. A. M., Martens, J. W. M., Demmers, J., & Verrijzer, C. P. (2014) · Molecular Cell · doi:10.1016/j.molcel.2013.12.017 · Cited by 131 · see citing works
Nek family of kinases in cell cycle, checkpoint control and cancer
Moniz, L. S., Dutt, P., Haider, N., & Stambolic, V. (2011) · Cell Division · doi:10.1186/1747-1028-6-18 · Cited by 133 · see citing works
Hsp27 Modulates p53 Signaling and Suppresses Cellular Senescence
O’Callaghan-Sunol, C., Gabai, V. L., & Sherman, M. Y. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-2441 · Cited by 134 · see citing works
Mdm2 Binds to Nbs1 at Sites of DNA Damage and Regulates Double Strand Break Repair
Alt, J. R., Bouska, A., Fernandez, M. R., Cerny, R. L., Xiao, H., & Eischen, C. M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413387200 · Cited by 131 · 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
New insights into p53 activation
Brooks, C. L., & Gu, W. J. (2010) · Cell Research · doi:10.1038/cr.2010.53 · Cited by 127 · see citing works
From structure to dynamics: Frequency tuning in the p53–Mdm2 network
Abou-Jaoudé, W., Ouattara, D. A., & Kaufman, M. (2009) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2009.02.005 · Cited by 127 · 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
Antiangiogenic Activity of the MDM2 Antagonist Nutlin-3
Secchiero, P., Corallini, F., Gonelli, A., Dell’Eva, R., Vitale, M., Capitani, S., Albini, A., & Zauli, G. (2006) · Circulation Research · doi:10.1161/01.res.0000253975.76198.ff · Cited by 125 · see citing works
Stress-mediated nuclear stabilization of p53 is regulated by ubiquitination and importin-α3 binding
Marchenko, N. D., Hanel, W., Li, D., Becker, K., Reich, N., & Moll, U. M. (2010) · Cell Death & Differentiation · doi:10.1038/cdd.2009.173 · Cited by 123 · see citing works
SIRT1 Regulates Autoacetylation and Histone Acetyltransferase Activity of TIP60
Wang, J., & Chen, J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.087585 · Cited by 121 · 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
“These substrates include the tumor suppressor p53 (Hu et al., 2006; Sheng et al., 2006), the Mdm2 E3 ubiquitin ligase (Hu et al., 2006; Sheng et al., 2006; Sarkari et al., 2010), the Mdm2 homolog Mdm4 (Sarkari et al., 2010) and mini-chromosome maintenance binding-protein MCM-BP (Jagannathan et al., 2014; Figure 1 and…”
BackgroundInfluentialQuantitative 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
Self-citationStabilization of p53 Is Involved in Quercetin-Induced Cell Cycle Arrest and Apoptosis in HepG2 Cells
TANIGAWA, S., FUJII, M., & HOU, D.-X. (2008) · Bioscience, Biotechnology, and Biochemistry · doi:10.1271/bbb.70680 · Cited by 135 · see citing works
The many substrates and functions of NEDD4-1
Huang, X., Chen, J., Cao, W., Yang, L., Chen, Q., He, J., Yi, Q., Huang, H., Zhang, E., & Cai, Z. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-2142-8 · Cited by 114 · see citing works
Saha, A., Murakami, M., Kumar, P., Bajaj, B. G., Sims, K., & Robertson, E. S. (2009) · Journal of Virology · doi:10.1128/jvi.02408-08 · Cited by 114 · see citing works
Oscillations and bistability in the stochastic model of p53 regulation
Puszyński, K., Hat, B., & Lipniacki, T. (2008) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2008.05.039 · Cited by 112 · see citing works
The Fbw7 and BetaTRCP E3 ubiquitin ligases and their roles in tumorigenesis
Alan, W. L. (2012) · Frontiers in bioscience · doi:10.2741/4045 · Cited by 112 · see citing works
STAR RNA-binding protein Quaking suppresses cancer via stabilization of specific miRNAPreprint
Chen, A.-J., Paik, J.-H., Zhang, H., Shukla, S. A., Mortensen, R., HU, J. L., Ying, H., Hu, B., Hurt, J. A., Farny, N. G., et al. (2012) · Genes & Development · doi:10.1101/gad.189001.112 · Cited by 111 · see citing works
Targeting intrinsically disordered proteins involved in cancer
Santofimia‐Castaño, P., Rizzuti, B., Xia, Y., Abián, O., Peng, L., Velázquez‐Campoy, A., Neira, J. L., & Iovanna, J. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03347-3 · Cited by 110 · see citing works
Hu, W., Feng, Z., Ma, L., Wagner, J., Rice, J. J., Stolovitzky, G. A., & Levine, A. J. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-2656 · Cited by 112 · see citing works
Yi, F., Saha, A., Murakami, M., Kumar, P., Knight, J. S., Cai, Q., Choudhuri, T., & Robertson, E. S. (2009) · Virology · doi:10.1016/j.virol.2009.03.027 · Cited by 109 · see citing works
Wienken, M., Dickmanns, A., Nemajerová, A., Kramer, D., Najafova, Z., Weiss, M., Karpiuk, O., Kassem, M. S., Zhang, Y., Lozano, G., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.12.008 · Cited by 109 · see citing works
High Levels of Heat Shock Protein Hsp72 in Cancer Cells Suppress Default Senescence Pathways
Yaglom, J. A., Gabai, V. L., & Sherman, M. Y. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-3796 · Cited by 110 · see citing works
Zhao, R., Yeung, S. J., Chen, J., Iwakuma, T., Su, C., Chen, B., Qu, C., Zhang, F., Chen, Y., Lin, Y., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44111 · Cited by 106 · see citing works
Gannon, H. S., Woda, B. A., & Jones, S. N. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.04.011 · Cited by 105 · see citing works
DNA damage strength modulates a bimodal switch of p53 dynamics for cell-fate control
Chen, X., Chen, J., Gan, S., Guan, H., Zhou, Y., Ouyang, Q., & Shi, J. (2013) · BMC Biology · doi:10.1186/1741-7007-11-73 · Cited by 105 · 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
Menon, V., & Povirk, L. F. (2014) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-017-9211-0_17 · Cited by 103 · see citing works
Jain, A. K., Allton, K. L., Duncan, A. D., & Barton, M. C. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.01705-12 · Cited by 99 · see citing works
MdmX is a substrate for the deubiquitinating enzyme USP2a
Allende-Vega, N., Sparks, A., Lane, D. P., & Saville, M. K. (2010) · Oncogene · doi:10.1038/onc.2009.330 · Cited by 100 · see citing works
Regulation of Mdm2 protein stability and the p53 response by NEDD4-1 E3 ligase
Xu, C., Fan, C., & Wang, X. (2014) · Oncogene · doi:10.1038/onc.2013.557 · Cited by 99 · see citing works
Fourier analysis and systems identification of the p53 feedback loop
Geva‐Zatorsky, N., Dekel, E., Batchelor, E., Lahav, G., & Alon, U. S. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1001107107 · Cited by 97 · see citing works
p53 is activated in response to disruption of the pre-mRNA splicing machinery
Allende-Vega, N., Dayal, S., Agarwala, U., Sparks, A., Bourdon, J., & Saville, M. K. (2012) · Oncogene · doi:10.1038/onc.2012.38 · Cited by 96 · see citing works
PPAR gamma protects cardiomyocytes against oxidative stress and apoptosis via Bcl-2 upregulation
Ren, Y., Sun, C., Sun, Y., Tan, H., Wu, Y., Cui, B., & Wu, Z. (2009) · Vascular Pharmacology · doi:10.1016/j.vph.2009.06.004 · Cited by 96 · 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
Nucleolin inhibits Hdm2 by multiple pathways leading to p53 stabilization
Saxena, A. D., Rorie, C. J., Dimitrova, D. D., Daniely, Y., & Borowiec, J. A. (2006) · Oncogene · doi:10.1038/sj.onc.1209714 · Cited by 92 · see citing works
Zebrafish as a model system to study DNA damage and repair
Pei, D., & Strauss, P. R. (2012) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2012.10.003 · Cited by 93 · see citing works
Marinov, M., Ziogas, A., Pardo, O. E., Tan, L. T., Dhillon, T., Mauri, F. A., Lane, H. A., Lemoine, N. R., Zangemeister‐Wittke, U., Seckl, M. J., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-2166 · Cited by 89 · see citing works
Gankyrin: a new oncoprotein and regulator of pRb and p53
Dawson, S. P., Higashitsuji, H., Wilkinson, A. J., Fujita, J., & Mayer, R. J. (2006) · Trends in Cell Biology · doi:10.1016/j.tcb.2006.03.001 · Cited by 88 · see citing works
Roberts, A. M., Watson, I. R., Evans, A. J., Foster, D. A., Irwin, M. S., & Ohh, M. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-1770 · Cited by 88 · 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
Self-citationLu, T., Huang, G., Lu, T., Wu, J.-B., Wu, C., Yang, T., Iizuka, A., & Chen, Y.-F. (2009) · Food and Chemical Toxicology · doi:10.1016/j.fct.2009.05.023 · 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
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
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
Self-citation
- Authors
- Stommel, J. M., & Wahl, G. M.
- Affiliations
- Salk Institute for Biological Studies (US)
- Corresponding author
- Wahl, Geoffrey M
- Venue
- The EMBO Journal
- Published
- 2004-03-18
- Volume
- 23
- Issue
- 7
- Pages
- 1547-1556
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC391059
- OpenAlex
- W2091818021
- Cited by
- 386
- References
- 54
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 9 · 2023: 13 · 2022: 10 · 2021: 16 · 2020: 13 · 2019: 19 · 2018: 10 · 2017: 9 · 2016: 8 · 2015: 15 · 2014: 21 · 2013: 13 · 2012: 24
- FWCI
- 11.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- National Institutes of Health
- National Cancer Institute (CA61449, R01CA061449)
- 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, p53 activation, DNA damage response, E3 ubiquitin ligase, p53 stabilization, cell cycle arrest
- MeSH terms
- Animals, Cell Line, Cell Nucleus, Cytoplasm, DNA Damage, Gene Expression Regulation, Humans, Nuclear Proteins, Proto-Oncogene Proteins, Transcription, Genetic, Transcriptional Activation, Tumor Suppressor Protein p53, Phosphatidylinositol 3-Kinases, Active Transport, Cell Nucleus, Proteasome Endopeptidase Complex, Mice, Proto-Oncogene Proteins c-mdm2, Proteasome Inhibitors
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